Field of the Invention

The invention relates to a process for producing labelled compounds suitable for use in medical imaging applications, and particularly compounds labelled with radioisotopes, such as ¹⁸ F. The invention also relates to precursor compounds for use in producing the labelled compounds, and to a process for producing the precursors. Methods of imaging either using the labelled compounds or by administering their precursors are also described.

Background of the Invention

Positron Emission Tomography (PET) and Single Photon Emission Computed Tomography (SPECT) rely on radiolabeled pharmaceuticals to generate images. SPECT imaging uses radiopharmaceuticals with an isotope that decays under gamma radiation emission, and enables imaging of biological processes with kinetics in the order of hours to days. The most commonly used SPECT radionuclide is ^99m Tc. Positron Emission Tomography (PET) is of ever increasing importance in diagnostic medicine today. PET requires the use of a positron emitting radionuclide to trace a physiological or biochemical process in tissue. In order to take a PET scan, a short half-life radionuclide which decays through positron emission is incorporated into a metabolically active molecule. This is injected into the patient and allowed to circulate round the body in order to obtain its optimum biodistribution. The subject is then placed within the PET scanner. A relatively accurate image can be drawn of the radiotracer distribution within the area of interest. PET most commonly utilizes the radioactive forms of carbon ( ¹¹ C), nitrogen ( ¹³ N), oxygen ( ¹⁵ O) and fluorine ( ¹⁸ F). Use of these isotopes allows the labelling of many different substrates without altering the biological activity. The half lives of the nuclei are relatively short, which poses a time-scale problem for radio-chemists and can leave little room for manoeuvre between introducing the radioisotope into the tracer, and conducting the scan. Of these isotopes F has the most convenient (longest) half life, of 109.7 minutes. An important aspect of radiopharmaceutical production requiring consideration by radiochemists is the method by which the radionuclide is incorporated into the tracer molecule. Lengthy production and purification steps need to be avoided due to the short half lives of the radionuclei used, and the resultant decrease in non-decay corrected radiochemical yield. On the other hand, the method of choice must be effective enough to ensure a high level of radiochemical purity, and should result in a biologically compatible product with an appropriate solubility profile for in vivo use. There therefore exists a continuing need to develop improved methods for the production of labelled compounds.

Summary of the Invention

The inventors have provided a simple process which enables the rapid synthesis of labelled molecules via a "traceless" Staudinger ligation. The ligation results in a peptide linkage between the label and the tracer moiety without inclusion of the phosphine oxide moiety in the final product; this ensures that the resulting labelled tracer remains biocompatible and retains an appropriate solubility profile for biological use. The inventors have additionally found that the process can be performed using fluorous derivatives of the phosphinothioester reactant compound, in which case fluorodetagging takes place during the ligation reaction to produce a non-fluorous labelled product. The labelled product is then readily separable from the unwanted fluorous starting materials and by-products, e.g. by using a Fluorous Solid Phase Extraction (FSPE) procedure. This greatly facilitates product purification. Furthermore, it is thought that the traceless Staudinger ligation could be performed in vivo, thus enabling the tracer moiety to be administered to the patient first, before administration of the radiolabel. This would advantageously provide ample time for high build-up of tracer at the desired target in vivo before the radiolabel is administered, thereby increasing signal-to-noise ratio and improving image quality.

Accordingly, the invention provides a process for producing a labelled compound, which process comprises treating a compound of formula (I) wherein

X is a moiety to be labelled or a detectable label;

R ¹ and R ² , which are the same or different, are independently selected from hydrogen, unsubstituted or substituted C _1-10 alkyl, unsubstituted or substituted aryl, unsubstituted or substituted C _3-10 cycloalkyl, unsubstituted or substituted C _3-10 heterocyclyl, and unsubstituted or substituted heteroaryl, or wherein R ¹ , R ² and the carbon atom to which R ¹ and R ² are both bonded together form an unsubstituted or substituted C _3-I0 cycloalkyl group; and R ³ and R ⁴ , which are the same or different, are independently selected from unsubstituted or substituted aryl, unsubstituted or substituted C _1-20 alkyl, unsubstituted or substituted C _3-10 cycloalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted C _3-10 heterocyclyl, and a fluorous group; which fluorous group is a group selected from: (i) R _f ;

(ii) -L ⁴ -C _1-20 alkyl, which C _1-20 alkyl is substituted by one, two or three groups selected from R _f and -Z-R _f and is otherwise unsubstituted or substituted;

(iii) -L ⁵ -aryl, which aryl is substituted by one, two or three groups selected from R _f and -Z-R _f and is otherwise unsubstituted or substituted; and

(iv) -L ⁶ -Si(-L ⁷ -R _f ) _n (R ¹⁸ ) _3-n , wherein:

R _f is a straight-chained or branched C _3-20 perfluoroalkyl group, a perfluoroaryl group, a straight-chained or branched C _1-20 perfluoroalkyl group substituted with one, two or three perfluoroaryl groups; or a perfluoroaryl group substituted with one, two or three straight-chained or branched C _1-20 perfluoroalkyl groups; provided that said straight-chained or branched C _1-20 and C _3-20 perfluoroalkyl groups are uninterrupted or interrupted by one, two or three perfluoroarylene groups;

L ⁴ and L ⁵ are independently selected from a single bond, -arylene-, -alk-, -alk- arylene-, -arylene-alk-, -alk-Z-, -arylene-Z-, -alk-arylene-Z, -alk-Z- arylene-, -alk-Z-arylene-Z-, -arylene-Z-alk-, -arylene-alk-Z- and -arylene-Z-alk-Z-, wherein alk is unsubstituted or substituted Ci _-I0 alkylene which is optionally interrupted by N(R"), O, S, C(O), C(O)N(R") or arylene, wherein R" is H, C _1-6 alkyl or aryl;

L ⁶ and L ⁷ are independently selected from a single bond, -arylene-, -alk-, -alk-arylene-, -arylene-alk-, -alk-Z-arylene- and -arylene-Z-alk-, wherein alk is unsubstituted or substituted Ci-io alkylene which is optionally interrupted by N(R"), O, S, C(O), C(O)N(R") or arylene, wherein R" is H, C _1-6 alkyl or aryl;

Z is N(R"), O, S, C(O) or C(O)N(R"), wherein R" is H, C _1-6 alkyl or aryl;

R ¹⁸ is hydrogen, unsubstituted or substituted aryl, or unsubstituted or substituted Ci _-20 alkyl; and n is 1, 2 or 3; with a compound of formula (II)

N ₃ -L-Y ₍ π ₎ wherein

Y is a detectable label or a moiety to be labelled, provided that if X in the compound of formula (I) is a moiety to be labelled, then Y is a detectable label and if X in the compound of formula (I) is a detectable label, then Y is a moiety to be labelled; and L is a bond or a linking group; thereby producing a labelled compound of formula (III)

O

^X H (III) wherein the detectable label comprises a fluorine atom, a radionuclide, an optical label, an ultrasound-responsive agent, an X-ray responsive agent, a fluorophore or a luminescent moiety, wherein the radionuclide is selected from ³ H, ¹¹ C, ¹³ N, ¹⁵ O, ¹⁸ F, ⁵¹ Cr, ⁵² Fe, ^52m Mn, ⁵⁵ Co, ⁶⁰ Cu, ⁶¹ Cu, ⁶² Zn, ⁶² Cu, ⁶³ Zn, ⁶⁴ Cu, ⁶⁶ Ga, ⁶⁷ Ga, ⁶⁸ Ga, ⁷⁰ As, ⁷¹ As, ⁷² As, ⁷⁴ As, ⁷⁵ Se, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ^8Om Br, ^82m Br, ⁸² Rb, ⁸⁶ Y, ⁸⁸ Y, ⁸⁹ Sr, ⁸⁹ Zr, ⁹⁷ Ru, ^99m Tc, ¹¹⁰ In, ¹¹¹ In, ^113m In, ^U4m In, ^117m Sn, ¹²⁰ 1, ¹²² Xe, ¹²³ 1, ¹²⁴ 1, ¹²⁵ 1, ¹³¹ 1, ¹⁶⁶ Ho, ¹⁶⁷ Tm, ¹⁶⁹ Yb, ^193m Pt, ^195m Pt, ²⁰¹ Tl and ²⁰³ Pb. In another aspect, the invention provides a method of imaging a human or non-human patient in need thereof, which method comprises: (a) producing a labelled compound of formula (III) by the process of the invention as defined above; (b) administering the labelled compound to the patient; and (c) imaging the patient. hi another aspect, the invention provides a method of imaging a cell or in vitro sample, which method comprises: (a) producing a labelled compound of formula (III) by the process of the invention as defined above; (b) contacting the cell or in vitro sample with said labelled compound; and (c) imaging the cell or in vitro sample. hi another aspect, the invention provides a compound of formula (I)

wherein

R ¹ and R ² , which are the same or different, are independently selected from hydrogen, unsubstituted or substituted C _1-10 alkyl, unsubstituted or substituted aryl, unsubstituted or substituted C _3-10 cycloalkyl, unsubstituted or substituted C _3-10 heterocyclyl, and unsubstituted or substituted heteroaryl, or wherein R ¹ , R ² and the carbon atom to which R ¹ and R ² are both bonded together form an unsubstituted or substituted C _3-10 cycloalkyl group;

R ³ and R ⁴ , which are the same or different, are independently selected from unsubstituted or substituted aryl, unsubstituted or substituted C _1-20 alkyl, unsubstituted or substituted C _3- io cycloalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted C _3-10 heterocyclyl, and a fluorous group; which fluorous group is a group selected from:

(i) R _f ; (ii) -L ⁴ -C _1-20 alkyl, which C _1-20 alkyl is substituted by one, two or three groups selected from R _f and -Z-R _f and is otherwise unsubstituted or substituted;

(iii) -L ⁵ -aryl, which aryl is substituted by one, two or three groups selected from R _f and -Z-R _f and is otherwise unsubstituted or substituted; and (iv) -L ⁶ -Si(-L ⁷ -R _f ) _n (R ¹⁸ ) _3-n , wherein:

R _f is a straight-chained or branched C _3-20 perfluoroalkyl group, a perfluoroaryl group, a straight-chained or branched C _1-20 perfluoroalkyl group substituted with one, two or three perfluoroaryl groups; or a perfluoroaryl group substituted with one, two or three straight-chained or branched C _1-20 perfluoroalkyl groups; provided that said straight-chained or branched C _1-20 and C _3-20 perfluoroalkyl groups are uninterrupted or interrupted by one, two or three perfluoroarylene groups;

L ⁴ and L ⁵ are independently selected from a single bond, -arylene-, -alk-, -alk-arylene-, -arylene-alk-, -alk-Z-, -arylene-Z-, -alk-arylene-Z, -alk-Z-arylene-, -alk-Z-arylene-Z-, -arylene-Z-alk-, -arylene-alk-Z- and -arylene-Z-alk-Z-, wherein alk is unsubstituted or substituted C _1-10 alkylene which is optionally interrupted by N(R"), O, S, C(O), C(O)N(R") or arylene, wherein R" is H, C _1-6 alkyl or aryl;

L ⁶ and L ⁷ are independently selected from a single bond, -arylene-, -alk-, -alk-arylene-, -arylene-alk-, -alk-Z-arylene- and -arylene-Z-alk-, wherein alk is unsubstituted or substituted C _1-I0 alkylene which is optionally interrupted by N(R"), O, S, C(O), C(O)N(R") or arylene, wherein R" is H, C _1-6 alkyl or aryl;

Z is N(R"), O, S, C(O) or C(O)N(R"), wherein R" is H, C _1-6 alkyl or aryl;

R is hydrogen, unsubstituted or substituted aryl, or unsubstituted or substituted C _1-20 alkyl; and n is 1, 2 or 3; and

X is a tracer moiety, a further-reactable moiety, or a detectable label, wherein the further-reactable moiety comprises a functional group suitable for attaching the compound of formula (I) to a tracer moiety.

Typically, in the compound of formula (I) of the invention as defined above, X is other than the following groups of formula (IV), (IVa) and (IVb):

In another aspect, the invention provides a compound of formula (I)

(I) wherein

R ¹ and R ² , which are the same or different, are independently selected from hydrogen, unsubstituted or substituted C _1-10 alkyl, unsubstituted or substituted aryl, unsubstituted or substituted C _3-I0 cycloalkyl, unsubstituted or substituted C _3-10 heterocyclyl, and unsubstituted or substituted heteroaryl, or wherein R ¹ , R ² and the carbon atom to which R ¹ and R ² are both bonded together form an unsubstituted or substituted C _3-10 cycloalkyl group;

R ³ and R ⁴ , which are the same or different, are independently selected from unsubstituted or substituted aryl, unsubstituted or substituted C _1-20 alkyl, unsubstituted or substituted C _3-10 cycloalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted C _3-I0 heterocyclyl, and a fluorous group, provided that at least one of R ³ and R ⁴ is a said fluorous group; wherein a said fluorous group is a group selected from:

(i) R _f ; (ii) -L ⁴ -C _1-20 alkyl, which C _1-20 alkyl is substituted by one, two or three groups selected from R _f and -Z-R _f and is otherwise unsubstituted or substituted;

(iii) -iΛaryl, which aryl is substituted by one, two or three groups selected from R _f and -Z-R _f and is otherwise unsubstituted or substituted; and (iv) -L ⁶ -Si(-L ⁷ -R _f ) _n (R ¹⁸ ) _3-n , wherein:

R _f is a straight-chained or branched C _3-20 perfluoroalkyl group, a perfluoroaryl group, a straight-chained or branched C _1-20 perfluoroalkyl group substituted with one, two or three perfluoroaryl groups; or a perfluoroaryl group substituted with one, two or three straight-chained or branched C _1-20 perfluoroalkyl groups; provided that said straight-chained or branched C _1-20 and C _3-20 perfluoroalkyl groups are uninterrupted or interrupted by one, two or three perfluoroarylene groups;

L ⁴ and L ⁵ are independently selected from a single bond, -arylene-, -alk-, -alk-arylene-, -arylene-alk-, -alk-Z-, -arylene-Z-, -alk-arylene-Z, -alk-Z-arylene-, -alk-Z-arylene-Z-, -arylene-Z-alk-, -arylene-alk-Z- and -arylene-Z-alk-Z-, wherein alk is unsubstituted or substituted C _1-10 alkylene which is optionally interrupted by N(R"), O, S, C(O), C(O)N(R") or arylene, wherein R" is H, C _1-6 alkyl or aryl; L ⁶ and L ⁷ are independently selected from a single bond, -arylene-, -alk-, -alk-arylene-, -arylene-alk-, -alk-Z-arylene- and -arylene-Z-alk-, wherein alk is unsubstituted or substituted Ci _-10 alkylene which is optionally interrupted by N(R"), O, S, C(O), C(O)N(R") or arylene, wherein R" is H, C _1-6 alkyl or aryl; Z is N(R"), O, S, C(O) or C(O)N(R"), wherein R" is H, C _1-6 alkyl or aryl;

R ¹⁸ is hydrogen, unsubstituted or substituted aryl, or unsubstituted or substituted C _1-20 alkyl; and n is 1, 2 or 3; and

X is a moiety to be labelled or a detectable label. hi another aspect, the invention provides a process for producing a compound of formula (I)

wherein R ¹ and R ² , which are the same or different, are independently selected from hydrogen, unsubstituted or substituted C _1-I0 alkyl, unsubstituted or substituted aryl, unsubstituted or substituted C _3-10 cycloalkyl, unsubstituted or substituted C _3-I0 heterocyclyl, and unsubstituted or substituted heteroaryl, or wherein R ¹ , R ² and the carbon atom to which R ¹ and R ² are both bonded together form an unsubstituted or substituted C _3-10 cycloalkyl group;

R ³ and R ⁴ , which are the same or different, are independently selected from unsubstituted or substituted aryl, unsubstituted or substituted C _1-20 alkyl, unsubstituted or substituted C _3-10 cycloalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted C _3-10 heterocyclyl, and a fluorous group; which fluorous group is a group selected from:

(i) R _f ;

(ii) -L ⁴ -Ci _-2 o alkyl, which C _1-20 alkyl is substituted by one, two or three groups selected from R _f and -Z-R _f and is otherwise unsubstituted or substituted; (iii) -L ⁵ -aryl, which aryl is substituted by one, two or three groups selected from R _f and -Z-R _f and is otherwise unsubstituted or substituted; and (iv) -L ⁶ -Si(-L ⁷ -R _f ) _n (R ¹⁸ ) _3-n , wherein: R _f is a straight-chained or branched C _3-20 perfluoroalkyl group, a perfluoroaryl group, a straight-chained or branched C _1-20 perfluoroalkyl group substituted with one, two or three perfluoroaryl groups; or a perfluoroaryl group substituted with one, two or three straight-chained or branched Ci _-20 perfluoroalkyl groups; provided that said straight-chained or branched C _1-20 and C _3-20 perfluoroalkyl groups are uninterrupted or interrupted by one, two or three perfluoroarylene groups;

L ⁴ and L ⁵ are independently selected from a single bond, -arylene-, -alk-, -alk-arylene-, -arylene-alk-, -alk-Z-, -arylene-Z-, -alk-arylene-Z, -alk-Z-arylene-, -alk-Z-arylene-Z-, -arylene-Z-alk-, -arylene-alk-Z- and -arylene-Z-alk-Z-, wherein alk is unsubstituted or substituted C _1-10 alkylene which is optionally interrupted by N(R"), O, S, C(O), C(O)N(R") or arylene, wherein R" is H, C _1-6 alkyl or aryl;

L ⁶ and L ⁷ are independently selected from a single bond, -arylene-, -alk-, -alk-arylene-, -arylene-alk-, -alk-Z-arylene- and -arylene-Z-alk-, wherein alk is unsubstituted or substituted Ci _-I0 alkylene which is optionally interrupted by N(R"), O, S, C(O), C(O)N(R") or arylene, wherein R" is H, C _1-6 alkyl or aryl; Z is N(R"), O, S, C(O) or C(O)N(R"), wherein R" is H, C _1-6 alkyl or aryl;

R ¹⁸ is hydrogen, unsubstituted or substituted aryl, or unsubstituted or substituted Ci _-20 alkyl; and n is 1, 2 or 3; and

X is a moiety to be labelled or a detectable label; the process comprising

(a) condensing a thiol of formula (V)

with an acid of formula (VI) O

X OH (VI) to produce a phosphinoborane of formula (VII)

and (b) deprotecting the phosphinoborane of formula (VII) to produce the compound of formula (I).

In another aspect, the invention provides a method of imaging a human or non-human patient, a cell or an in vitro sample, which method comprises:

(a) administering to the patient, cell or in vitro sample a compound of formula (I)

wherein

X is a tracer moiety; R ¹ and R ² , which are the same or different, are independently selected from hydrogen, unsubstituted or substituted C _1-10 alkyl, unsubstituted or substituted aryl, unsubstituted or substituted C _3-10 cycloalkyl, unsubstituted or substituted C _3-10 heterocyclyl, and unsubstituted or substituted heteroaryl, or wherein R ¹ , R ² and the carbon atom to which R ¹ and R ² are both bonded together form an unsubstituted or substituted C _3-10 cycloalkyl group; and

R ³ and R ⁴ , which are the same or different, are independently selected from unsubstituted or substituted aryl, unsubstituted or substituted C _1-20 alkyl, unsubstituted or substituted C _3-10 cycloalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted C _3-10 heterocyclyl, and a fluorous group; which fluorous group is a group selected from:

(i) R _f ; (ii) -L ⁴ -Ci _-2 o alkyl, which Ci _-20 alkyl is substituted by one, two or three groups selected from R _f and -Z-R _f and is otherwise unsubstituted or substituted;

(iii) -iΛaryl, which aryl is substituted by one, two or three groups selected from R _f and -Z-R _f and is otherwise unsubstituted or substituted; and

(iv) -L ⁶ -Si(-L ⁷ -R _f ) _n (R ¹⁸ ) _3-n , wherein:

R _f is a straight-chained or branched C _3-20 perfluoroalkyl group, a perfluoroaryl group, a straight-chained or branched C _1-20 perfluoroalkyl group substituted with one, two or three perfluoroaryl groups; or a perfluoroaryl group substituted with one, two or three straight-chained or branched Ci _-20 perfluoroalkyl groups; provided that said straight-chained or branched C _1-20 and C _3-20 perfluoroalkyl groups are uninterrupted or interrupted by one, two or three perfluoroarylene groups;

L ⁴ and L ⁵ are independently selected from a single bond, -arylene-, -alk-, -alk-arylene-, -arylene-alk-, -alk-Z-, -arylene-Z-, -alk-arylene-Z, -alk-Z-arylene-, -alk-Z-arylene-Z-, -arylene-Z-alk-, -arylene-alk-Z- and -arylene-Z-alk-Z-, wherein alk is unsubstituted or substituted Ci-I ₀ alkylene which is optionally interrupted by N(R"), O, S, C(O), C(O)N(R") or arylene, wherein R" is H, C _1-6 alkyl or aryl;

L ⁶ and L ⁷ are independently selected from a single bond, -arylene-, -alk-, -alk-arylene-, -arylene-alk-, -alk-Z-arylene- and -arylene-Z-alk-, wherein alk is unsubstituted or substituted C _1-I0 alkylene which is optionally interrupted by N(R"), O, S, C(O), C(O)N(R") or arylene, wherein R" is H, Ci _-6 alkyl or aryl;

Z is N(R"), O, S, C(O) or C(O)N(R"), wherein R" is H, Ci _-6 alkyl or aryl;

R ¹⁸ is hydrogen, unsubstituted or substituted aryl, or unsubstituted or substituted Ci _-20 alkyl; and n is 1, 2 or 3;

(b) administering to the same patient, cell or in vitro sample a compound of formula (II)

N ₃ -L-Y _(π) wherein

Y is a detectable label; and L is a bond or a linking group; and

(c) imaging the patient, cell or in vitro sample.

In another aspect, the invention provides a method of imaging a human or non-human patient, a cell or an in vitro sample, which method comprises: (a) administering to the patient, cell or in vitro sample a compound of formula (IT)

N ₃ -L-Y _(π) wherein Y is a tracer moiety; and

L is a linking group;

(b) administering to the same patient, cell or in vitro sample a compound of formula (I)

wherein

X is a detectable label;

R ¹ and R ² , which are the same or different, are independently selected from hydrogen, unsubstituted or substituted C _1-10 alkyl, unsubstituted or substituted aryl, unsubstituted or substituted C _3-10 cycloalkyl, unsubstituted or substituted C _3-10 heterocyclyl, and unsubstituted or substituted heteroaryl, or wherein R , R and the carbon atom to which R ¹ and R ² are both bonded together form an unsubstituted or substituted C _3-10 cycloalkyl group; and

R ³ and R ⁴ , which are the same or different, are independently selected from unsubstituted or substituted aryl, unsubstituted or substituted C _1-20 alkyl, unsubstituted or substituted C _3-10 cycloalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted C _3-10 heterocyclyl, and a fiuorous group; which fiuorous group is a group selected from:

0) R _f ; (ii) -L ⁴ -C _1-20 alkyl, which C _1-20 alkyl is substituted by one, two or three groups selected from R _f and -Z-R _f and is otherwise unsubstituted or substituted;

(iii) -L ⁵ -aryl, which aryl is substituted by one, two or three groups selected from R _f and -Z-R _f and is otherwise unsubstituted or substituted; and

(iv) -L ⁶ -Si(-L ⁷ -R _f ) _n (R ¹⁸ ) _3-n , wherein:

R _f is a straight-chained or branched C _3-20 perfluoroalkyl group, a perfluoroaryl group, a straight-chained or branched C _1-20 perfluoroalkyl group substituted with one, two or three perfluoroaryl groups; or a perfluoroaryl group substituted with one, two or three straight-chained or branched C _1-20 perfluoroalkyl groups; provided that said straight-chained or branched C _1-20 and C _3-20 perfluoroalkyl groups are uninterrupted or interrupted by one, two or three perfluoroarylene groups;

L ⁴ and L ⁵ are independently selected from a single bond, -arylene-, -alk-, -alk-arylene-, -arylene-alk-, -alk-Z-, -arylene-Z-, -alk-arylene-Z, -alk-Z-arylene-, -alk-Z-arylene-Z-, -arylene-Z-alk-, -arylene-alk-Z- and -arylene-Z-alk-Z-, wherein alk is unsubstituted or substituted C _1-10 alkylene which is optionally interrupted by N(R"), O, S, C(O), C(O)N(R") or arylene, wherein R" is H, Ci _-6 alkyl or aryl;

L ⁶ and L ⁷ are independently selected from a single bond, -arylene-, -alk-, -alk-arylene-, -arylene-alk-, -alk-Z-arylene- and -arylene-Z-alk-, wherein alk is unsubstituted or substituted Ci _-I0 alkylene which is optionally interrupted by N(R"), O, S, C(O), C(O)N(R") or arylene, wherein R" is H, C _1-6 alkyl or aryl;

Z is N(R"), O, S, C(O) or C(O)N(R"), wherein R" is H, C _1-6 alkyl or aryl; R ¹⁸ is hydrogen, unsubstituted or substituted aryl, or unsubstituted or substituted C _1-20 alkyl; and n is 1, 2 or 3; and

(c) imaging the patient, cell or in vitro sample. In another aspect, the invention provides a compound of formula (III)

O

* K cm) wherein Y is F;

L is a linking group; and

X is a tracer moiety comprising: an oligopeptide, a polypeptide, a protein, a sugar, a lipid, a fatty acid, a nucleo base, a nucleoside, a nucleotide, or a nucleic acid; a ligand capable of binding to a tumour receptor, selected from bombesin, octreotide, lanreotide, pentetriotide, somatostatin, a somatostatin analogue, estradiol, trastuzumab, cetuximab, testosterone, a peptide secreted by an endocrine cell, tamoxifen, flutamide, an antioestrogen, an antiandrogen, a steroid, a progestin, an androgen, fulvestrant, metaiodobenzylguanidine, 3,4-dihydroxyphenylalanine, erlatinib, epidermal growth factor, transforming growth factor, ¹⁸ F-FDHT, ll-β-methoxy-17-α- ¹²³ I- iodovinylestradiol, ¹⁸ F-FES, 21- ¹⁸ F-fluoro-16-α-ethyl-19-norprogesterone, N-(4-(6,7- dimethoxy-3,4-dihydroisoquinolin-2- H-yl-)butyl), 2-(2- F-fluoroethoxy)-5- methylbenzamide, ^π C-gefltinib, ^{l u} In-octreatide, ⁶⁸ Ga-DOT A-octreotide, ⁶⁴ Cu- TETA-octreotide, ¹¹¹ In-DTPA-EGF, ⁶⁸ Ga-DOTA-EGF, Cy5.5-EGF, ¹⁸ F-galacto- RGD, RGD-USPIO, RGD-Cy5.5, [ ^{π 1} In-DTP A-Prol,Tyr4]bombesin, ⁶⁴ Cu-DOTA- [Lys3]bombesin, Bombesin-CLIO (Cy5.5), ⁶⁸ Ga-DOTA-F(ab') ₂ -trastuzumab, ¹¹¹ In-DTP A- trastuzumab, Polylactic acid nanoparticle-trastuzumab, RhodG- trastuzumab, (Avidin-Gd)-biotinylated anti-HER2/neu monoclonal antibody, ⁶⁴ Cu- DOTA-cetuximab and Cy5.5-cetuximab; or a metal complex, [M], which comprises a metal, M, and one or more ligands, as defined herein; or

X is a further-reactable moiety, which further-reactable moiety comprises a functional group suitable for attaching the compound of formula (DI) to a tracer moiety, which further-reactable moiety is a group of formula (XII)

wherein L ² is an unsubstituted or substituted C _1-20 alkylene group or an unsubstituted or substituted arylene group; or X is a group of formula (X) wherein

R ⁵ is selected from hydrogen, unsubstituted or substituted Ci _-10 alkyl, or a group of formula alk-R ¹⁶ , wherein alk is an unsubstituted or substituted Ci _-I0 alkylene group and R ¹⁶ is selected from hydroxyl, thiol, Ci _-6 alkylthio, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, carboxyl, amido, amino, -NH ₃ ⁺ and -N(H)-C(=NH ₂ ⁺ )-NH ₂ ; R ⁶ is hydrogen; provided that R ⁵ and R ⁶ may together form a propylene group; R ⁷ is an amino acid, a dipeptide, an oligopeptide, a polypeptide, a protein, a tracer moiety as defined herein, or a group of formula (XI)

wherein

R ⁸ is selected from hydrogen, unsubstituted or substituted Ci _-I0 alkyl, or a group of formula alk-R ¹⁶ , wherein alk is an unsubstituted or substituted Ci _-I0 alkylene group and R ¹⁶ is selected from hydroxyl, thiol, C _1-6 alkylthio, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, carboxyl, amido, amino, -NH ₃ ⁺ and -N(H)-C(=NH ₂ ⁺ )-NH ₂ ;

R ⁹ is hydrogen, provided that R ⁸ and R ⁹ may together form a propylene group;

R ¹⁰ is hydrogen or an amino protecting group; provided that R ¹⁰ and the R ⁹ substituent bonded to the same nitrogen atom as R ¹⁰ may together form an amino protecting group; and n is an integer of from 1 to 100; provided that R ⁶ and R ⁷ may together form an amino protecting group; or

X is a group of formula (XIII) wherein R ⁷ is hydrogen, an amino protecting group, an amino acid, a dipeptide, an oligopeptide, a polypeptide, a protein, a tracer moiety as defined in any one of claims 16 to 28, or a group of formula (XI) as defined above; or X is a group of formula -L ⁹ -Ar, wherein Ar is unsubstitutued or substituted aryl or unsubstitutued or substituted heteroaryl, and L ⁹ is an unsubstituted C _2-20 alkylene group.

Typically, X does not comprise oxytocin.

In another aspect, the invention provides a method of imaging a human or non-human patient in need thereof, which method comprises (a) administering to the patient a compound of formula (IH) of the invention as defined above; and (b) imaging the patient.

In another aspect, the invention provides a method of imaging a cell or in vitro sample, which method comprises: (a) contacting the cell or in vitro sample with a compound of formula (III) of the invention as defined above; and (b) imaging the cell or in vitro sample.

In another aspect, the invention provides a combination product for medical imaging comprising

(a) a compound of formula (I)

X wherein

X is a moiety to be labelled or a detectable label;

R ¹ and R ² , which are the same or different, are independently selected from hydrogen, unsubstituted or substituted C _1-10 alkyl, unsubstituted or substituted aryl, unsubstituted or substituted C _3-10 cycloalkyl, unsubstituted or substituted C _3-I0 heterocyclyl, and unsubstituted or substituted heteroaryl, or wherein R ¹ , R ² and the carbon atom to which R ¹ and R ² are both bonded together form an unsubstituted or substituted C _3-10 cycloalkyl group; and

R ³ and R ⁴ , which are the same or different, are independently selected from unsubstituted or substituted aryl, unsubstituted or substituted C _1-20 alkyl, unsubstituted or substituted C _3-10 cycloalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted C _3-10 heterocyclyl, and a fluorous group; which fluorous group is a group selected from:

(i) R _f ; (ii) -L ⁴ -C _1-20 alkyl, which C _1-20 alkyl is substituted by one, two or three groups selected from R _f and -Z-R _f and is otherwise unsubstituted or substituted;

(iii) -iAaryl, which aryl is substituted by one, two or three groups selected from R _f and -Z-R _f and is otherwise unsubstituted or substituted; and (iv) -L ⁶ -Si(-L ⁷ -Rf) _n (R ¹⁸ ) _3-n , wherein:

R _f is a straight-chained or branched C _3-20 perfluoroalkyl group, a perfluoroaryl group, a straight-chained or branched C _1-20 perfluoroalkyl group substituted with one, two or three perfluoroaryl groups; or a perfluoroaryl group substituted with one, two or three straight-chained or branched C _1-20 perfluoroalkyl groups; provided that said straight-chained or branched C _1-20 and C _3-20 perfluoroalkyl groups are uninterrupted or interrupted by one, two or three perfluoroarylene groups;

L ⁴ and L ⁵ are independently selected from a single bond, -arylene-, -alk-, -alk-arylene-, -arylene-alk-, -alk-Z-, -arylene-Z-, -alk-arylene-Z, -alk-Z-arylene-, -alk-Z-arylene-Z-, -arylene-Z-alk-, -arylene- alk-Z- and -arylene-Z-alk-Z-, wherein alk is unsubstituted or substituted C _1-10 alkylene which is optionally interrupted by N(R"), O, S, C(O), C(O)N(R") or arylene, wherein R" is H, C _1-6 alkyl or aryl;

L ⁶ and L ⁷ are independently selected from a single bond, -arylene-, -alk-, -alk-arylene-, -arylene-alk-, -alk-Z-arylene- and -arylene-Z-alk-, wherein alk is unsubstituted or substituted Ci _-I0 alkylene which is optionally interrupted by N(R"), O, S, C(O), C(O)N(R") or arylene, wherein R" is H, C _1-6 alkyl or aryl;

Z is N(R"), O, S, C(O) or C(O)N(R"), wherein R" is H, C _1-6 alkyl or aryl; R ¹⁸ is hydrogen, unsubstituted or substituted aryl, or unsubstituted or substituted C] _-20 alkyl; and n is 1, 2 or 3; and (b) a compound of formula (II)

N ₃ -L-Y _(π) wherein

Y is a detectable label or a moiety to be labelled, provided that if X in the compound of formula (I) is a moiety to be labelled, then Y is a detectable label and if X in the compound of formula (I) is a detectable label, then Y is a moiety to be labelled; and

L is a bond or a linking group, wherein the detectable label comprises a fluorine atom, a radionuclide, an optical label, an ultrasound-responsive agent, an X-ray responsive agent, a fluorophore or a luminescent moiety, wherein the radionuclide is selected from ³ H, ¹¹ C, ¹³ N, ¹⁵ O, ¹⁸ F, ⁵¹ Cr, ⁵² Fe, ^52m Mn, ⁵⁵ Co, ⁶⁰ Cu, ⁶¹ Cu, ⁶² Zn, ⁶² Cu, ⁶³ Zn, ⁶⁴ Cu, ⁶⁶ Ga, ⁶⁷ Ga, ⁶⁸ Ga, ⁷⁰ As, ⁷¹ As, ⁷² As, ⁷⁴ As, ⁷⁵ Se, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ^8Om Br, ^82m Br, ⁸² Rb, ⁸⁶ Y, ⁸⁸ Y, ⁸⁹ Sr, ⁸⁹ Zr, ⁹⁷ Ru, ^99m Tc, ¹¹⁰ In, ¹¹¹ In, ^113m In, ^114m In, ^117m Sn, ¹²⁰ 1, ¹²² Xe, ¹²³ 1, ¹²⁴ 1, ¹²⁵ 1, ¹³¹ 1, ¹⁶⁶ Ho, ¹⁶⁷ Tm, ¹⁶⁹ Yb, ^193m Pt, ^195m Pt, ²⁰¹ Tl and ²⁰³ Pb. hi another aspect, the invention provides a process for producing a labelled compound, which process comprises treating a compound of formula (I)

X wherein

X is a moiety to be labelled or a detectable label;

R ¹ and R ² , which are the same or different, are independently selected from hydrogen, unsubstituted or substituted C _1-10 alkyl, unsubstituted or substituted aryl, unsubstituted or substituted C _3-10 cycloalkyl, unsubstituted or substituted C _3-10 heterocyclyl, and unsubstituted or substituted heteroaryl, or wherein R ¹ , R ² and the carbon atom to which R ¹ and R ² are both bonded together form an unsubstituted or substituted C _3-10 cycloalkyl group; and

R ³ and R ⁴ , which are the same or different, are independently selected from unsubstituted or substituted aryl, unsubstituted or substituted C _1-20 alkyl, unsubstituted or substituted C _3-10 cycloalkyl, unsubstituted or substituted heteroaryl and unsubstituted or substituted C _3-10 heterocyclyl; with a compound of formula (II)

N ₃ -L-Y _(π) wherein

Y is a detectable label or a moiety to be labelled, provided that if X in the compound of formula (I) is a moiety to be labelled, then Y is a detectable label and if X in the compound of formula (I) is a detectable label, then Y is a moiety to be labelled; and L is a bond or a linking group; thereby producing a labelled compound of formula (DI)

O

* K (DO.

In another aspect, the invention provides a compound of formula (I)

wherein

R ¹ and R ² , which are the same or different, are independently selected from hydrogen, unsubstituted or substituted C _1-10 alkyl, unsubstituted or substituted aryl, unsubstituted or substituted C _3-10 cycloalkyl, unsubstituted or substituted C _3-I0 heterocyclyl, and unsubstituted or substituted heteroaryl, or wherein R ¹ , R ² and the carbon atom to which R ¹ and R ² are both bonded together form an unsubstituted or substituted C _3-10 cycloalkyl group;

R ³ and R ⁴ , which are the same or different, are independently selected from unsubstituted or substituted aryl, unsubstituted or substituted C _1-20 alkyl, unsubstituted or substituted C _3-10 cycloalkyl, unsubstituted or substituted heteroaryl and unsubstituted or substituted C _3-10 heterocyclyl; and

X is a tracer moiety, a further-reactable moiety, or a detectable label, wherein the further-reactable moiety comprises a functional group suitable for attaching the compound of formula (I) to a tracer moiety.

Typically, in the compound of formula (I) of the invention as defined above, X is other than the following group of formula (IV):

The invention also provides a process for producing a compound of formula (I)

X wherein

R ¹ and R ² , which are the same or different, are independently selected from hydrogen, unsubstituted or substituted Ci _-10 alkyl, unsubstituted or substituted aryl, unsubstituted or substituted C _3-10 cycloalkyl, unsubstituted or substituted C _3-10 heterocyclyl, and unsubstituted or substituted heteroaryl, or wherein R ¹ , R ² and the carbon atom to which R ¹ and R ² are both bonded together form an unsubstituted or substituted C _3-10 cycloalkyl group;

R ³ and R ⁴ , which are the same or different, are independently selected from unsubstituted or substituted aryl, unsubstituted or substituted C _1-20 alkyl, unsubstituted or substituted C _3-I0 cycloalkyl, unsubstituted or substituted heteroaryl and unsubstituted or substituted C _3-10 heterocyclyl; and

X is a tracer moiety, a further-reactable moiety, or a detectable label, wherein the further-reactable moiety comprises a functional group suitable for attaching the compound of formula (I) to a tracer moiety, the process comprising

(a) condensing a thiol of formula (V) with an acid of formula (VI)

to produce a phosphinoborane of formula (VII)

and

(b) deprotecting the phosphinoborane of formula (VlT) to produce the compound of formula (T).

Typically, in the process of the invention for producing a compound of formula (I), X is other than a group of formula (TV)

hi another aspect, the invention provides a method of imaging a human or non-human patient, a cell or an in vitro sample, which method comprises:

(a) administering to the patient, cell or in vitro sample a compound of formula (I)

wherein

X is a tracer moiety; R ¹ and R ² , which are the same or different, are independently selected from hydrogen, unsubstituted or substituted C _1-10 alkyl, unsubstituted or substituted aryl, unsubstituted or substituted C _3-10 cycloalkyl, unsubstituted or substituted C _3-10 heterocyclyl, and unsubstituted or substituted heteroaryl, or wherein R ¹ , R ² and the carbon atom to which R ¹ and R ² are both bonded together form an unsubstituted or substituted C _3-10 cycloalkyl group; and R ³ and R ⁴ , which are the same or different, are independently selected from unsubstituted or substituted aryl, unsubstituted or substituted C _1-20 alkyl, unsubstituted or substituted C _3-10 cycloalkyl, unsubstituted or substituted heteroaryl and unsubstituted or substituted C _3-10 heterocyclyl;

(b) administering to the same patient, cell or in vitro sample a compound of formula (II)

N ₃ -L-Y _(π) wherein

Y is a detectable label; and L is a bond or a linking group; and

(c) imaging the patient, cell or in vitro sample.

In another aspect, the invention provides a method of imaging a human or non-human patient, a cell or an in vitro sample, which method comprises:

(a) administering to the patient, cell or in vitro sample a compound of formula (II)

N ₃ -L-Y _(π) wherein

Y is a tracer moiety; and L is a bond or a linking group; and

(b) administering to the same patient, cell or in vitro sample a compound of formula (I)

wherein X comprises a detectable label; R ¹ and R ² , which are the same or different, are independently selected from hydrogen, unsubstituted or substituted C _MO alkyl, unsubstituted or substituted aryl, unsubstituted or substituted C _3-10 cycloalkyl, unsubstituted or substituted C _3-10 heterocyclyl, and unsubstituted or substituted heteroaryl, or wherein R ¹ , R ² and the carbon atom to which R ¹ and R ² are both bonded together form an unsubstituted or substituted C _3-I0 cycloalkyl group; and

R ³ and R ⁴ , which are the same or different, are independently selected from unsubstituted or substituted aryl, unsubstituted or substituted C _1-20 alkyl, unsubstituted or substituted C _3-1O cycloalkyl, unsubstituted or substituted heteroaryl and unsubstituted or substituted C _3-I0 heterocyclyl; and (c) imaging the patient, cell or in vitro sample. In another aspect, the invention provides a compound of formula (III)

wherein Y is F;

X is a tracer moiety or a further-reactable moiety, which further-reactable moiety comprises a functional group suitable for attaching the compound of formula (III) to a tracer moiety; and

L is a bond or a linking group. hi another aspect, the invention provides a combination product for medical imaging comprising

(a) a compound of formula (I)

wherein

X is a moiety to be labelled or a detectable label;

R ¹ and R ² , which are the same or different, are independently selected from hydrogen, unsubstituted or substituted C] _-10 alkyl, unsubstituted or substituted aryl, unsubstituted or substituted C _3-10 cycloalkyl, unsubstituted or substituted C _3-I0 heterocyclyl, and unsubstituted or substituted heteroaryl, or wherein R ¹ , R ² and the carbon atom to which R ¹ and R ² are both bonded together form an unsubstituted or substituted C _3-10 cycloalkyl group; and

R ³ and R ⁴ , which are the same or different, are independently selected from unsubstituted or substituted aryl, unsubstituted or substituted C _1-20 alkyl, unsubstituted or substituted C _3-10 cycloalkyl, unsubstituted or substituted heteroaryl and unsubstituted or substituted C _3-10 heterocyclyl; and

(b) a compound of formula (II)

N ₃ -L-Y _(π) wherein

Y is a detectable label or a moiety to be labelled, provided that if X in the compound of formula (I) is a moiety to be labelled, then Y is a detectable label and if X in the compound of formula (I) is a detectable label, then Y is a moiety to be labelled; and

L is a bond or a linking group. hi another aspect, the invention provides a method of imaging a human or non-human patient in need thereof, which method comprises (a) administering to the patient a compound of formula (IH) of the invention as defined above; and (b) imaging the patient. hi another aspect, the invention provides a method of imaging a cell or in vitro sample, which method comprises: (a) contacting the cell or in vitro sample with a compound of formula (III) of the invention as defined above; and (b) imaging the cell or in vitro sample.

Brief Description of the Figure

Figure 1 shows schematic illustrations of Staudinger ligation reactions; (a) is a normal Staudinger ligation whereas (b) is the "traceless" Staudinger ligation used in the present invention. Detailed Description of the Invention

The following substituent definitions apply with respect to the compounds defined herein:

A C _1-20 alkyl group is an unsubstituted or substituted, straight or branched chain saturated hydrocarbon radical. Typically it is C _1-10 alkyl, for example methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl or decyl, or C _1-6 alkyl, for example methyl, ethyl, propyl, butyl, pentyl or hexyl, or C _1-4 alkyl, for example methyl, ethyl, i-propyl, n-propyl, t-butyl, s-butyl or n-butyl. When an alkyl group is substituted it typically bears one or more substituents selected from substituted or unsubstituted C _1-20 alkyl, substituted or unsubstituted aryl (as defined herein), cyano, amino, C _1-10 alkylamino, di(C _1-10 )alkylamino, arylamino, diarylamino, arylalkylamino, amido, acylamido, hydroxy, oxo, halo, carboxy, ester, acyl, acyloxy, C _1-20 alkoxy, aryloxy, haloalkyl, sulfonic acid, sulfhydryl (i.e. thiol, -SH), C _1-10 alkylthio, arylthio, sulfonyl, phosphoric acid, phosphate ester, phosphonic acid and phosphonate ester. Examples of substituted alkyl groups include haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl and alkaryl groups. The term alkaryl, as used herein, pertains to a C _1-20 alkyl group in which at least one hydrogen atom has been replaced with an aryl group. Examples of such groups include, but are not limited to, benzyl (phenylmethyl, PhCH ₂ -), benzhydryl (Ph ₂ CH-), trityl (triphenylmethyl, Ph ₃ C-), phenethyl (phenylethyl, Ph-CH ₂ CH ₂ -), styryl (Ph-CH=CH-), cinnamyl (Ph-CH=CH-CH ₂ -).

Typically a substituted C _1-20 alkyl group carries 1, 2 or 3 substituents, for instance 1 or 2.

A C _1-2O perfluoroalkyl group is a straight or branched chain saturated perfluorinated hydrocarbon radical having from 1 to 20 carbon atoms. A C _3-20 perfluoroalkyl group is a straight or branched chain saturated perfluorinated hydrocarbon radical having from 3 to 20 carbon atoms. "Perfluorinated" in this context means completely fluorinated such that there are no carbon-bonded hydrogen atoms replaceable with fluorine. A C _1-20 or C _3-20 perfluoroalkyl group may however be substituted with one, two or three perfluoroaryl groups. In such a substituted C _3-20 perfluoroalkyl group, one, two or three of the carbon-bonded fluorine atoms are replaced with a perfluoroaryl substituent group. Where more than one perfluoroaryl substituent group is present, the perfluoroaryl substituent groups may be bonded to the same or different carbon atoms of the substituted perfluoroalkyl group. Alternatively a C _3-20 perfluoroalkyl group may be unsubstituted, such that none of the carbon-bonded fluorine atoms is replaced with another group such as a perfluoroaryl group. Typically a C _1-20 or C _3-20 perfluoroalkyl group is a is C _3-12 perfluoroalkyl group. Examples of C _3-12 perfluoro alkyl groups are perfluoropropyl (C ₃ ) (including perfluoro-n-propyl and perfluoro-ώo-propyl), perfluorobutyl (C ₄ ) (including perfluoro-«-butyl, perfluoro-sec-butyl and perfluoro-tert-butyl), perfluoropentyl (C ₅ ), perfluorohexyl (C ₆ ), perfluoroheptyl (C ₇ ), perfluorooctyl (C ₈ ), perfluorononyl (C ₉ ), perfluorodecyl (C ₁₀ ), perfluoroundecyl (C ₁₁ ) and perfiuorododecyl (C ₁₂ ), including straight chained and branched isomers thereof. C _1-20 perfluoroalkyl also of course includes longer-chain perfluoroalkyls, with up to 20 carbon atoms, and shorter ones including -CF ₃ and -CF ₂ -CF ₃ .

A C _3-10 cycloalkyl group is an unsubstituted or substituted alkyl group which is also a cyclyl group; that is, a monovalent moiety obtained by removing a hydrogen atom from an alicyclic ring atom of a carbocyclic ring of a carbocyclic compound, which moiety has from 3 to 10 carbon atoms (unless otherwise specified), including from 3 to 10 ring atoms. Thus, the term "cycloalkyl" includes the sub-classes cycloalkyenyl and cycloalkynyl. Examples of groups of C _3-10 cycloalkyl groups include C _3-7 cycloalkyl. When a C _3-10 cycloalkyl group is substituted it typically bears one or more substituents selected from C _1-6 alkyl which is unsubstituted, aryl (as defined herein), cyano, amino, C _1-10 alkylamino, di(C _1-10 )alkylamino, arylamino, diarylamino, arylalkylamino, amido, acylamido, hydroxy, oxo, halo, carboxy, ester, acyl, acyloxy, C _1-20 alkoxy, aryloxy, haloalkyl, sulfonic acid, sulfhydryl (i.e. thiol, - SH), C _1-10 alkylthio, arylthio, phosphoric acid, phosphate ester, phosphonic acid and phosphonate ester and sulfonyl. Typically a substituted C _3-10 cycloalkyl group carries 1, 2 or 3 substituents, for instance 1 or 2.

Examples of C _3-10 cycloalkyl groups include, but are not limited to, those derived from saturated monocyclic hydrocarbon compounds, which C _3-10 cycloalkyl groups are unsubstituted or substituted as defined above: cyclopropane (C ₃ ), cyclobutane (C ₄ ), cyclopentane (C ₅ ), cyclohexane (C ₆ ), cycloheptane (C ₇ ), methylcyclopropane (C ₄ ), dimethylcyclopropane (C ₅ ), methylcyclobutane (C ₅ ), dimethylcyclobutane (C ₆ ), methylcyclopentane (C ₆ ), dimethylcyclopentane (C ₇ ), methylcyclohexane (C ₇ ), dimethylcyclohexane (C ₈ ), menthane (C ₁₀ ); unsaturated monocyclic hydrocarbon compounds: cyclopropene (C ₃ ), cyclobutene (C ₄ ), cyclopentene (C ₅ ), cyclohexene (C ₆ ), methylcyclopropene (C ₄ ), dimethylcyclopropene (C ₅ ), methylcyclobutene (C ₅ ), dimethylcyclobutene (C ₆ ), methylcyclopentene (C ₆ ), dimethylcyclopentene (C ₇ ), methylcyclohexene (C ₇ ), dimethylcyclohexene (C ₈ ); saturated polycyclic hydrocarbon compounds: thujane (C ₁₀ ), carane (C ₁₀ ), pinane (C ₁₀ ), bornane (C ₁₀ ), norcarane (C ₇ ), norpinane (C ₇ ), norbornane (C ₇ ), adamantane (C io), decalin (decahydronaphthalene) (C _JO ); unsaturated polycyclic hydrocarbon compounds: camphene (C ₁₀ ), limonene (C ₁₀ ), pinene (C ₁₀ ), polycyclic hydrocarbon compounds having an aromatic ring: indene (Cg), indane (e.g., 2,3-dihydro-lH-indene) (Cg), tetraline

(1 ,2,3,4-tetrahydronaphthalene) (C ₁ O).

A C _3-I0 heterocyclyl group is an unsubstituted or substituted monovalent moiety obtained by removing a hydrogen atom from a ring atom of a heterocyclic compound, which moiety has from 3 to 10 ring atoms (unless otherwise specified), of which from 1 to 5 are ring heteroatoms. Preferably, each ring has from 3 to 7 ring atoms, of which from 1 to 4 are ring heteroatoms. When a C _3-10 heterocyclyl group is substituted it typically bears one or more substituents selected from Ci _-6 alkyl which is unsubstituted, aryl (as defined herein), cyano, amino, C _1-10 alkylamino, di(d- jo)alkylamino, arylamino, diarylamino, arylalkylamino, amido, acylamido, hydroxy, oxo, halo, carboxy, ester, acyl, acyloxy, C _1-20 alkoxy, aryloxy, haloalkyl, sulfonic acid, sulfliydryl (i.e. thiol, -SH), C _1-10 alkylthio, arylthio, phosphoric acid, phosphate ester, phosphonic acid and phosphonate ester and sulfonyl. Typically a substituted C _3-10 heterocyclyl group carries 1, 2 or 3 substituents, for instance 1 or 2.

Examples of groups of heterocyclyl groups include C _5-10 heterocyclyl, C _3-7 heterocyclyl, C _5-7 heterocyclyl, and C _5-6 heterocyclyl.

Examples of (non-aromatic) monocyclic C _3-10 heterocyclyl groups include, but are not limited to, those derived from: N ₁ : aziridine (C ₃ ), azetidine (C ₄ ), pyrrolidine (tetrahydropyrrole) (C ₅ ), pyrroline (e.g., 3-pyrroline, 2,5-dihydropyrrole) (C ₅ ), 2H-pyrrole or 3H-pyrrole (isopyrrole, isoazole) (C ₅ ), piperidine (C ₆ ), dihydropyridine (C ₆ ), tetrahydropyridine (C ₆ ), azepine (C ₇ ); O ₁ : oxirane (C ₃ ), oxetane (C ₄ ), oxolane (tetrahydrofuran) (C ₅ ), oxole

(dihydrofuran) (C ₅ ), oxane (tetrahydropyran) (C ₆ ), dihydropyran (C ₆ ), pyran (C ₆ ), oxepin (C ₇ );

S ₁ : thiirane (C ₃ ), thietane (C ₄ ), thiolane (tetrahydrothiophene) (C ₅ ), thiane (tetrahydrothiopyran) (C ₆ ), thiepane (C ₇ ); O ₂ : dioxolane (C ₅ ), dioxane (C ₆ ), and dioxepane (C ₇ );

O ₃ : trioxane (C ₆ );

N ₂ : imidazolidine (C ₅ ), pyrazolidine (diazolidine) (C ₅ ), imidazoline (C ₅ ), pyrazoline (dihydropyrazole) (C ₅ ), piperazine (C ₆ );

N ₁ O ₁ : tetrahydrooxazole (C ₅ ), dihydrooxazole (C ₅ ), tetrahydroisoxazole (C ₅ ), dihydroisoxazole (C ₅ ), morpholine (C ₆ ), tetrahydrooxazine (C ₆ ), dihydrooxazine (C ₆ ), oxazine (C ₆ );

N ₁ S ₁ : thiazoline (C ₅ ), thiazolidine (C ₅ ), thiomorpholine (C ₆ );

N ₂ O ₁ : oxadiazine (C ₆ );

O ₁ S ₁ : oxathiole (C ₅ ) and oxathiane (thioxane) (C ₆ ); and, N ₁ O ₁ S ₁ : oxathiazine (C ₆ ).

Examples of substituted (non-aromatic) monocyclic heterocyclyl groups include those derived from saccharides, in cyclic form, for example, furanoses (C ₅ ), such as arabinofuranose, lyxofuranose, ribofuranose, and xylofuranse, and pyranoses (C ₆ ), such as allopyranose, altropyranose, glucopyranose, mannopyranose, gulopyranose, idopyranose, galactopyranose, and talopyranose.

Examples of C _3-10 heterocyclyl groups which are also aryl groups are described below as heteroaryl groups.

<

An aryl group is a substituted or unsubstituted, monocyclic or bicyclic aromatic group which typically contains from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms in the ring portion. Examples include phenyl, naphthyl, indenyl and indanyl groups. An aryl group is unsubstituted or substituted. When an aryl group as defined above is substituted it typically bears one or more substituents selected from C ₁ -C ₆ alkyl which is unsubstituted (to form an aralkyl group), aryl which is unsubstituted, cyano, amino, C _1-I0 alkylamino, di(C _1-1 o)alkylamino, arylamino, diarylamino, arylalkylamino, amido, acylamido, hydroxy, halo, carboxy, ester, acyl, acyloxy, C _1-20 alkoxy, aryloxy, haloalkyl, sulfhydryl (i.e. thiol, -SH), Ci _-10 alkylthio, arylthio, sulfonic acid, phosphoric acid, phosphate ester, phosphonic acid and phosphonate ester and sulfonyl. Typically it carries 0, 1, 2 or 3 substituents. A substituted aryl group may be substituted in two positions with a single Ci _-6 alkylene group, or with a bidentate group represented by the formula -X-C _1-6 alkylene, or -X- C _1-6 alkylene-X-, wherein X is selected from O, S and NR, and wherein R is H, aryl or Ci _-6 alkyl. Thus a substituted aryl group may be an aryl group fused with a cycloalkyl group or with a heterocyclyl group. The term aralkyl as used herein, pertains to an aryl group in which at least one hydrogen atom (e.g., 1, 2, 3) has been substituted with a C _1-6 alkyl group. Examples of such groups include, but are not limited to, tolyl (from toluene), xylyl (from xylene), mesityl (from mesitylene), and cumenyl (or cumyl, from cumene), and duryl (from durene).

The ring atoms of an aryl group may include one or more heteroatoms (as in a heteroaryl group). Such an aryl group (a heteroaryl group) is a substituted or unsubstituted mono- or bicyclic heteroaromatic group which typically contains from 6 to 10 atoms in the ring portion including one or more heteroatoms. It is generally a 5- or 6-membered ring, containing at least one heteroatom selected from O, S, N, P, Se and Si. It may contain, for example, 1, 2 or 3 heteroatoms. Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiadiazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, indolyl (e.g. 3-indolyl), quinolyl and isoquinolyl. A heteroaryl group may be unsubstituted or substituted, for instance, as specified above for aryl. Typically it carries 0, 1, 2 or 3 substituents.

A perfluoroaryl group is a perfluorinated aromatic group which may be monocyclic or bicyclic and which typically contains from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms in the ring portion. "Perfluorinated" in this context means completely fiuorinated such that there are no carbon-bonded hydrogen atoms replaceable with fluorine. Examples include perfluorophenyl (-C ₆ F ₅ ), perfluoronaphthyl (-Ci ₀ F ₇ ), perfluorobiphenylyl (-C ₆ F ₄ -C ₆ F ₅ ), perfluoroindenyl 29 selected from C ₁ -C ₆ alkyl which is unsubstituted (to form an aralkyl group), aryl which is unsubstituted, cyano, amino, C _1-10 alkylamino, di(C _1-1 o)alkylamino, arylamino, diarylamino, arylalkylamino, amido, acylamido, hydroxy, halo, carboxy, ester, acyl, acyloxy, Ci _-20 alkoxy, aryloxy, haloalkyl, sulfhydryl (i.e. thiol, -SH), Ci _-1 O alkylthio, arylthio, sulfonic acid, phosphoric acid, phosphate ester, phosphonic acid and phosphonate ester and sulfonyl. Typically it carries 0, 1, 2 or 3 substituents. A substituted aryl group may be substituted in two positions with a single Ci _-6 alkylene group, or with a bidentate group represented by the formula -X-Ci _-6 alkylene, or -X- Ci _-6 alkylene-X-, wherein X is selected from O, S and NR, and wherein R is H, aryl or Ci _-6 alkyl. Thus a substituted aryl group may be an aryl group fused with a cycloalkyl group or with a heterocyclyl group. The term aralkyl as used herein, pertains to an aryl group in which at least one hydrogen atom (e.g., 1, 2, 3) has been substituted with a Ci _-6 alkyl group. Examples of such groups include, but are not limited to, tolyl (from toluene), xylyl (from xylene), mesityl (from mesitylene), and cumenyl (or cumyl, from cumene), and duryl (from durene).

The ring atoms of an aryl group may include one or more heteroatoms (as in a heteroaryl group). Such an aryl group (a heteroaryl group) is a substituted or unsubstituted mono- or bicyclic heteroaromatic group which typically contains from 6 to 10 atoms in the ring portion including one or more heteroatoms. It is generally a 5- or 6-membered ring, containing at least one heteroatom selected from O, S, N, P, Se and Si. It may contain, for example, 1, 2 or 3 heteroatoms. Examples of heteroaryl groups include pyridyl, pyrazinyl, pyrimidinyl, pyridazinyl, furanyl, thienyl, pyrazolidinyl, pyrrolyl, oxazolyl, oxadiazolyl, isoxazolyl, thiadiazolyl, thiazolyl, isothiazolyl, imidazolyl, pyrazolyl, indolyl (e.g. 3-indolyl), quinolyl and isoquinolyl. A heteroaryl group may be unsubstituted or substituted, for instance, as specified above for aryl. Typically it carries 0, 1, 2 or 3 substituents.

A perfluoroaryl group is a perfluorinated aromatic group which may be monocyclic or bicyclic and which typically contains from 6 to 14 carbon atoms, preferably from 6 to 10 carbon atoms in the ring portion. "Perfluorinated" in this context means completely fluorinated such that there are no carbon-bonded hydrogen atoms replaceable with fluorine. Examples include perfluorophenyl (-C ₆ F ₅ ), perfluoronaphthyl (-Ci ₀ F ₇ ), perfluorobiphenylyl (-C ₆ F ₄ -C ₆ F ₅ ), perfluoroindenyl 30

(-CgF ₆ ) and perfluoroindanyl (-C ₉ F ₉ ) groups. A perfluoroaryl group may however be substituted with one, two or three perfluoroalkyl groups, for instance C _1-20 , C _3-20 and/or C _3-12 perfluoroalkyl groups. In such a substituted perfluoroaryl group, one, two or three of the carbon-bonded fluorine atoms are replaced with a perfluoroalkyl substituent group. Alternatively a perfluoroaryl group may be unsubstituted, such that none of the carbon-bonded fluorine atoms is replaced with another group such as a perfluoroalkyl group.

A C _1-20 alkylene group is an unsubstituted or substituted bidentate moiety obtained by removing two hydrogen atoms, either both from the same carbon atom, or one from each of two different carbon atoms, of a hydrocarbon compound having from 1 to 20 carbon atoms (unless otherwise specified), which may be aliphatic or alicyclic, and which may be saturated, partially unsaturated, or fully unsaturated. Thus, the term "alkylene" includes the sub-classes alkenylene, alkynylene, cycloalkylene, etc., discussed below. Typically it is Ci _-10 alkylene, for instance C _1-6 alkylene. Typically it is C _M alkylene, for example methylene, ethylene, i-propylene, n-propylene, t-butylene, s-butylene or n-butylene. It may also be pentylene, hexylene, heptylene, octylene and the various branched chain isomers thereof. An alkylene group may be unsubstituted or substituted, for instance, as specified above for alkyl. Typically a substituted alkylene group carries 1, 2 or 3 substituents, for instance 1 or 2.

In this context, the prefixes (e.g., C _1-4 , Ci _-7 , C _1-20 , C _2-7 , C _3-7 , etc.) denote the number of carbon atoms, or range of number of carbon atoms. For example, the term "C _1-4 alkylene," as used herein, pertains to an alkylene group having from 1 to 4 carbon atoms. Examples of groups of alkylene groups include Ci _-4 alkylene ("lower alkylene"), Ci _-7 alkylene, C _1-10 alkylene and C _1-20 alkylene.

Examples of linear saturated C _1-7 alkylene groups include, but are not limited to, -(CH ₂ ) _n - where n is an integer from 1 to 7, for example, -CH ₂ - (methylene), -CH ₂ CH ₂ - (ethylene), -CH ₂ CH ₂ CH ₂ - (propylene), and -CH ₂ CH ₂ CH ₂ CH ₂ - (butylene). Examples of branched saturated Ci _-7 alkylene groups include, but are not limited to, -CH(CH ₃ )-, -CH(CH ₃ )CH ₂ -, -CH(CH ₃ )CH ₂ CH ₂ -, -CH(CH ₃ )CH ₂ CH ₂ CH ₂ -, -CH ₂ CH(CH ₃ )CH ₂ -, -CH ₂ CH(CH ₃ )CH ₂ CH ₂ -, -CH(CH ₂ CH ₃ )-, -CH(CH ₂ CH ₃ )CH ₂ -, and -CH ₂ CH(CH ₂ CH ₃ )CH ₂ -. 31

Examples of linear partially unsaturated C _1-7 alkylene groups include, but is not limited to, -CH=CH- (vinylene), -CH=CH-CH ₂ -, -CH ₂ -CH=CH ₂ -, -CH=CH-CH ₂ -CH ₂ -, -CH=CH-CH ₂ -CH ₂ -CH ₂ -, -CH=CH-CH=CH-, -CH=CH-CH=CH-CH ₂ -, -CH=CH-CH=CH-CH ₂ -CH ₂ -, -CH=CH-CH ₂ -CH=CH-, and -CH=CH-CH ₂ -CH ₂ -CH=CH-.

Examples of branched partially unsaturated C _1-7 alkylene groups include, but is not limited to, -C(CH ₃ )=CH-, -C(CH ₃ )=CH-CH ₂ -, and -CH=CH-CH(CH ₃ )-.

Examples of alicyclic saturated C _1-7 alkylene groups include, but are not limited to, cyclopentylene (e.g., cyclopent-l,3-ylene), and cyclohexylene (e.g., cyclohex- 1 ,4-ylene) .

Examples of alicyclic partially unsaturated C _1-7 alkylene groups include, but are not limited to, cyclopentenylene (e.g., 4-cyclopenten-l,3-ylene), cyclohexenylene (e.g., 2-cyclohexen-l,4-ylene; 3-cyclohexen-l,2-ylene; 2,5-cyclohexadien-l,4- ylene). C _1-20 alkylene and C _1-20 alkyl groups as defined herein are either uninterrupted or interrupted by one or more heteroatoms or heterogroups, such as S, O or N(R") wherein R" is H, C _1-6 alkyl or aryl (typically phenyl), or by one or more arylene (typically phenylene) groups, or by one or more -C(O)- or -C(O)N(R")- groups. The phrase "optionally interrupted" as used herein thus refers to a C _1-20 alkyl group or an alkylene group, as defined above, which is uninterrupted or which is interrupted between adjacent carbon atoms by a heteroatom such as oxygen or sulfur, by a hetero group such as N(R") wherein R" is H, aryl or C ₁ -C ₆ alkyl, or by an arylene group, or by a -C(O)- or -C(O)N(R")- group, again wherein R" is H, aryl or C ₁ -C ₆ alkyl. For instance, a C _1-20 alkyl group such as n-butyl may be interrupted by the heterogroup N(R") as follows: -CH ₂ N(R")CH ₂ CH ₂ CH ₃ , -CH ₂ CH ₂ N(R")CH ₂ CH ₃ , or -CH ₂ CH ₂ CH ₂ N(R")CH ₃ . Similarly, an alkylene group such as n-butylene may be interrupted by the heterogroup N(R") as follows: -CH ₂ N(R")CH ₂ CH ₂ CH ₂ -, -CH ₂ CH ₂ N(R")CH ₂ CH ₂ -, or -CH ₂ CH ₂ CH ₂ N(R")CH ₂ -. Typically an interrupted group, for instance an interrupted C _1-20 alkylene or C _1-20 alkyl group, is interrupted by 1, 2 or 3 heteroatoms or heterogroups or by 1, 2 or 3 arylene (typically phenylene) groups. More typically, an interrupted group, for instance an interrupted C _1-20 32 alkylene or C _1-20 alkyl group, is interrupted by 1 or 2 heteroatoms or heterogroups or by 1 or 2 arylene (typically phenylene) groups. For instance, a C _1-20 alkyl group such as n-butyl may be interrupted by 2 heterogroups N(R") as follows: -CH ₂ N(R")CH ₂ N(R")CH ₂ CH ₃ . An arylene group is an unsubstituted or substituted bidentate moiety obtained by removing two hydrogen atoms, one from each of two different aromatic ring atoms of an aromatic compound, which moiety has from 5 to 14 ring atoms (unless otherwise specified). Typically, each ring has from 5 to 7 or from 5 to 6 ring atoms. An arylene group may be unsubstituted or substituted, for instance, as specified above for aryl.

In this context, the prefixes (e.g., C _5-20 , C _6-20 , C _5-14 , C _5-7 , C _5-6 , etc.) denote the number of ring atoms, or range of number of ring atoms, whether carbon atoms or heteroatoms. For example, the term "C _5-6 arylene," as used herein, pertains to an arylene group having 5 or 6 ring atoms. Examples of groups of arylene groups include C _5-20 arylene, C _6-20 arylene, C _5-14 arylene, C _6-14 arylene, C _6-I0 arylene, C _5-12 arylene, C _5-10 arylene, C _5-7 arylene, C _5-6 arylene, C ₅ arylene, and C ₆ arylene.

The ring atoms may be all carbon atoms, as in "carboarylene groups" (e.g., C _6-20 carboarylene, C _6-I4 carboarylene or C _6-10 carboarylene).

Examples of C _6-20 arylene groups which do not have ring heteroatoms (i.e., C _6-20 carboarylene groups) include, but are not limited to, those derived from the compounds discussed above in regard to aryl groups, e.g. phenylene, and also include those derived from aryl groups which are bonded together, e.g. phenylene- phenylene (diphenylene) and phenylene-phenylene-phenylene (triphenylene).

Alternatively, the ring atoms may include one or more heteroatoms, as in "heteroarylene groups" (e.g., C _5-10 heteroarylene).

Examples of C _5-10 heteroarylene groups include, but are not limited to, those derived from the compounds discussed above in regard to heteroaryl groups.

A perfluoro arylene group is a perfluorinated bidentate arylene moiety, which moiety has from 5 to 14 ring atoms (unless otherwise specified). "Perfluorinated" in this context means completely fluorinated such that there are no carbon-bonded hydrogen atoms replaceable with fluorine. Examples include perfluorophenylene 33

(-C ₆ F ₄ -), perfluoronaphthylene (-Ci ₀ F ₆ -) and perfluorobiphenylene (-C ₆ F ₄ -C ₆ F ₄ -) groups. Typically, a perfluoroarylene group, as specified herein is a perfluorophenylene group (-C ₆ F ₄ -).

C _{1-20 ,} C _3-20 and C _3-I2 perfluoroalkyl groups as defined herein are either uninterrupted or interrupted by one or more, typically one, two or three, perfluoroarylene groups (typically perfluorophenylene groups). The phrase "optionally interrupted" as used herein may therefore refer to a perfluoroalkyl group, as defined above, which is uninterrupted or which is interrupted between adjacent carbon atoms by one or more, typically one, two or three, perfluoroarylene groups (typically perfluorophenylene groups). Unless otherwise specified, the perfluoroalkyl group is usually uninterrupted.

For instance, a Ci _-20 perfluoroalkyl group such as n-perfluorobutyl may be interrupted by one perfluoroarylene group, perfluorophenylene (-C ₆ F ₄ -), as follows: -CF ₂ (-C ₆ F ₄ -)CF ₂ CF ₂ CF _3i -CF ₂ CF ₂ (-C ₆ F ₄ -)CF ₂ CF ₃ , or -CF ₂ CF ₂ CF ₂ (-C ₆ F ₄ -)CF ₃ . As used herein the term oxo represents a group of formula: =O

As used herein the term acyl represents a group of formula: -C(=O)R, wherein R is an acyl substituent, for example, a substituted or unsubstituted Ci _-20 alkyl group, a substituted or unsubstituted C _3-20 heterocyclyl group, or a substituted or unsubstituted aryl group. Examples of acyl groups include, but are not limited to, -C(=O)CH ₃ (acetyl), -C(^O)CH ₂ CH ₃ (propionyl), -C(=O)C(CH ₃ ) ₃ (t-butyryl), and -C(=O)Ph (benzoyl, phenone).

As used herein the term acyloxy (or reverse ester) represents a group of formula: -OC(=O)R, wherein R is an acyloxy substituent, for example, substituted or unsubstituted Ci _-20 alkyl group, a substituted or unsubstituted C _3-2 oheterocyclyl group, or a substituted or unsubstituted aryl group, typically a Ci _-6 alkyl group.

Examples of acyloxy groups include, but are not limited to, -OC(=O)CH ₃ (acetoxy), -OQ=O)CH ₂ CH ₃ , -OC(=O)C(CH ₃ ) ₃ , -OC(=O)Ph, and -OC(=O)CH ₂ Ph.

As used herein the term ester (or carboxylate, carboxylic acid ester or oxycarbonyl) represents a group of formula: -C(=O)OR, wherein R is an ester substituent, for example, a substituted or unsubstituted Ci _-20 alkyl group, a substituted or unsubstituted C _3-20 heterocyclyl group, or a substituted or unsubstituted aryl group 34

(typically a phenyl group). Examples of ester groups include, but are not limited to, -C(O)OCH ₃ , -C(O)OCH ₂ CH ₃ , -C(O)0C(CH ₃ ) ₃ , and -C(O)OPh.

As used herein the term amino represents a group of formula -NH ₂ . The term Ci-C _1O alkylamino represents a group of formula -NHR' wherein R' is a C _1-10 alkyl group, preferably a C _1-6 alkyl group, as defined previously. The term di(Ci_

₁₀ )alkylamino represents a group of formula -NR 'R" wherein R' and R" are the same or different and represent C _MO alkyl groups, preferably C _1-6 alkyl groups, as defined previously. The term arylamino represents a group of formula -NHR' wherein R' is an aryl group, preferably a phenyl group, as defined previously. The term diarylamino represents a group of formula -NR 'R" wherein R' and R" are the same or different and represent aryl groups, preferably phenyl groups, as defined previously. The term arylalkylamino represents a group of formula -NR 'R" wherein R' is a Ci _-10 alkyl group, preferably a C _1-6 alkyl group, and R" is an aryl group, preferably a phenyl group. A halo group is chlorine, fluorine, bromine or iodine (a chloro group, a fluoro group, a bromo group or an iodo group). It is typically chlorine, fluorine or bromine. As used herein the term amido represents a group of formula: -C(O)NR R , wherein R and R are independently amino substituents, as defined for diCQ. io)alkylamino groups. Examples of amido groups include, but are not limited to, -CC=O)NH ₂ , -C(O)NHCH ₃ , -C(O)N(CH ₃ ) ₂ , -C(O)NHCH ₂ CH ₃ , and

-C(=O)N(CH ₂ CH ₃ ) ₂ , as well as amido groups in which R and R , together with the nitrogen atom to which they are attached, form a heterocyclic structure as in, for example, piperidinocarbonyl, morpholinocarbonyl, thiomorpholinocarbonyl, and piperazinocarbonyl. As used herein the term acylamido represents a group of formula:

-NR ¹ C(O)R ² , wherein R ¹ is an amide substituent, for example, hydrogen, a Ci _-20 alkyl group, a C _3-20 heterocyclyl group, an aryl group, preferably hydrogen or a Ci _-2O alkyl group, and R ² is an acyl substituent, for example, a Ci. ₂ o alkyl group, a C _3-2O heterocyclyl group, or an aryl group, preferably hydrogen or a Ci _-20 alkyl group. Examples of acylamide groups include, but are not limited to, -NHC(O)CH ₃ ,

-NHC(O)CH ₂ CH ₃ , -NHC(O)Ph, -NHC(O)Ci ₅ H _3I and -NHC(O)C ₉ H] ₉ . Thus, a substituted Ci _-20 alkyl group may comprise an acylamido substituent defined by the 35 formula -NHC(=O)-C _1-20 alkyl, such as -NHC(=O)Ci ₅ H ₃₁ or -NHC(O)C ₉ H ₁₉ . R ¹ and R ² may together form a cyclic structure, as in, for example, succinimidyl, maleimidyl, and phthalimidyl:

succinimidyl maleimidyl phthalimidyl A C _1-10 alkylthio group is a said C _1-10 alkyl group, preferably a C _1-6 alkyl group, attached to a thio group. An arylthio group is an aryl group, preferably a phenyl group, attached to a thio group.

A C _1-20 alkoxy group is a said substituted or unsubstituted C _1-20 alkyl group attached to an oxygen atom. A C _1-6 alkoxy group is a said substituted or unsubstituted C _1-6 alkyl group attached to an oxygen atom. A C _1-4 alkoxy group is a substituted or unsubstituted C _1-4 alkyl group attached to an oxygen atom. Said C _1-20 , C _1-6 and C _1-4 alkyl groups are optionally interrupted as defined herein. Examples of C _1-4 alkoxy groups include, -OMe (methoxy), -OEt (ethoxy), -O(nPr) (n-propoxy), -O(iPr) (isopropoxy), -O(nBu) (n-butoxy), -O(sBu) (sec-butoxy), -O(iBu) (isobutoxy), and -O(tBu) (tert-butoxy). Further examples of C _1-20 alkoxy groups are -O(Adamantyl), - O-CH ₂ -Adamantyl and -0-CH ₂ -CH ₂ - Adamantyl. An aryloxy group is a substituted or unsubstituted aryl group, as defined herein, attached to an oxygen atom. An example of an aryloxy group is -OPh (phenoxy).

Unless otherwise specified, included in the above are the well known ionic, salt, solvate, and protected forms of these substituents. For example, a reference to carboxylic acid or carboxyl group (-C00H) also includes the anionic (carboxylate) form (-COO ^" ), a salt or solvate thereof, as well as conventional protected forms. Similarly, a reference to an amino group includes the protonated form (-N ⁺ HR ¹ R ² ), a salt or solvate of the amino group, for example, a hydrochloride salt, as well as conventional protected forms of an amino group. Similarly, a reference to a hydroxyl group also includes the anionic form (-0 ^" ), a salt or solvate thereof, as well as conventional protected forms. 36

Certain compounds may exist in one or more particular geometric, optical, enantiomeric, diasteriomeric, epimeric, atropic, stereoisomeric, tautomeric, conformational, or anomeric forms, including but not limited to, cis- and trans-forms; E- and Z-forms; c-, t-, and r- forms; endo- and exo-forms; R-, S-, and meso-forms; D- and L-forms; d- and 1-forms; (+) and (-) forms; keto-, enol-, and enolate-forms; syn- and anti-forms; synclinal- and anticlinal-forms; α- and β-forms; axial and equatorial forms; boat-, chair-, twist-, envelope-, and halfchair-forms; and combinations thereof, hereinafter collectively referred to as "isomers" (or "isomeric forms"). Note that, except as discussed below for tautomeric forms, specifically excluded from the term "isomers," as used herein, are structural (or constitutional) isomers (i.e., isomers which differ in the connections between atoms rather than merely by the position of atoms in space). For example, a reference to a methoxy group, -OCH ₃ , is not to be construed as a reference to its structural isomer, a hydroxymethyl group, -CH ₂ OH. Similarly, a reference to ortho-chlorophenyl is not to be construed as a reference to its structural isomer, meta-chlorophenyl. However, a reference to a class of structures may well include structurally isomeric forms falling within that class (e.g., C^alkyl includes n-propyl and iso-propyl; butyl includes n-, iso-, sec-, and tert-butyl; methoxyphenyl includes ortho-, meta-, and para-methoxyphenyl).

The above exclusion does not pertain to tautomeric forms, for example, keto, enol, and enolate forms, as in, for example, the following tautomeric pairs: keto/enol (illustrated below), imine/enamine, amide/imino alcohol, amidine/arnidine, nitroso/oxime, thioketone/enethiol, N-nitroso/hyroxyazo, and nitro/aci-nitro. keto enol enolate

Note that specifically included in the term "isomer" are compounds with one or more isotopic substitutions. For example, H may be in any isotopic form, including ¹ H, ² H (D), and ³ H (T); C may be in any isotopic form, including ¹² C, ¹³ C, and ¹⁴ C; O may be in any isotopic form, including ¹⁶ O and ¹⁸ O; F may be in any isotopic form, including ¹⁹ F and ¹⁸ F, and the like. 37

Unless otherwise specified, a reference to a particular compound includes all such isomeric forms, including (wholly or partially) racemic and other mixtures thereof. Methods for the preparation (e.g., asymmetric synthesis) and separation (e.g., fractional crystallisation and chromatographic means) of such isomeric forms are either known in the art or are readily obtained by adapting known methods, in a known manner.

Unless otherwise specified, a reference to a particular compound also includes ionic, salt, solvated and protected forms.

The term "detectable label", as used herein, means any atom, group or moiety which is capable of detection such that an image of compound distribution can be obtained.

Thus, the detectable label may be any suitable imaging label. For instance, the detectable label may be a radionuclide, group which comprises a radionuclide, a MRI-imageable agent, a spin label, an optical label, an ultrasound-responsive agent, an X-ray responsive agent, a fluorophore or a luminescent dye. The detectable label should be directly suitable for imaging, without a further round of administration of a labelled antibody or the like being necessary.

Typically, the detectable label comprises a fluorine atom, a radionuclide, an optical label, an ultrasound-responsive agent, an X-ray responsive agent, a fluorophore or a luminescent moiety. More typically, the detectable label comprises a fluorine atom, a radionuclide, a fluorophore or a luminescent moiety. Even more typically, the detectable label comprises a fluorine atom or a radionuclide. Typically, in these embodiments, the radionuclide is selected from ³ H, ¹¹ C, ¹³ N, ¹⁵ O, ¹⁸ F, ⁵¹ Cr, ⁵² Fe, ^52m Mn, ⁵⁵ Co, ⁶⁰ Cu, ⁶¹ Cu, ⁶² Zn, ⁶² Cu, ⁶³ Zn, ⁶⁴ Cu, ⁶⁶ Ga, ⁶⁷ Ga, ⁶⁸ Ga, ⁷⁰ As, ⁷¹ As, ⁷² As, ⁷⁴ As, ⁷⁵ Se, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ^8Om Br, ^82m Br, ⁸² Rb, ⁸⁶ Y, ⁸⁸ Y, ⁸⁹ Sr, ⁸⁹ Zr, ⁹⁷ Ru, ^99m Tc, ¹¹⁰ In, ¹¹¹ In, ^113m In, ^114m In, ^117m Sn, ¹²⁰ 1, ¹²² Xe, ¹²³ 1, ¹²⁴ 1, ¹²⁵ 1, ¹³¹ 1, ¹⁶⁶ Ho, ¹⁶⁷ Tm, ¹⁶⁹ Yb, ^193m Pt, ^195m Pt, ²⁰¹ Tl and ²⁰³ Pb.

Typically, the detectable label is a radionuclide or a group which comprises a radionuclide. Suitable radionuclides include ³ H, ¹¹ C, ¹³ N, ¹⁵ O, ¹⁸ F, ⁵¹ Cr, ⁵² Fe, ^52m Mn, ⁵⁵ Co,

⁶⁰ Cu, ⁶¹ Cu, ⁶² Zn, ⁶² Cu, ⁶³ Zn, ⁶⁴ Cu, ⁶⁶ Ga, ⁶⁷ Ga, ⁶⁸ Ga, ⁷⁰ As, ⁷¹ As, ⁷² As, ⁷⁴ As, ⁷⁵ Se, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ^8Om Br, ^82m Br, ⁸² Rb, ⁸⁶ Y, ⁸⁸ Y, ⁸⁹ Sr, ⁸⁹ Zr, ⁹⁷ Ru, ^99m Tc, ¹¹⁰ In, ¹¹¹ In, ^113m In, 38 i i ₄ i " ¹ In, ^117m Sn, ¹²⁰ 1, ¹²² Xe, ¹²³ 1, ¹²⁴ 1, ¹²⁵ 1, ¹³¹ 1, ¹⁶⁶ Ho, ¹⁶⁷ Tm, ¹⁶⁹ Yb, ^193m Pt, ^195m Pt, ²⁰¹ Tl and ²⁰³ Pb.

In one embodiment, the radionuclide is ¹⁸ F, ¹¹ C, ¹³ N, ¹⁵ 0, ¹²³ I or ^99m Tc. In another embodiment, the radionuclide is ¹⁸ F, ¹¹ C, ¹³ N or ¹⁵ O. More typically, the radionuclide is ¹⁸ F.

In one embodiment the detectable label is small size PET or SPECT label, such as ¹⁸ F, ¹¹ C, ¹³ N, ¹⁵ O or ¹²³ I, more typically ¹⁸ F, ¹¹ C or ¹²³ I. Due to their small size, these PET and SPECT labels are ideally suited for monitoring intracellular events as they do not greatly affect the properties of the targeting device in general and its membrane transport in particular.

Typically, the detectable label is a fluorine atom, F. Thus, the detectable label may be fluorine, hi one embodiment, when the detectable label is fluorine, it is the fluorine radioisotope ¹⁸ F. ¹⁸ F-labelled compounds are useful as radiotracers in PET imaging. Alternatively, the detectable label is ¹⁹ F, i.e. "cold" fluorine. ¹⁹ F-containing compounds are useful in magnetic resonance imaging (MRI) applications. Thus, ¹⁹ F is a "detectable label" within the meaning of the term used herein. Compounds containing ¹⁹ F are also useful as cold "reference" products, e.g. for HPLC characterisation of a corresponding F-radiolabelled compound. Thus, the detectable label may be ¹⁸ F or ¹⁹ F. hi one embodiment, it is ¹⁸ F. In another embodiment, it is ¹⁹ F. hi one embodiment, X in the compound of formula (I) is a detectable label. When X in the compound of formula (I) is a detectable label, Y in the compound of formula (II) is a moiety to be labelled. hi another embodiment, X in the compound of formula (I) is a moiety to be labelled. When X is a moiety to be labelled, then Y in the compound of formula (II) is the detectable label.

This also applies to the compound of formula (IH). Thus, in one embodiment of the compound of formula (III), X is a detectable label and Y is a moiety to be labelled. More typically, X is a moiety to be labelled and Y is a detectable label. Accordingly, in one embodiment, when X is a detectable label, X is F.

Typically, in this embodiment, X is ¹⁸ F or ¹⁹ F. hi one embodiment, X is ¹⁹ F. hi another embodiment, X is F. 39

When Y is a detectable label, in one embodiment Y is F. Typically, in this embodiment, Y is ¹⁸ F or ¹⁹ F. hi one embodiment, Y is ¹⁹ F. hi another embodiment, Y is ¹⁸ F.

Typically, in the compound of formula (I), R ¹ and R ² are the same or different and are independently selected from hydrogen, unsubstituted or substituted C _1-6 alkyl and unsubstituted or substituted aryl. Typically the unsubstituted or substituted aryl is unsubstituted or substituted phenyl. More typically, R ¹ and R ² are independently selected from hydrogen, unsubstituted C _1-6 alkyl and unsubstituted phenyl. Typically, one of R ¹ and R ² is hydrogen. More typically, R ¹ and R ² are both hydrogen. hi the compound of formula (I), R ³ and R ⁴ , which are the same or different, are independently selected from unsubstituted or substituted aryl, unsubstituted or substituted Ci _-20 alkyl, unsubstituted or substituted C _3- I ₀ cycloalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted C _3-10 heterocyclyl, and a fluorous group as defined herein.

Thus, one or both or R ³ and R ⁴ may be a fluorous group. Generally, a fluorous group is a group which comprises a heavily fluorinated extension (a fluorous tag), which often comprises a perfluorinated alkyl chain and/or a perfluorinated aryl group. These tags allow the reactivity of the compound to mimic that of the analogous organic molecule, and yet be readily separable from one another, as well as other organic species. The use of such fluorous tags within organic chemistry can facilitate the separation of compounds with tags from those without, and separation between compounds with fluorous tags of different sizes. Fluorous molecules can be further classed as either being light fluorous or heavy fluorous. These refer to the proportion by weight of fluorine atoms within a molecule. Heavy fluorous molecules typically have at least 39 fluorine atoms, fluorine usually accounting for approximately 60% of the molecular weight. Light fluorous molecules on the other hand have a maximum of, say, 24, 26 or 28 fluorine atoms, hi light fluorous molecules, fluorine usually accounts for up to approximately 40% of the molecular weight. A heavy fluorous sugar and the light fluorous mappicine are shown below. 40

Heavy f luorous sugar MW=3838, %F= ₅ 8 Light fluorous mappicine MW=881, %F=37

In the present invention, when R ³ and/or R ⁴ is a fluorous group, the fluorous group is a group selected from:

(i) R _f ; (ii) -L ⁴ -C _1-2 o alkyl, which C _1-20 alkyl is substituted by one, two or three groups selected from R _f and -Z-R _f and is otherwise unsubstituted or substituted;

(iii) -L ⁵ -aryl, which aryl is substituted by one, two or three groups selected from R _f and -Z-R _f and is otherwise unsubstituted or substituted; and (iv) -L ⁶ -Si(-L ⁷ -R _f ) _n (R ¹⁸ ) _3-n , wherein:

R _f is a straight-chained or branched C _3-20 perfluoroalkyl group, a perfluoroaryl group, a straight-chained or branched C _1-20 perfluoroalkyl group substituted with one, two or three perfluoroaryl groups; or a perfluoroaryl group substituted with one, two or three straight-chained or branched C _1-20 perfluoroalkyl groups; provided that said straight-chained or branched C _1-20 and C _3-20 perfluoroalkyl groups are uninterrupted or interrupted by one, two or three perfluoroarylene groups;

L ⁴ and L ⁵ are independently selected from a single bond, -arylene-, -alk-, -alk-arylene-, -arylene-alk-, -alk-Z-, -arylene-Z-, -alk-arylene-Z, -alk-Z-arylene-, -alk-Z-arylene-Z-, -arylene-Z-alk-, -arylene-alk-Z- and -arylene-Z-alk-Z-, wherein alk is unsubstituted or substituted C _1-10 alkylene which is optionally interrupted by N(R"), O, S, C(O), C(O)N(R") or arylene, wherein R" is H, C _1-6 alkyl or aryl;

L ⁶ and L ⁷ are independently selected from a single bond, -arylene-, -alk-, -alk-arylene-, -arylene-alk-, -alk-Z-arylene- and -arylene-Z-alk-, wherein alk is unsubstituted or substituted C _1-I0 alkylene which is optionally interrupted by N(R"), O, S, C(O) ₅ C(O)N(R") or arylene, wherein R" is H, C _1-6 alkyl or aryl;

Z is N(R"), O, S, C(O) or C(O)N(R"), wherein R" is H, C _1-6 alkyl or aryl; 41

R ¹⁸ is hydrogen, unsubstituted or substituted aryl, or unsubstituted or substituted C _1-20 alkyl; and n is 1, 2 or 3.

Typically, when R ³ and/or R ⁴ in the compound of formula (I) is a fluorous group, as defined above, the compound of formula (I) is a light fluorous compound. Typically, therefore, the compound of formula (T) contains up to 28, more typically up to 26, or up to 24, fluorine atoms.

In one embodiment, the fluorine atoms present in the compound of formula (T) account for no more than 40% of the molecular weight of the compound of formula (I).

Alternatively, however, when R ³ and/or R ⁴ is a fluorous group, the compound of formula (I) may be a heavy fluorous compound. Thus, the compound of formula (I) may contain at least 39 fluorine atoms. In one embodiment, the fluorine atoms present in the compound of formula (T) account for at least 60% of the molecular weight.

The characteristics of compounds falling in these different classifications (light fluorous and heavy fluorous) lend themselves preferentially to one of two major purification techniques: fluorous solid phase extraction and fluorous liquid- liquid extraction. Fluorous Solid Phase Extraction (FSPE) and fluorous liquid-liquid extraction are well known in the art. Compounds featuring between 21 and 39 fluorine atoms may be applied to both of these techniques, however generally demonstrate less efficient purification. Liquid-Liquid Extraction is largely applied to heavy fluorous molecules and allows the separation of fluorous from organic compounds into two phases, or of fluorous from organic and inorganic compounds into three phases.

Fluorous Solid Phase Extraction (FSPE), on the other hand, uses light fluorous compounds, and involves loading a crude reaction mixture containing organic and light fluorous components onto a column of fluorous silica gel. Fluorous silica has a high affinity for fluorous material. The column is first eluted with a fluorophobic eluent to wash through the organic compounds and leave the fluorous components adsorbed. Further elution with a fluorophilic solvent will then remove the fluorous compounds. 42

A number of common organic solvents have differing levels of fluorophilic and fluorophobic character, and so the correct elution for specific separations can be determined through trial and error. It is the solubility of light fluorous compounds in these organic solvents with makes them applicable to FSPE (and subsequently makes heavy fluorous compounds inappropriate candidates).

FSPE is an easily implemented separation technique, which can be run by automated systems, and doesn't involve the use of fluorous solvents. Furthermore, reactions can be carried out in a homogeneous phase. This allows much more favourable reaction kinetics then solid phase synthesis techniques. Other well known fluorous separation techniques that can be employed include fluorous chromatography, fluorous biphasic catalysis, and also fluorous triphasic reactions.

Accordingly, when at least one of R ³ and R ⁴ in the compound of formula (I) is a fluorous group as defined above, the process of the present invention for producing the labelled compound of formula (UI) can take advantage of fluorous chemistry to purify the labelled compound, by separating it from the one or more unwanted fluorous compounds which comprise the perfluorinated group R _f .

Indeed, when at least one of R ³ and R ⁴ is a fluorous group, the fluorous compound of formula (I) is "detagged" in the process of the invention upon reaction with the compound of formula (IT), to produce a non-fluorous, labelled compound of formula (HT). Usually, therefore, the reaction mixture comprises (a) the non-fluorous (detagged) labelled product of formula (III) and (b) one or more fluorous by-products which comprise the perfluorinated group R _f . In particular, the reaction mixture usually includes the fluorous phosphine oxide by-product P(-O)(R ³ )(R ⁴ )-C(R ¹ )(R ² )SH (see Fig. Ib). Furthermore, labelling procedures, in particular radio labelling procedures such as F radiolabelling procedures, often use a large excess of the non-labelled starting material relative to the starting material containing the label. Typically, therefore, the reaction mixture also comprises an amount of unreacted fluorous starting material of formula (I) (which of course comprises the fluorous group R ³ and/or R ⁴ , including the perfluorinated Rf group). Accordingly, in order to purify and/or recover the fluorine-labelled compound of formula (III) in such cases, the compound must usually be separated from one or 43 more fluorous compounds which comprise the group R _f , including excess starting material as well as unwanted fluorous by-product. Fluorous separation techniques can advantageously be used here. In particular, fluorous purification techniques can be used to separate the compound of formula (IE) from the fluorous precursor compound of formula (I), the fluorous phosphine oxide by-product

P(=O)(R ³ )(R ⁴ )-C(R ¹ )(R ² )SH), and any other unwanted fluorous by-products or impurities in the reaction mixture.

Typically, therefore, when at least one of R ³ and R ⁴ in the compound of formula (I) is a fluorous group, as defined herein, the process of the invention for producing a labelled compound comprises: (b) separating the compound of formula (III) from one or more fluorous compounds which comprise R _f .

Typically, the one or more fluorous compounds which comprise R _f from which the compound of formula (111) is separated include unreacted compound of formula (I). Typically, said one or more residual fluorous compounds include one or more by-products which comprise the group R _f . More typically, the one or more residual fluorous compounds include one or more by-products which comprise the group R _f and unreacted compound of formula (I).

In one embodiment, at least one of R ³ and R ⁴ in the compound of formula (I) is a fluorous group as defined herein. Typically, both of R ³ and R ⁴ are fluorous groups as defined herein, in which case R ³ and R ⁴ may be the same type of fluorous group or different fluorous groups. Thus, in one embodiment, R ³ and R ⁴ are both fluorous groups and are the same or different. Usually, in this embodiment, R ³ and R ⁴ are the same fluorous group.

Alternatively, one of R ³ and R ⁴ may be a fluorous group, as defined herein, and the other of R ³ and R ⁴ is a non- fluorous group, hi that case, the other (non- fluorous) one of R ³ and R ⁴ may be selected from unsubstituted or substituted aryl, unsubstituted or substituted C _1-20 alkyl, unsubstituted or substituted C _3-10 cycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted C _3-10 heterocyclyl. A fluorous group is typically a group selected from: (i) R _f ; (ii) -L ⁴ -C _1-2 o alkyl, which C _1-20 alkyl is substituted by one, two or three groups selected from R _f and 44

-Z-R _f and is otherwise unsubstituted or substituted; (iii) -L ⁵ -aryl, which aryl is substituted by one, two or three groups selected from R _f and -Z-R _f and is otherwise unsubstituted or substituted; and (iv) -L ⁶ -Si(-L ⁷ -R _f ) _n (R ¹⁸ ) _3-n .

More typically, the or each fluorous group is a group selected from: (i) R _f ; (ii) -L ⁴ -Ci _-20 alkyl, which C _1-20 alkyl is substituted by one, two or three groups selected from R _f and -Z-R _f and is otherwise unsubstituted or substituted; and (iii) -iΛaryl, which aryl is substituted by one, two or three groups selected from R _f and -Z-R _f and is otherwise unsubstituted or substituted.

Usually, the or each fluorous group is a group selected from: (ii) -L ⁴ -C _1-20 alkyl, which C _1-20 alkyl is substituted by one, two or three groups selected from R _f and -Z-R _f and is otherwise unsubstituted or substituted; and (iii) -L ⁵ -aryl, which aryl is substituted by one, two or three groups selected from R _f and -Z-R _f and is otherwise unsubstituted or substituted.

Even more typically, the or each fluorous group is a group selected from: (ii) -L ⁴ -C _1-6 alkyl, which C _1-6 alkyl is substituted by one group R _f and is otherwise unsubstituted; and (iii) -iΛaryl, which aryl is substituted by one group R _f and is otherwise unsubstituted.

Typically, in the fluorous groups defined herein, R _f is a straight-chained or branched C _3-20 perfluoroalkyl group which is unsubstituted, or a straight-chained or branched C _1-20 perfluoroalkyl group substituted with one, two or three perfluoroaryl groups, provided that said straight-chained or branched C _1-20 and C _3-20 perfluoroalkyl groups are uninterrupted or interrupted by one, two or three perfluoroarylene groups. Typically, they are uninterrupted.

More typically, in the fluorous groups defined herein, R _f is a straight-chained or branched C _3-20 perfluoroalkyl group.

Even more typically, in the fluorous groups defined herein, R _f is a straight- chained or branched C _3-12 perfluoroalkyl group. hi a preferred embodiment, R _f in the fluorous groups defined herein is a straight-chained or branched C _3-10 perfluoroalkyl group, or more preferably a straight-chained or branched C _3-8 perfluoroalkyl group, hi one embodiment, R _f is a straight-chained or branched C _3-6 perfluoroalkyl group. Thus, R _f may for instance be 45 perfluoropropyl (-C ₃ F ₇ ), perfluorobutyl (-C ₄ Fg), perfluoropentyl (-CsF ₁₁ ) or perfluorohexyl (-C ₆ F ₁₃ ).

Alternatively, however, R _f in the fluorous groups defined herein may be a perfluoroaryl group which is unsubstituted, or a perfluoroaryl group which is substituted with one, two or three straight-chained or branched Cj _-20 perfluoroalkyl groups. Said straight-chained or branched Ci _-20 perfluoroalkyl groups are uninterrupted or interrupted by one, two or three perfluoroarylene groups (for instance perfluorophenylene groups), but are typically uninterrupted. Typically, in this embodiment, R _f is a perfluorophenyl group which is unsubstituted, or a perfluorophenyl group which is substituted with one, two or three straight-chained or branched C _1-20 perfluoroalkyl groups.

Typically, in the fluorous groups defined herein L ⁴ is -arylene-. Typically the arylene group L ⁴ is unsubstituted. More typically in the fluorous groups defined herein L ⁴ is phenylene, typically unsubstituted phenylene. L ⁵ , in the fluorous groups defined herein, is usually a single bond, -arylene- or -alk-. Usually, alk is unsubstituted C _1-10 alkylene. Usually, arylene is unsubstituted phenylene.

L ⁶ , in the fluorous groups defined herein, is usually -arylene-, -alk-, -alk-arylene- or -arylene-alk-. Typically, alk is unsubstituted Ci _-I0 alkylene, or for instance unsubstituted Ci _-6 alkylene. Usually, arylene is unsubstituted phenylene. In one embodiment L ⁶ is -alk-arylene- wherein alk is unsubstituted Ci _-4 alkylene and arylene is unsubstituted phenylene.

L ⁷ is usually -alk-. Typically, alk is unsubstituted Ci _-I0 alkylene, or for instance unsubstituted Ci _-6 alkylene or unsubstituted Ci _-4 alkylene. Usually, n is 3 and R ¹⁸ is not therefore present.

However, when R ¹⁸ is present, it is typically hydrogen, unsubstituted phenyl, or unsubstituted C _1-6 alkyl.

In one embodiment, the or each fluorous group is R _f , wherein R _f is as defined herein. hi another embodiment, the or each fluorous group is -iΛaryl, which aryl is substituted by one, two or three groups selected from R _f and -Z-R _f and is otherwise unsubstituted or substituted. Typically, in this embodiment, said aryl is substituted by 46 only one group R _f and is otherwise unsubstituted. L ⁵ is typically a single bond, - arylene- or -alk-. Usually, alk is unsubstituted C _1-10 alkylene. Usually, arylene is unsubstituted phenylene.

In another embodiment, the or each fluorous group is -L ⁶ -Si(-L ⁷ -R _f ) _n (R ¹⁸ ) _3-n . L ⁶ is usually -arylene-, -alk-, -alk-arylene- or -arylene-alk-. Typically, alk is unsubstituted C _1-10 alkylene, or for instance unsubstituted C _1-6 alkylene. Usually, arylene is unsubstituted phenylene. In one embodiment L ⁶ is -alk-arylene- wherein alk is unsubstituted C _1-4 alkylene and arylene is unsubstituted phenylene. L ⁷ is usually -alk-. Typically, alk is unsubstituted C _1-10 alkylene, or for instance unsubstituted C _1-6 alkylene or unsubstituted C _1-4 alkylene. Usually, n is 3 and R ¹⁸ is not therefore present.

In a preferred embodiment, the or each fluorous group is -L ⁴ -C _1-20 alkyl, which C _1-2O alkyl is substituted by one, two or three groups selected from R _f and -Z-R _f and is otherwise unsubstituted or substituted. Usually, in this embodiment, said C _1-20 alkyl is substituted by only one group R _f and is otherwise unsubstituted. Typically, L ⁴ is arylene. Typically the arylene group L ⁴ is unsubstituted. More typically, L ⁴ is phenylene, usually unsubstituted phenylene. Typically, both of R ³ and R ⁴ are fluorous groups of this kind.

Thus, usually, the or each fluorous group is -phenylene-C _1-20 alkyl, which C _{1- 20} alkyl is substituted by one group R _f and is otherwise unsubstituted. More typically, the or each fluorous group is -phenylene-C _1-6 alkyl, which C _1-6 alkyl is substituted by one group R _f and is otherwise unsubstituted. Even more typically, the or each fluorous group is -phenylene-C _1-6 alkylene-R _f , which C _1-6 alkylene is unsubstituted. R _f in these embodiments is as defined herein but is usually a straight-chained or branched C _3-12 perfluoroalkyl group, or more preferably a straight-chained or branched C _3-8 perfluoroalkyl group, or a straight-chained or branched C _3-6 perfluoroalkyl group. Thus, R _f may for instance be perfluoropropyl (-C ₃ F ₇ ), perfluorobutyl (-C ₄ Fg), perfluoropentyl (-C ₅ F ₁₁ ) or perfluorohexyl (-C ₆ F ₁₃ ). hi one embodiment, the or each fluorous group is:

47 Typically, both R ³ and R ⁴ are fluorous groups of the above formula.

Typically, the or each fluorous group is a group of formula -L -R _f , wherein L is a single bond, -alk-, -arylene-, -alk-arylene-, alk-Z-, -arylene-Z-, -alk-arylene-Z, -alk-Z-arylene-, -alk-Z-arylene-Z-, -arylene-alk-, -arylene-Z-alk-, -arylene-alk-Z- or -arylene-Z-alk-Z-, wherein Z is N(R"), O, S, C(O) or C(O)N(R") and wherein alk is unsubstituted or substituted C _1-10 alkylene which is optionally interrupted by N(R"), O, S, C(O), C(O)N(R") or arylene, wherein R" is H, Ci _-6 alkyl or aryl; and R _f is a straight-chained or branched C _3-12 perfluoroalkyl group. Usually, L is -phenylene-C^o alkylene- which C _1-20 alkylene is unsubstituted. Thus, usually, -L ⁸ -R _f is -phenylene-C _]-20 alkylene-R _f which Ci _-20 alkylene is unsubstituted. More typically L ⁸ is -phenylene-C _1-6 alkylene- which Ci _-6 alkylene is unsubstituted. R _f is usually a straight-chained or branched C _4- io perfluoroalkyl group, or more preferably a straight-chained or branched C _4-8 perfluoroalkyl group, or a straight-chained or branched C _4-6 perfluoroalkyl group. Typically, both R ³ and R ⁴ are fluorous groups of formula -L -R _f as defined herein.

In one preferred embodiment, the or each fluorous group is a group of formula -phenylene-alk-R _f , wherein alk is C _1-6 alkylene and R _f is a straight-chained or branched C _3-I2 perfluoroalkyl group. R _f may for instance be a straight-chained or branched C _4-I0 perfluoroalkyl group, or more preferably a straight-chained or branched C _4-8 perfluoroalkyl group, or a straight-chained or branched C _4-6 perfluoroalkyl group.

In other embodiments of the invention, R ³ and R ⁴ are not fluorous groups. Thus, in other embodiments, R ³ and R ⁴ , which are the same or different, are independently selected from unsubstituted or substituted aryl, unsubstituted or substituted Ci _-20 alkyl, unsubstituted or substituted C _3-1O cycloalkyl, unsubstituted or substituted heteroaryl, and unsubstituted or substituted C _3-1O heterocyclyl. Typically, in this embodiment, R ³ and R ⁴ , are the same or different and are independently selected from unsubstituted or substituted Ci _-6 alkyl and unsubstituted or substituted aryl. More typically, R ³ and R ⁴ are independently selected from unsubstituted or substituted aryl. Even more typically, R ³ and R ⁴ are independently selected from unsubstituted or substituted phenyl groups. In one embodiment, R ³ and R ⁴ are both unsubstituted phenyl. 48

Typically, in the compound of formula (H) and in the compound of formula (III), L is a linking group, hi another embodiment, however, L is a bond. When L is a bond, L is typically a single bond.

When L is a linking group, L may be any suitable linking group. L may for instance be an unsubstituted or substituted arylene group, an unsubstituted or substituted heteroarylene group, or an unsubstituted or substituted C _1-20 alkylene group, which C _1-20 alkylene group is optionally interrupted by N(R"), O, S, C(O), C(O)N(R") or arylene, wherein R" is C _1-6 alkyl or aryl. Alternatively, L may be an oligomeric or polymeric linking group, or a macromolecular linking group. Thus, for instance, L may comprise a poly(alkylene glycol), for instance poly(ethylene glycol), a conjugated organic polymer or copolymer, or, for instance, a peptide chain. Typically, L is an unsubstituted or substituted C _1-20 alkylene group, which C _1-20 alkylene group is optionally interrupted by N(R"), O, S, C(O), C(O)N(R") or arylene. More typically, L is an unsubstituted or substituted C _2-20 alkylene group, which C _2-20 alkylene group is optionally interrupted by N(R"), O, S, C(O), C(O)N(R") or arylene, wherein R" is C _1-6 alkyl or aryl. More typically, L is an unsubstituted C _1-20 alkylene group, or an unsubstituted Ci _-10 alkylene group, even more typically an unsubstituted C _2-20 alkylene group, for instance an unsubstituted C _2-10 alkylene group, an unsubstituted C _2-6 alkylene group, or an unsubstituted C _2-4 alkylene group. In one embodiment, L is an ethylene group (-CH ₂ -CH ₂ -).

Thus, in one embodiment, the compound of formula (IT) is:

N ₃ "

The F atom may be ¹⁸ F or ¹⁹ F. Thus, in one embodiment, the compound of formula (II) is:

N ₃ ^ ^

Typically, the moiety to be labelled comprises a tracer moiety. The term "tracer moiety", as used herein, means a moiety which has an affinity for a biological target or any moiety which, when labelled, enables the imaging and quantification of a biochemical process or of a specific low density protein target in vivo. 49

The tracer moiety may be present in a protected form when the process of the invention for producing the labelled compound of formula (IH) is carried out, so that the tracer moiety itself is unaffected by the reaction. The protected tracer moiety can then be deprotected after production of the labelled compound of formula (IS). For instance, the tracer moiety may comprise an amino acid, oligopeptide or polypeptide, whose terminal amino or terminal carboxyl group is protected. Suitable amino protecting groups are well known to the skilled person, and include, but are not limited to, t-Butyl carbamate (Boc), 9-fluorenyhnethyl carbamate (Fmoc), benzyl carbamate, acyl groups, trityl, tosyl and benzyl. Typically, the amino protecting group is t-Butyl carbamate (Boc) or acyl. Other amino protecting groups include alkyl and aryl groups. Suitable reaction conditions for deprotection are well known to the skilled person, and include nucleophilic substitution and and catalytic hydrogenation. Suitable carboxyl (COOH) protecting groups are also well known to the skilled person, and include, but are not limited to, unsubstituted or substituted C _{1- 6} alkyl (for instance methyl and ethyl) and alkaryl (for instance benzyl); these protecting groups form simple esters to protect the carboxyl group. Suitable reaction conditions for deprotection are well known to the skilled person, and include ester hydrolysis (saponification) and catalytic hydrogenation. Alternatively, the tracer moiety may comprise a hydroxyl group which is protected. Suitable hydroxyl (OH) protecting groups are well known to the skilled person, and include, but are not limited to, acyl groups (for instance, acetyl, benzoyl) and substituted or unsubstituted alkyl, alkenyl or alkaryl groups, for instance methoxymethyl (MOM), tetrahydropyranyl (THP), tert-butyl, benzyl, allyl, and tert-butyldimethylsilyl (TBDMS). Suitable reaction conditions for deprotection are well known to the skilled person, and include hydrogenolysis and acid hydrolysis. hi one embodiment, the tracer moiety comprises an amino acid, a dipeptide, an oligopeptide, a polypeptide, a protein, a sugar, a lipid, a fatty acid, a nucleo base, a nucleoside, a nucleotide, a nucleic acid, or a pharmaceutically active compound. Such molecules are typically involved in metabolic pathways, thus are suitable as tracer moieties. For the avoidance of doubt, a "nucleo base" as defined herein, is a nitrogenous base in DNA or RNA that is invoved in pairing. Examples of nucleo bases include adenine, thymine, guanine, cytosine and uracil. 50

A wide variety of different tracer molecules and biological ligands can be incorporated into the compounds of formula (I) and (II). Such compounds can be incorporated into the phosphinothioester compounds of formula (T), for instance, by reaction of a carboxylic acid functionality of a tracer moiety with a phosphinothiol compound of formula (V) as defined herein (thereby coupling the tracer moiety to the phosphinothiol compound to form a compound of formula (I) containing the tracer as group X). Thus, peptide- and protein-based tracer moieties can easily be incorporated into compounds of formula (I) by coupling the carboxyl-terminus of the peptide with a phosphinothiol compound of formula (V). Tracer molecules which do not contain a carboxylic acid functionality, on the other hand, such as sugars or, for example, estradiol, may first be derivatised with an appropriate reactive functionality, if necessary via a suitable linker, which functionality is itself capable of reaction with the thiol moiety of a phosphinothiol. The reactive functionality is typically a carboxylic acid group. The derivatised tracer moiety can then be coupled to the phosphinothiol compound to form a compound of formula (I) containing the tracer. Likewise, compounds of formula (IT), wherein Y comprises a tracer moiety, can be produced by attaching an azide group to the tracer molecule, if necessary via a linker L, using appropriate coupling chemistry.

In one embodiment, the tracer moiety comprises a ligand capable of binding to a biological target. Typically, the biological target is a cell surface molecule, a structural protein, an intracellular target, a pathogen or a receptor. For instance, the biological target may be a cell surface receptor, a cell surface glycoprotein, Golgi bodies, mitochondria, RNA, DNA, an enzyme, a component of a cell signalling pathway, a virus, a bacterium, a fungus, a compound or protein whose presence or expression level is upregulated or downregulated in a certain disorder, or a metabolic pathway which is upregulated or downregulated during a disease.

Typically, the biological target is a tumour receptor. The tumour receptor may for instance be an estrogen receptor (ER), an androgen receptor (AR), a progesterone receptor (PR), a Sigma-2 receptor, an epidermal growth factor receptor (EGFR), a steroid receptor, a somatostatin receptor (SSTR), an integrin receptor, a bombesin receptor or HER2. Ligands capable of binding to these receptors are discussed in J. Nuc. Med., Vol. 49, No. 6 (Suppl), June 2008, 149S-163S. 51

PET imaging also has major application in neuroscience and cardiology. Accordingly, in another embodiment, the biological target is a neurological target or a target relevant to cardiology. Thus, the tracer moiety may comprise a cardiac imaging agent or an agent which binds to a neurological target. Cardiac imaging agents and agents which bind to neurological targets are well known in the art.

In one embodiment, the tracer moiety comprises a ligand capable of binding to a tumour receptor. The ligand may be a small molecule ligand, a peptide ligand, an antibody or a fragment. When the ligand is an antibody, it is typically a monoclonal antibody. Ligands capable of binding to a tumour receptor include bombesin, octreotide, lanreotide, pentetriotide, somatostatin, a somatostatin analogue, estradiol, trastuzumab, cetuximab, testosterone, a peptide secreted by an endocrine cell, tamoxifen, flutamide, an antioestrogen, an antiandrogen, a steroid, a progestin, an androgen, fulvestrant, metaiodobenzylguanidine, 3,4-dihydroxyphenylalanine, erlatinib, epidermal growth factor and transforming growth factor. These ligands are described in J. Nuc. Med., Vol. 49, No. 6 (Suppl), June 2008, 149S-163S. The tracer moiety to be labelled in accordance with the present invention may be selected from any of these ligands.

Optionally the tracer moiety which is to be labeled in accordance with the present invention is already labelled with an imaging label, for instance a radionuclide. Typically this label is different from the label that is introduced in the process of the present invention. If, in this situation, the traceless Staudinger ligation is performed in vivo, i.e. by first administering the compound of formula (I) or (II) which comprises the already- labeled tracer moiety and then, in a second step, administering the other compound of formula (I) or (IT) which comprises the detectable label to be added, administration of the tracer moiety in the first step gives rise to a first image, which is subsequently overlaid with a second image when the second step is performed. This combination of two imaging labels, one being present in the tracer moiety and the other in the labelling that is administered thereafter, can advantageously provide better target localization, artefact elimination, and delineation of non relevant clearance and other pharmacokinetic pathways. 52

Accordingly, in one embodiment, the tracer moiety comprises any one of the following tumour receptor imaging agents, which are already labelled: ¹⁸ F-FDHT, 1 l-β-methoxy-17-α- ¹²³ I-iodovinylestradiol, ¹⁸ F-FES, 21- ¹⁸ F-fluoro-16-α-ethyl-19- norprogesterone, N-(4-(6,7-dimethoxy-3,4-dihydroisoquinolin-2- ¹ H-yl-)butyl), 2-(2- ¹⁸ F-fluoroethoxy)-5-methylbenzamide, ¹¹ C-gefitinib, ¹¹ ^-octreatide, ⁶⁸ Ga-DOT A- octreotide, ⁶⁴ Cu-TETA-octreotide, ¹¹¹ In-DTPA-EGF, ⁶⁸ Ga-DOTA-EGF, Cy5.5-EGF, ¹⁸ F-galacto-RGD, RGD-USPIO, RGD-Cy5.5, [ ^{n 1} In-DTP A-Prol,Tyr4]bombesin, ⁶⁴ Cu-DOTA-[Lys3]bombesin, Bombesin-CLIO (Cy5.5), ⁶⁸ Ga-DOTA-F(ab') ₂ - trastuzumab, ^{n 1} Ui-DTP A-trastuzumab, Polylactic acid nanoparticle-trastuzumab, RhodG- trastuzumab, (Avidin-Gd)-biotinylated anti-HER2/neu monoclonal antibody, ^Cu-DOTA-cetuximab, Cy5.5-cetuximab. These tumour receptor imaging agents are described in J. Nuc. Med., Vol. 49, No. 6 (Suppl), June 2008, 149S-163S.

Other tracers which are already labelled include tracer moieties which comprise a metal complex wherein the metal is a metal radionuclide. In one embodiment, the moiety to be labelled in the compound of formula (I) or (II) in accordance with the present invention is a moiety which comprises a metal complex, [M], which metal complex [M] comprises a metal, M, and one or more ligands.

In one embodiment, the metal complex comprises a ligand selected from a bis(semithiocarbazone), diethylenetriaminepentaacetic acid (DTPA) or 1,4,7,10- tetraazacyclododecane-iV//',N"JV'"-tetraacetic acid (DOTA) ligand.

In one embodiment, the moiety which comprises a metal complex, [M], comprises a chelating ligand which (a) chelates a metal and (b) is linked to a peptide. Typically, the metal is a radiometal, for instance ^99m Tc, ¹¹¹ In, ⁶⁸ Ga or ⁶⁴ Cu. Typically, the chelating ligand is selected from a bis(semithiocarbazone), diethylenetriaminepentaacetic acid (DTPA) or 1, 4,7,10-tetraazacyclododecane- NJV',N",N'"-tetτaa.ce.ύc acid (DOTA). The peptide to which the chelating ligand is linked may comprise bombesin, somatostatin, or a somatostatin analogue. Somatostatin analogues include, but are not limited to octreotide, lanreotide, pentetriotide.

In one embodiment, the tracer moiety is a group of formula (VIII) 53

[M]—[L ³ ] _m ^^ (VUI) wherein [M] is a metal complex comprising a metal M and one or more ligands; m is 0 or 1 ; and L ² and L ³ , which are the same or different, are independently selected from unsubstituted or substituted C _1-20 alkylene and unsubstituted or substituted arylene, which C _1-20 alkylene is optionally interrupted by N(R"), O, S, C(O), C(O)N(R") or arylene wherein R" is Ci _-6 alkyl or aryl. More typically, L ² and L ³ , which are the same or different, are independently selected from unsubstituted or substituted Ci _-I0 alkylene and unsubstituted or substituted arylene. Typically, Y is said detectable label and X is the tracer moiety. Typically, L ² is unsubstituted or substituted arylene and therefore the tracer moiety is a group of formula (Villa)

wherein A is arylene, and m, L ³ and [M] are as defined above.

More typically, L ² is unsubstituted phenylene and therefore the tracer moiety is a group of formula (VIIIb)

wherein m, L ³ and [M] are as defined above. Typically, m is O.

Typically, [M] is a bis(semithiocarbazone) complex of formula (IX)

wherein

M is a metal atom; 54

R ¹⁴ and R ¹⁵ , which are the same or different, are independently selected from hydrogen, unsubstituted or substituted C _1-10 alkyl, unsubstituted or substituted aryl, unsubstituted or substituted C _3-10 cycloalkyl, unsubstituted or substituted C _3-10 heterocyclyl, and unsubstituted or substituted heteroaryl; and R ¹ \ R ¹² and R ¹³ , which are the same or different, are independently selected from hydrogen, unsubstituted or substituted C _1-10 alkyl, unsubstituted or substituted aryl, unsubstituted or substituted C _3-10 cycloalkyl, unsubstituted or substituted C _3-J0 heterocyclyl, unsubstituted or substituted heteroaryl, and amino, provided that R ¹¹ , R ¹² and the nitrogen atom to which R ¹¹ and R ¹² are both bonded may together form an unsubstituted or substituted C _5-10 heterocyclyl group.

Typically, R ¹⁴ and R ¹⁵ are the same or different and are independently selected from hydrogen and unsubstituted or substituted C _1-10 alkyl. More typically, R ¹⁴ and R ¹⁵ are the same or different and are independently selected from hydrogen and unsubstituted Ci _-6 alkyl. hi one embodiment, one of R ¹⁴ and R ¹⁵ is H and the other is unsubstituted C _1-6 alkyl. In another embodiment, R ¹⁴ and R ¹⁵ are the same and are both an unsubstituted Ci _-6 alkyl group; for instance, R ¹⁴ and R ¹⁵ may both be methyl groups, hi another embodiment, R ¹⁴ and R ¹⁵ are both hydrogen. Typically, R ^u , R ¹² and R ¹³ , which are the same or different, are independently selected from hydrogen and unsubstituted or substituted C _1-10 alkyl. More typically R ¹¹ , R ¹² and R ¹³ are independently selected from hydrogen and unsubstituted C _1-6 alkyl. Even more typically, R ¹¹ , R ¹² and R ¹³ are independently selected from hydrogen and methyl. In one embodiment, R ¹ ' and R ¹³ are both hydrogen and R ¹² is a methyl group.

Typically, M is selected from Zn, Cu, Ga, In or Tc. In one embodiment, M is a metal radionuclide. Thus, for instance, M may be selected from ⁶⁴ Cu, ^99m Tc, ¹¹¹ In and ⁶⁸ Ga.

Typically, the step of treating the compound of formula (I) with the compound of formula (II) is performed in the presence of a solvent. Any suitable solvent may be used. Typically, the solvent comprises a mixture of water and a polar organic solvent. The polar organic solvent may for instance comprise tetrahydrofuran (THF), dimethylformamide (DMF) or acetronitrile (MeCN). 55

Typically, the step of treating the compound of formula (I) with the compound of formula (II) is performed in the presence of heat. Typically, the reaction is heated to a temperature of from 40°C to 100°C, more typically at a temperature of from 60°C to 100 ⁰ C, for instance at about 8O ⁰ C. Typically, the reaction is heated at this temperature for up to 1 hour, more typically for up to about half an hour, for instance from 10 to 40 minutes.

Typically, the process of the invention for producing the labelled compound of formula (III) further comprises the step of (b) recovering the compound of formula (UI). The compound of formula (HI) may be recovered by any suitable method, and may be recovered as a neat solid or liquid, as an oil, or as a solution (typically a pure solution) of the compound.

Step (b) is typically performed by chromatography.

For instance, when the detectable label is not a radionuclide (e.g. when it is "cold" fluorine) and therefore the compound can be prepared in bulk, step (b) typically comprises concentrating the reaction mixture followed by purification by chromatography. Flash chromatography may be used, e.g. flash chromatography in silica gel. When the detectable label is a radionuclide (for instance ¹⁸ F) step (b) may comprise a chromatography step (HPLC, for instance) to produce a solution of the radiolabeled compound. As mentioned above, when at least one of R ³ and R ⁴ in the compound of formula (I) is a fluorous group as defined above, the process of the present invention for producing the labelled compound of formula (IH) can take advantage of fluorous chemistry to purify the labelled compound, by separating it from the one or more unwanted fluorous compounds (starting material, by-products and/or impurities) which comprise the perfluorinated group R _f .

Typically, therefore, when at least one of R ³ and R ⁴ in the compound of formula (I) is a fluorous group as defined herein, the process of the invention for producing a fluorine-labelled compound comprises: (b) separating the compound of formula (III) from one or more fluorous compounds which comprise R _f . Typically, said one or more fluorous compounds which comprise R _f comprise unreacted compound of formula (I). Usually, the one or more fluorous compounds which comprise R _f include one or more by-products which comprise the group R _f . More 56 typically, the one or more fluorous compounds which comprise R _f include one or more by-products which comprise the group R _f and unreacted compound of formula (T). Usually, the one or more fluorous compounds include the by-product

Typically, when at least one of R ³ and R ⁴ in the compound of formula (T) is a fluorous group as defined herein, step (b) of the process of the invention for producing a labelled compound comprises separating the compound of formula (TTT) from said one or more fluorous compounds comprising R _f by Fluorous Solid Phase Extraction (FSPE). Typically, in this embodiment, the compound of formula (T) is a light fluorous compound. Typically, therefore, the compound of formula (T) contains up to 28, more typically up to 26, or up to 24, fluorine atoms. FSPE has the advantage of being a quick and effective purification process; this is especially important when using radioisotopes in PET chemistry, which is strongly influenced by the time constraints involved when using short half life positron emitters such as ¹⁸ F.

Typically, therefore, step (b) of the process of the invention for producing a labelled compound comprises:

(i) loading the reaction mixture onto a fluorous solid phase, and (ii) selectively eluting the compound of formula (EI) from said fluorous solid phase, such that said one or more fluorous compounds comprising R _f are retained on the solid phase. Typically, the fluorous solid phase is fluorous silica. Typically, step (ii) comprises eluting the compound of formula (DI) from said fluorous solid phase using a suitably fluorophobic eluent. hi one embodiment, the fluorophobic eluent is a mixture OfH ₂ O and another, less polar solvent, for instance MeCN, acetone, toluene or THF. Usually, the fluorophobic eluent is a mixture of H ₂ O and MeCN.

Usually, step (b) comprises a further step of (iii) washing the fluorous solid phase with the fluorophobic eluent. Optionally, after eluting the compound of formula (III), the fluorous compounds comprising R _f are then removed from the solid phase by further elution with a fluorophilic eluent. The fluorophilic eluent is typically neat MeCN. 57

Typically, the process further comprises recovering said compound of formula (III). The compound of formula (III) may be recovered as a solid or as a solution (typically a pure solution) of the compound.

In one embodiment, step (b) of the process of the invention for producing a labelled compound comprises:

(i) loading the reaction mixture onto a fluorous solid phase, and (ii) selectively eluting the compound of formula (HI) from said fluorous solid phase, using a suitably fluorophobic eluent, such that said one or more fluorous compounds comprising Rf are retained on the solid phase, and

(iii) recovering the compound of formula (IH) as a solution of said compound in said fluorophobic eluent.

In another embodiment, when at least one of R ³ and R ⁴ in the compound of formula (I) is a fluorous group as defined herein, step (b) of the process of the invention for producing a labelled compound comprises separating the compound of formula (HI) from said one or more fluorous compounds comprising R _f by Fluorous Liquid-Liquid Extraction. Typically, in this embodiment, the compound of formula (I) is a heavy fluorous compound. Thus, typically, the compound of formula (I) contains at least 39 fluorine atoms. hi yet another embodiment, when at least one of R ³ and R ⁴ in the compound of formula (I) is a fluorous group as defined herein, step (b) of the process of the invention for producing a labelled compound comprises separating the compound of formula (IH) from said one or more fluorous compounds comprising R _f by chromatography, for instance by HPLC. Again, when the detectable label is not a radionuclide (e.g. when it is "cold" fluorine) and therefore the compound can be prepared in bulk, step (b) can comprise concentrating the reaction mixture followed by purification by chromatography. Flash chromatography may be used, e.g. flash chromatography in silica gel. When the detectable label is a radionuclide (for instance ¹⁸ F) step (b) may comprise a chromatography step (HPLC, for instance) to produce a solution of the radiolabeled compound.

The moiety to be labelled, which may be X or Y but is typically X, may be modified after the compound of formula (IH) has been produced. Thus, in one 58 embodiment, the moiety to be labelled is a further-reactable moiety, which further- reactable moiety comprises a functional group suitable for attaching the compound of formula (EI) to a tracer moiety. In this embodiment, the process of the invention for producing a labelled compound may further comprise: attaching the compound of formula (EI) thus produced to a tracer moiety, thereby producing a further compound of formula (IE) which comprises a tracer moiety. The tracer moiety may be any of those defined hereinbefore.

The functional group of the further-reactable moiety may be any functional group suitable for coupling a tracer moiety to the compound of formula (IE). It may for instance be an aldehyde group, a carboxyl group, an amino group, a hydroxyl group, an azide group, an alkyne group, a protected carboxyl group, a protected amino group, or a protected hydroxyl group. As is well known to the skilled person, aldehyde, carboxyl, amino, hydroxyl, azide and alkyne groups are capable of performing coupling reactions with complementary functional groups, and can thereby be used to attach a tracer moiety. For instance, carboxyl and amino groups can react together in a condensation reaction to form a peptide bond to attach the tracer moiety; an aldehyde and an amino group can react together in an imine condensation; and an azide and an alkyne can react in a click reaction. Coupling reactions of this sort can be used to attach a wide variety of tracer moieties, including for instance amino acids, peptides and proteins. Protected carboxyl, amino group, and hydroxyl groups are well known to the skilled person and examples of such groups are given hereinbefore. As the skilled person would understand, the protected carboxyl, amino or hydroxyl group would first be deprotected (to form the corresponding carboxyl, amino or hydroxyl group respectively) and the tracer moiety would then be attached to the compound of formula (ET), in an appropriate coupling reaction, to form the further compound of formula (EI) which comprises the tracer moiety.

In one embodiment, the further-reactable moiety is a group of formula (XE)

(XE) 59 wherein L ² is an unsubstituted or substituted C _1-20 alkylene group or an unsubstituted or substituted arylene group, which Ci _-20 alkylene is optionally interrupted by N(R"), O, S, C(O), C(O)N(R") or arylene wherein R" is C _1-6 alkyl or aryl. More typically, L ² is an unsubstituted or substituted arylene group for instance an unsubstituted or substituted phenylene group, more typically an unsubstituted phenylene group. Typically, in this embodiment, Y is said detectable label and X is the further- reactable moiety.

Thus, the process may further comprise: condensing the compound of formula (ITT) with a compound of formula R ¹⁷ -NH ₂ , wherein R ¹⁷ is a tracer moiety as defined hereinbefore, thereby producing, by imine condensation, a further compound of formula (IQ) in which X is a group of formula (XIII)

^< * (XIII).

R ¹⁷ may for instance be a group of formula (DC) as defined herein.

Such an imine condensation is typically performed in the presence of a solvent. Any suitable solvent may be used. Typically, the reaction is heated to the reflex temperature of the solvent.

In another embodiment, the further-reactable moiety may be a group of formula (X)

wherein

R ⁵ is selected from hydrogen, unsubstituted or substituted C _1-10 alkyl, or a group of formula alk-R ¹⁶ , wherein alk is an unsubstituted or substituted C _1-10 alkylene group and R ¹⁶ is selected from hydroxyl, thiol, Ci _-6 alkylthio, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, carboxyl, amido, amino, -NH ₃ ⁺ and -N(H)-C(=NH ₂ ⁺ )-NH ₂ ; R ⁶ is hydrogen; provided that R ⁵ and R ⁶ may together form a propylene group; R ⁷ is hydrogen or an amino protecting group, provided that R ⁶ and R ⁷ may together form an amino protecting group, or R ⁷ is a group of formula (XI) 60

wherein

R ⁸ is selected from hydrogen, unsubstituted or substituted C _1-10 alkyl, or a group of formula alk-R ¹⁶ , wherein alk is an unsubstituted or substituted C _1-10 alkylene group and R ¹⁶ is selected from hydroxyl, thiol, C _1-6 alkylthio, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, carboxyl, amido, amino, -NH ₃ ⁺ and -N(H)-C(=NH ₂ ⁺ )-NH ₂ ;

R ⁹ is hydrogen; provided that R ⁸ and R ⁹ may together form a propylene group; and R ¹⁰ is hydrogen or an amino protecting group, provided that R ¹ and the R ⁹ substituent bonded to the same nitrogen atom as R ¹⁰ may together form an amino protecting group; and n is an integer of from 1 to 30. Typically, in this embodiment, Y is said detectable label and X is the further-reactable moiety. Thus, the process may further comprise: coupling a tracer moiety to the terminal -NR ⁶ R ⁷ group of the group of formula (X) or, when R ⁷ is a group of formula (XI), to the terminal -NR ⁹ R ¹⁰ of the group of formula (XI), thereby producing a further compound of formula (IQ) in which X comprises a tracer moiety.

As the skilled person will appreciate, further amino acids, or a peptide or a protein, could be coupled to the terminal -NR ⁶ R ⁷ group of the group of formula (X) or, when R ⁷ is a group of formula (XI), to the terminal -NR ⁹ R ¹⁰ of the group of formula (XI), using known protein synthesis methods. An initial amino deprotection step will typically be required where an amino protecting group is present.

The tracer moiety which is coupled to the terminal -NR ⁶ R ⁷ or -NR ⁹ R ¹⁰ group is therefore typically an amino acid, a dipeptide, an oligopeptide, a polypeptide or a protein, but may be any tracer moiety as defined hereinbefore.

The further-reactable moiety may in this embodiment be a group of formula (XII) or (XIII) 61

wherein R ⁷ is hydrogen or an amino protecting group. Thus, the process may comprise coupling a tracer moiety to the terminal -NHR ⁷ group of the group of formula (XII) or (XIII), thereby producing a further compound of formula (III) in which X comprises a tracer moiety. The tracer moiety which is coupled to the terminal -NHR ⁷ group of the group of formula (XII) or (Xffl) is typically an amino acid, a dipeptide, an oligopeptide, a polypeptide or a protein, but may be any tracer moiety as defined hereinbefore.

Accordingly, in one embodiment of the process of the invention for producing a labelled compound, the moiety to be labelled in the compound of formula (III) thus produced is a group of formula (X)

(X) wherein

R ⁵ is selected from hydrogen, unsubstituted or substituted C _1-10 alkyl, or a group of formula alk-R ¹⁶ , wherein alk is an unsubstituted or substituted C _1-10 alkylene group and R ¹⁶ is selected from hydroxyl, thiol, C _1-6 alkylthio, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, carboxyl, amido, amino, -NH ₃ ⁺ and -N(H)-C(=NH ₂ ⁺ )-NH ₂ ;

R ⁶ is hydrogen; provided that R ⁵ and R ⁶ may together form a propylene group;

R ⁷ is hydrogen, an amino protecting group, an amino acid, a dipeptide, an oligopeptide, a polypeptide, a protein, a tracer moiety as defined hereinbefore, or a group of formula (XI) 62

wherein

R is selected from hydrogen, unsubstituted or substituted C _1-10 alkyl, or a group of formula alk-R ¹⁶ , wherein alk is an unsubstituted or substituted C _1-10 alkylene group and R ¹⁶ is selected from hydroxyl, thiol, C _1-6 alkylthio, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, carboxyl, amido, amino, -NH ₃ ⁺ and -N(H)-C(=NH ₂ ⁺ )-NH ₂ ;

R ⁹ is hydrogen, provided that R ⁸ and R ⁹ may together form a propylene group; R ¹⁰ is hydrogen or an amino protecting group; provided that R ¹⁰ and the R ⁹ substituent bonded to the same nitrogen atom as R ¹⁰ may together form an amino protecting group; and n is an integer of from 1 to 1000; provided that R ⁶ and R ⁷ may together form an amino protecting group. Typically, in this embodiment, Y is said detectable label and X is said moiety to be labelled.

Typically, n is an integer of from 1 to 500, for instance from 1 to 100, or from 1 to 50, from 1 to 30 or from 1 to 20. The integer n may for example be from 1 to 10.

Typically, R ⁶ in the group of formula (X) as defined herein is hydrogen. R ⁶ may however form a propylene group together with R ⁵ . When R ⁵ does not form a propylene group together with R , R ⁵ is typically an amino acid side chain, selected from any one of the following amino acid side chains:

63

Similarly, in the groups of formula (XI) as defined herein, R ,9 is typically hydrogen. R ⁹ may however form a propylene group together with R ⁸ . When R ⁸ does not form a propylene group together with R , R is typically selected from any one of the amino acid side chains shown above.

In one embodiment, said moiety to be labelled is a group of formula (XH) or

(xπi)

wherein R ⁷ is hydrogen, an amino protecting group, an amino acid, a dipeptide, an oligopeptide, a polypeptide, a protein, a tracer moiety as defined herein, or a group of formula (XI) as defined herein. Typically, in this embodiment, Y is said detectable label and X is said moiety to be labelled. hi one embodiment, R ⁷ in the group of formula (X), (XII) or (XIII) is hydrogen or an amino protecting group. The amino protecting group is typically -C(O)CH ₃ . More typically, R ⁷ in the group of formula (X), (XII) or (XIU) is -C(O)CH ₃ . 64

In one embodiment of the process of the invention for producing the labelled compound, Y is said detectable label and X is said moiety to be labelled, and said moiety to be labelled is a group of formula (XTV)

-L ⁹ -Ar (XTV)

wherein Ar is unsubstitutued or substituted aryl or unsubstitutued or substituted heteroaryl, and L ⁹ is an unsubstituted C _2-20 alkylene group. Typically, in this embodiment, the moiety to be labelled, X, is:

In one embodiment of the process of the invention for producing the labelled compound, Y is ¹⁸ F or ¹⁹ F; L is an ethylene group; and X is selected from:

wherein [M] is a group of formula (IX)

wherein M, R , 11 , τ R _> \2 , τ R.13 , τ R. 14 and R I °S are as defined herein. 65

Compounds of formula (III) produced by the process of the invention, wherein the moiety to be labelled comprises a tracer moiety, may be used to image a patient or an in vitro sample, for instance a cell or an in vitro biopsy sample.

Accordingly, in one embodiment, the invention provides a method of imaging a human or non-human patient in need thereof, which method comprises: (a) producing a labelled compound of formula (III) by the process of the invention for producing a labelled compound; (b) administering the labelled compound to the patient; and (c) imaging the patient. Step (c), of imaging the patient, can be done using conventional techniques. In another embodiment, the invention provides a method of imaging a cell or in vitro sample, which method comprises: (a) producing a labelled compound of formula (III) by the process of the invention for producing a labelled compound; (b) contacting the cell or in vitro sample with said labelled compound; and (c) imaging the cell or in vitro sample. When step (c) is imaging the cell, the imaging of the cell can be done using conventional techniques. When step (c) is imaging the in vitro sample, the imaging of the in vitro sample can be performed using conventional techniques.

The method of imaging used in step (c) may be any suitable method. For instance, the method of imaging may be radioimaging, for instance using PET or SPECT; MRI-imaging; optical imaging, for instance fluorescence imaging; ultrasound imaging; or X-ray imaging. For imaging an in vitro sample or a patient, the imaging method used in step (c) is typically PET or SPECT. For imaging a cell, the imaging method used in step (c) is typically optical imaging, for instance fluorescence imaging. The invention provides novel compounds of formula (I)

χ wherein R ¹ , R ² , R ³ and R ⁴ are as defined herein and wherein X is a moiety to be labelled or a detectable label. More typically, X is a tracer moiety, a further-reactable moiety, or a detectable label, wherein the further-reactable moiety comprises a 66 functional group suitable for attaching the compound of formula (I) to a tracer moiety.

Typically, X is other than the following group of formula (IV):

More typically, X is other than the following groups of formulae (IV), (IVa) and (IVb):

Typically, R ¹ and R ² are both hydrogen and R ³ and R ⁴ are independently selected from unsubstituted or substituted phenyl and unsubstituted or substituted C _1- β alkyl. More typically, R ¹ and R ² are both hydrogen and R ³ and R ⁴ are both phenyl.

Usually, however, R ³ and R ⁴ , which are the same or different, are independently selected from unsubstituted or substituted aryl, unsubstituted or substituted C _1-20 alkyl, unsubstituted or substituted C _3-10 cycloalkyl, unsubstituted or substituted heteroaryl, unsubstituted or substituted C _3-10 heterocyclyl, and a fluorous group, provided that at least one of R ³ and R ⁴ is a said fluorous group as defined herein.

More typically, both R ³ and R ⁴ are fluorous groups as defined herein. Typically, X is a tracer moiety as defined herein. In one embodiment, said moiety to be labelled is a group of formula (X)

R ⁶

R ⁵ (X) wherein

R ⁵ is selected from hydrogen, unsubstituted or substituted C _1-10 alkyl, or a group of formula alk-R ¹⁶ , wherein alk is an unsubstituted or substituted C _1-10 alkylene group and R ¹⁶ is selected from hydroxyl, thiol, C _1-6 alkylthio, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, carboxyl, amido, amino, 67

-NH ₃ ⁺ and -N(H)-C(=NH ₂ ⁺ )-NH ₂ ;

R ⁶ is hydrogen; provided that R ⁵ and R ⁶ may together form a propylene group;

R ⁷ is hydrogen, an amino protecting group, an amino acid, a dipeptide, an oligopeptide, a polypeptide, a protein, a tracer moiety as defined herein, or a group of formula (XI)

wherein

R ⁸ is selected from hydrogen, unsubstituted or substituted C _1-10 alkyl, or a group of formula alk-R ¹⁶ , wherein alk is an unsubstituted or substituted Ci _-10 alkylene group and R ¹⁶ is selected from hydroxyl, thiol, C _1-6 alkylthio, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, carboxyl, amido, amino, -NH ₃ ⁺ and -N(H)-C(=NH ₂ ⁺ )-NH ₂ ;

R ⁹ is hydrogen, provided that R ⁸ and R ⁹ may together form a propylene group;

R ¹⁰ is hydrogen or an amino protecting group; provided that R ¹⁰ and the R ⁹ substituent bonded to the same nitrogen atom as

R , 10 may together form an amino protecting group; and n is an integer of from 1 to 1000; provided that R ⁶ and R ⁷ may together form an amino protecting group.

Typically, Y is said detectable label and X is said moiety to be labelled. Typically, n, R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ are as further defined herein.

The moiety to be labelled may be a group of formula (XH) or (XIII)

(XII) (XIII) 68 wherein R ⁷ is hydrogen, an amino protecting group, an amino acid, a dipeptide, an oligopeptide, a polypeptide, a protein, a tracer moiety as defined herein, or a group of formula (XI) as defined herein.

The moiety to be labelled may alternatively be a group of formula (XFV)

-L ^y -Ar (XTV)

wherein Ar is unsubstitutued or substituted aryl or unsubstitutued or substituted heteroaryl, and L ⁹ is an unsubstituted C _2-20 alkylene group. Typically, in this embodiment, the moiety to be labelled, X, is:

In one embodiment of the compound of formula (I) of the invention, Y is 18τ F or 19 F; L is an ethylene group; and X is selected from:

wherein [M] is a group of formula (FX)

wherein M, R , 1 ^u 1 , _D R12 , _D R13 , D R14 _ andJ Γ R> 15 are as defined herein. 69

In one embodiment of the compound of formula (I) of the invention, X is said further-reactable moiety, wherein the further-reactable moiety is a group of formula (XD)

wherein L ² is an unsubstituted or substituted C _1-20 alkylene group or an unsubstituted or substituted arylene group. More typically, in this embodiment, X is group of formula (XIIa)

Compounds of formula (I) can be produced in accordance with the process of the invention for producing a compound of formula (I)

wherein

R ¹ , R ² , R ³ and R ⁴ are as defined hereinbefore and wherein X is a moiety to be labelled or a detectable label, the process comprising:

(a) condensing a thiol of formula (V)

with an acid of formula (VI)

O

X A, OH (VI) to produce a phosphinoborane of formula (VII) 70

and

(b) deprotecting the phosphinoborane of formula (VII) to produce the compound of formula (T). Usually, in the process of the invention for producing a compound of formula

(T), X is a tracer moiety as defined herein, a further-reactable moiety as defined herein, or a detectable label as defined herein, wherein the further-reactable moiety comprises a functional group suitable for attaching the compound of formula (T) to a tracer moiety. hi the process of the invention for producing a compound of formula (T), X may be other than a group of formula (IV)

Furthermore, in some embodiments X can be other than the following groups of formulae (IV), (IVa) and (IVb):

A wide variety of tracer moieties, further-reactable moieties and detectable labels X can be introduced via step (a). For instance, as the skilled person will appreciate, the carboxy terminal of an amino acid, dipeptide, oligopeptide, polypeptide or protein moiety X can be condensed with the thiol of formula (V), in order to synthesise a phosphinoborane of formula (VTT) comprising that moiety X.

Step (a) of the process of the invention for producing a compound of formula (T) is typically performed in the presence of a solvent. Any suitable solvent may be used. Typically, the solvent comprises a polar organic solvent. The polar organic solvent may for instance comprise dichloromethane (DCM). The step is typically 71 performed at room temperature or with gentle heating. Usually, the reaction is performed in the presence of a suitable dehydrating agent and/or a suitable activating agent. Dicyclohexylcarbodiimide (DCC) is typically employed; DCC is an activating agent as well as a dehydrating agent. The reaction may be performed in the presence of 4-Dimethylaminopyridine (DMAP), which is usually present in a catalytic amount.

Typically, step (a) further comprises recovering the phosphinoborane product of formula (VIT). This may be achieved by any suitable purification technique, for instance by chromatography, The reaction mixture may for instance be concentrated and the resulting residue purified by flash chromatography.

Step (b) of the process of the invention for producing a compound of formula (I), namely the deprotection step, may be performed by any suitable method. Typically, however, deprotection of the phosphinoborane of formula (VTI) is performed by reacting the phosphinoborane with a lewis base, for instance with 1,4- diazabicyclo[2.2.2]octane (DABCO). Typically, step (b) is performed with gentle heating, e.g. at a temperature of from 40 ⁰ C to 8O ⁰ C. Usually a solvent is present. Any suitable solvent may be used. Typically, an organic solvent, for instance toluene, is employed.

Typically, the process of the invention for producing a compound of formula (I) further comprises: (c) recovering the compound of formula (T). This may be achieved by any suitable purification technique, for instance by chromatography. The reaction mixture may for instance be concentrated and the resulting residue purified by flash chromatography.

The process of the invention for producing a compound of formula (I) may further comprise producing said thiol of formula (V) from a thioacetate of formula (Va)

wherein R ¹ , R ² , R ³ and R ⁴ are as defined herein. Typically, said thiol of formula (V) is produced by treating the thioacetate of formula (Va) with a methanol solution of 72 sodium methoxide. The methanol is typically degassed methanol. The reaction is typically performed in an inert atmosphere, and usually at room temperature.

The thiol of formula (V) maybe produced in situ, i.e. it need not be isolated in solid form before reaction with the acid of formula (VI). hi the process of the invention for producing the compound of formula (I), the moiety to be labelled or the detectable label may be as further defined herein. The or each fluorous group, when present, may also be as further defined herein. In some embodiments of the process of the invention for producing the compound of formula (I), R ³ and R ⁴ are both fluorous groups, and are the same or different. The moiety to be labelled in the compound of formula (I), X, may be modified after the compound of formula (I) has been produced. Thus, in one embodiment, X is said further-reactable moiety which comprises a functional group suitable for attaching the compound of formula (I) to a tracer moiety. In this embodiment, the process of the invention for producing a compound of formula (I) may further comprise: attaching the compound of formula (I) thus produced to a tracer moiety, thereby producing a further compound of formula (I) which comprises a tracer moiety. The tracer moiety may be any of those defined hereinbefore.

The functional group may be any functional group suitable for coupling a tracer moiety to the compound of formula (T). The functional group may for instance be selected from an aldehyde group, a carboxyl group, an amino group, a hydroxyl group, an azide group, an alkyne group, a protected carboxyl group, a protected amino group, or a protected hydroxyl group. As is well known to the skilled person, aldehyde, carboxyl, amino, hydroxyl, azide and alkyne groups are capable of performing coupling reactions with complementary functional groups, and can thereby be used to attach a tracer moiety. For instance, carboxyl and amino groups can react together in a condensation reaction to form a peptide bond to attach the tracer moiety; an aldehyde and an amino group can react together in an imine condensation; and an azide and an alkyne can react in a click reaction. Coupling reactions of this sort can be used to attach a wide variety of tracer moieties, including for instance amino acids, peptides and proteins. Protected carboxyl, amino group, and hydroxyl groups are well known to the skilled person and examples of such groups are given hereinbefore. As the skilled person would understand, the protected 73 carboxyl, amino or hydroxyl group would first be deprotected (to form the corresponding carboxyl, amino or hydroxyl group respectively) and the tracer moiety would then be attached to the compound of formula (I), in an appropriate coupling reaction, to form the further compound of formula (I) which comprises the tracer moiety.

In one embodiment, X is said further-reactable moiety which comprises a functional group, and the process further comprises: attaching the compound of formula (I) to a tracer moiety, by reacting a tracer moiety with said functional group, thereby producing a further compound of formula (I) which comprises said tracer moiety.

In one embodiment, the further-reactable moiety is a group of formula (XII)

wherein L ² is an unsubstituted or substituted Ci _-20 alkylene group or an unsubstituted or substituted arylene group, and the process further comprises: condensing the compound of formula (I) with a compound of formula

R ¹⁷ -NH ₂ , wherein R ¹⁷ is a tracer moiety as defined herein, thereby producing, by imine condensation, a further compound of formula (I) in which X is a group of formula (XIII)

^V^ ^ (XIE). Such an imine condensation is typically performed in the presence of a solvent. Any suitable solvent may be used. Typically, the reaction is heated to the reflex temperature of the solvent.

R ¹⁷ may be a group of formula (IX) as defined herein. In another embodiment, the further-reactable moiety is a group of formula (X)

R ⁶

R ⁵ (X) wherein 74

R ⁵ is selected from hydrogen, unsubstituted or substituted C _1-10 alkyl, or a group of formula alk-R ¹⁶ , wherein alk is an unsubstituted or substituted C _1-1O alkylene group and R ¹⁶ is selected from hydroxyl, thiol, C _1-6 alkylthio, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, carboxyl, amido, amino, -NH ₃ ⁺ and -N(H)-C(=NH ₂ ⁺ )-NH ₂ ;

R ⁶ is hydrogen; provided that R ⁵ and R ⁶ may together form a propylene group;

R ⁷ is hydrogen or an amino protecting group, provided that R ⁶ and R ⁷ may together form an amino protecting group, or R ⁷ is a group of formula (XI)

wherein

R ⁸ is selected from hydrogen, unsubstituted or substituted C _1-10 alkyl, or a group of formula alk-R ¹⁶ , wherein alk is an unsubstituted or substituted C _1-I o alkylene group and R ¹⁶ is selected from hydroxyl, thiol, C _1-6 alkylthio, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, carboxyl, amido, amino, -NH ₃ ⁺ and -N(H)-C(=NH ₂ ⁺ )-NH ₂ ;

R ⁹ is hydrogen; provided that R ⁸ and R ⁹ may together form a propylene group; and

R ¹⁰ is hydrogen or an amino protecting group, provided that R ¹⁰ and the R ⁹ substituent bonded to the same nitrogen atom as R ¹⁰ may together form an amino protecting group; and n is an integer of from 1 to 30; and the process comprises coupling a tracer moiety to the terminal -NR ⁶ R ⁷ group of the group of formula (X) or, when R ⁷ is a group of formula (XI), to the terminal -NR ⁹ R ¹⁰ of the group of formula (XI), thereby producing a further compound of formula (I) in which X comprises a tracer moiety.

As the skilled person will appreciate, further amino acids, or a peptide or a protein, could be coupled to the terminal -NR ⁶ R ⁷ group of the group of formula (X) or, when R ⁷ is a group of formula (XI), to the terminal -NR ⁹ R ¹⁰ of the group of 75

formula (XI), using known protein synthesis methods. An initial amino deprotection step will typically be required where an amino protecting group is present.

The tracer moiety which is coupled to the terminal -NR ⁶ R ⁷ or -NR ⁹ R ¹⁰ group in this process is typically therefore an amino acid, a dipeptide, an oligopeptide, a polypeptide or a protein, but may be any tracer moiety as defined hereinbefore.

Typically, said further-reactable moiety is a group of formula (XII) or (XIII)

wherein R ⁷ is hydrogen or an amino protecting group, and wherein the process comprises coupling a tracer moiety to the terminal -NHR ⁷ group of the group of formula (XIl) or (XIII), thereby producing a further compound of formula (I) in which X comprises a tracer moiety.

The tracer moiety coupled to the terminal -NHR ⁷ group in this process may be a dipeptide, an oligopeptide, a polypeptide, a protein, or a tracer moiety as defined herein. Accordingly, in one embodiment of the process of the invention for producing a compound of formula (I), X in the compound of formula (I) thus produced is a group of formula (X)

wherein

R ⁵ is selected from hydrogen, unsubstituted or substituted C _1-10 alkyl, or a group of formula alk-R ¹⁶ , wherein alk is an unsubstituted or substituted C _1-I0 alkylene group and R ¹⁶ is selected from hydroxyl, thiol, C _1-6 alkylthio, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, carboxyl, amido, amino, -NH ₃ ⁺ and -N(H)-C(=NH ₂ ⁺ )-NH ₂ ;

R ⁶ is hydrogen; provided that R ⁵ and R ⁶ may together form a propylene group; 76

R ⁷ is hydrogen, an amino protecting group, an amino acid, a dipeptide, an oligopeptide, a polypeptide, a protein, a tracer moiety as defined hereinbefore, or a group of formula (XI)

wherein

R ⁸ is selected from hydrogen, unsubstituted or substituted C _1-10 alkyl, or a group of formula alk-R ¹⁶ , wherein alk is an unsubstituted or substituted C _1-1O alkylene group and R ¹⁶ is selected from hydroxyl, thiol, C _1-6 alkylthio, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, carboxyl, amido, amino, -NH ₃ ⁺ and -N(H)-C(=NH ₂ ⁺ )-NH ₂ ;

R ⁹ is hydrogen, provided that R ⁸ and R ⁹ may together form a propylene group;

R ¹⁰ is hydrogen or an amino protecting group; provided that R ¹⁰ and the R ⁹ substituent bonded to the same nitrogen atom as R ¹⁰ may together form an amino protecting group; and n is an integer of from 1 to 1000; provided that R ⁶ and R ⁷ may together form an amino protecting group.

Typically, n is an integer of from 1 to 500, for instance from 1 to 100, or from 1 to 50, from 1 to 30 or from 1 to 20. The integer n may for example be from 1 to 10. R ⁵ , R ⁶ , R ⁷ , R ⁸ and R ⁹ may as further defined herein.

A "pre-targeting" imaging method is advantageous, especially when the detectable label employed in the present invention is a radionuclide, for instance ¹⁸ F. In this method, a first compound comprising a tracer moiety (e.g. a receptor ligand) and either a phosphine or azide group is administered to the patient or sample in a pre-targeting step. This pre-targeting step is carried out for as long as needed in order to achieve optimal uptake of the tracer at the desired target. Another, targeting step is then carried out using second compound comprising a radioactive isotope linked to a complementary phosphine or azide group. The second compound then couples to the 77 first compound in vivo (or in the sample), by a traceless Staudinger ligation, after the first compound has achieved optimal target uptake.

The second compound comprising the radioactive isotope is typically linked to an azide group. The azide moiety is small and is therefore able to passively diffuse in and out of cells until it finds its binding partner. It may also cross the blood brain barrier and thus allow imaging of regions in the brain.

This pre-targeting method generally increases signal-to-noise ratio. Also, if the tracer moiety in the first compound is already labelled with a detectable label (for instance a different radionuclide or a different type of label such as a fluorescent label), the pre-targeting method allows the use of different imaging agents or different types of radionuclides to visualise the same target in one method. This enables better target localization, artefact elimination, and delineation of non relevant clearance and other pharmacokinetic pathways.

Accordingly, in one embodiment, the invention provides a method of imaging a human or non-human patient or an in vitro sample, which method comprises:

(a) administering to the patient or in vitro sample a compound of formula (I)

wherein X is a tracer moiety;

R ¹ and R ² , which are the same or different, are independently selected from hydrogen, unsubstituted or substituted C _1-10 alkyl, unsubstituted or substituted aryl, unsubstituted or substituted C _3-10 cycloalkyl, unsubstituted or substituted C _3-10 heterocyclyl, and unsubstituted or substituted heteroaryl, or wherein R ¹ , R ² and the carbon atom to which R ¹ and R ² are both bonded together form an unsubstituted or substituted C _3-10 cycloalkyl group; and

R ³ and R ⁴ , which are the same or different, are independently selected from unsubstituted or substituted aryl, unsubstituted or substituted Ci _-20. alkyl, unsubstituted or substituted C _3-I0 cycloalkyl, unsubstituted or substituted heteroaryl unsubstituted or substituted C _3-I0 heterocyclyl, and a fluorous group; 78 which fluorous group is a group selected from:

(0 R _f ;

(ii) -L ⁴ -C _1-20 alkyl, which C _1-20 alkyl is substituted by one, two or three groups selected from R _f and -Z-R _f and is otherwise unsubstituted or substituted;

(iii) -L ⁵ -aryl, which aryl is substituted by one, two or three groups selected from R _f and -Z-R _f and is otherwise unsubstituted or substituted; and (iv) -L ⁶ -Si(-L ⁷ -R _f ) _n (R ¹⁸ ) _3-n , wherein: R _f is a straight-chained or branched C _3-20 perfluoroalkyl group, a perfluoroaryl group, a straight-chained or branched C _1-20 perfluoroalkyl group substituted with one, two or three perfluoroaryl groups; or a perfluoroaryl group substituted with one, two or three straight-chained or branched C _1-20 perfluoroalkyl groups; provided that said straight-chained or branched C _1-20 and C _3-20 perfluoroalkyl groups are uninterrupted or interrupted by one, two or three perfluoroarylene groups;

L ⁴ and L ⁵ are independently selected from a single bond, -arylene-, -alk-, -alk-arylene-, -arylene-alk-, -alk-Z-, -arylene-Z-, -alk-arylene-Z, -alk-Z-arylene-, -alk-Z-arylene-Z-, -arylene-Z-alk-, -arylene-alk-Z- and -arylene-Z-alk-Z-, wherein alk is unsubstituted or substituted Ci _-10 alkylene which is optionally interrupted by N(R"), O, S, C(O), C(O)N(R") or arylene, wherein R" is H, C _1-6 alkyl or aryl;

L ⁶ and L ⁷ are independently selected from a single bond, -arylene-, -alk-, -alk-arylene-, -arylene-alk-, -alk-Z-arylene- and -arylene-Z-alk-, wherein alk is unsubstituted or substituted Ci _-10 alkylene which is optionally interrupted by N(R"), O, S, C(O), C(O)N(R") or arylene, wherein R" is H, C _]-6 alkyl or aryl; Z is N(R"), O, S, C(O) or C(O)N(R"), wherein R" is H, Ci _-6 alkyl or aryl;

R ¹⁸ is hydrogen, unsubstituted or substituted aryl, or unsubstituted or substituted C _1-20 alkyl; and n is 1, 2 or 3;

(b) administering to the same patient or in vitro sample a compound of formula (II)

N ₃ -L-Y

(II) 79 wherein

Y is a detectable label; and

L is a bond or a linking group; and (c) imaging the patient or in vitro sample. In another embodiment, the invention provides a method of imaging a human or non-human patient or an in vitro sample, which method comprises:

(a) administering to the patient or in vitro sample a compound of formula (II)

^N3 - ^L - ^γ (π) wherein

Y is a tracer moiety; and

L is a bond or a linking group; and

(b) administering to the same patient or in vitro sample a compound of formula (I)

wherein

X comprises a detectable label;

R ¹ and R ² , which are the same or different, are independently selected from hydrogen, unsubstituted or substituted C _1-10 alkyl, unsubstituted or substituted aryl, unsubstituted or substituted C _3-10 cycloalkyl, unsubstituted or substituted C _3-10 heterocyclyl, and unsubstituted or substituted heteroaryl, or wherein R ¹ , R ² and the carbon atom to which R ¹ and R ² are both bonded together form an unsubstituted or substituted C _3-10 cycloalkyl group; and

R ³ and R ⁴ , which are the same or different, are independently selected from unsubstituted or substituted aryl, unsubstituted or substituted C _1-20 alkyl, unsubstituted or substituted C _3-10 cycloalkyl, unsubstituted or substituted heteroaryl and unsubstituted or substituted C _3-10 heterocyclyl, and a fluorous group; which fluorous group is a group selected from:

(i) R _f ; 80

(ii) -L ⁴ -Ci _-20 alkyl, which C _1-20 alkyl is substituted by one, two or three groups selected from R _f and -Z-R _f and is otherwise unsubstituted or substituted;

(iii) -L ⁵ -aryl, which aryl is substituted by one, two or three groups selected from R _f and -Z-R _f and is otherwise unsubstituted or substituted; and

(iv) -L ⁶ -Si(-L ⁷ -R _f ) _n (R ¹⁸ ) _3-n , wherein:

R _f is a straight-chained or branched C _3-20 perfluoroalkyl group, a perfluoroaryl group, a straight-chained or branched C _1-20 perfluoroalkyl group substituted with one, two or three perfluoroaryl groups; or a perfluoroaryl group substituted with one, two or three straight-chained or branched C _1-20 perfluoroalkyl groups; provided that said straight-chained or branched C _1-20 and C _3-20 perfluoroalkyl groups are uninterrupted or interrupted by one, two or three perfluoroarylene groups;

L ⁴ and L ⁵ are independently selected from a single bond, -arylene-, -alk-, -alk-arylene-, -arylene-alk-, -alk-Z-, -arylene-Z-, -alk-arylene-Z, -alk-Z-arylene-, -alk-Z-arylene-Z-, -arylene-Z-alk-, -arylene-alk-Z- and -arylene-Z-alk-Z-, wherein alk is unsubstituted or substituted Ci _-10 alkylene which is optionally interrupted by N(R"), O, S, C(O), C(O)N(R") or arylene, wherein R" is H, C _1-6 alkyl or aryl;

L ⁶ and L ⁷ are independently selected from a single bond, -arylene-, -alk-, -alk-arylene-, -arylene-alk-, -alk-Z-arylene- and -arylene-Z-alk-, wherein alk is unsubstituted or substituted C _1-10 alkylene which is optionally interrupted by N(R"), O, S, C(O), C(O)N(R") or arylene, wherein R" is H, C _1-6 alkyl or aryl;

Z is N(R"), O, S, C(O) or C(O)N(R"), wherein R" is H, C _1-6 alkyl or aryl;

R ¹⁸ is hydrogen, unsubstituted or substituted aryl, or unsubstituted or substituted C _1-20 alkyl; and n is 1, 2 or 3; and

(c) imaging the patient or in vitro sample.

The detectable label may be any of the detectable label types defined herein but is typically a radionuclide. For instance, the detectable label maybe ³ H, ¹¹ C, ¹³ N, ¹⁵ O, ¹⁸ F, ⁵¹ Cr, ⁵² Fe, ^52m Mn, ⁵⁵ Co, ⁶⁰ Cu, ⁶¹ Cu, ⁶² Zn, ⁶² Cu, ⁶³ Zn, ⁶⁴ Cu, ⁶⁶ Ga, ⁶⁷ Ga, ⁶⁸ Ga, ⁷⁰ As, ⁷¹ As, ⁷² As, ⁷⁴ As, ⁷⁵ Se, ⁷⁵ Br, ⁷⁶ Br, ⁷⁷ Br, ^8Om Br, ^82m Br, ⁸² Rb, ⁸⁶ Y, ⁸⁸ Y, ⁸⁹ Sr, ⁸⁹ Zr, ⁹⁷ Ru, ^99m Tc, ¹¹⁰ In, ¹¹¹ In, ^113m In, ^114m In, ^U7m Sn, ¹²⁰ 1, ¹²² Xe, ¹²³ 1, ¹²⁴ 1, ¹²⁵ 1, ¹³¹ 1, ¹⁶⁶ Ho, 81

¹⁶⁷ Tm, ¹⁶⁹ Yb, ^193m Pt, ^195m Pt, ²⁰¹ Tl or ²⁰³ Pb. More typically, the detectable label is ¹⁸ F, ¹¹ C, ¹³ N, ¹⁵ 0, ¹²³ I or ^99m Tc. Usually, the radionuclide is ¹⁸ F, ¹¹ C, ¹³ N or ¹⁵ O. Even

18 more typically, the radionuclide is F.

The tracer moiety may be any of the tracer moieties defined herein. In one embodiment, the tracer moiety is already labelled with an imaging label, for instance a radionuclide. Typically this label is different from the label that is introduced in the process of the present invention. In this embodiment, the tracer moiety may be any of the tracer moieties listed hereinbefore which are already labelled with a radionuclide.

The invention also provides novel compounds of formula (III) wherein Y is F; X is a tracer moiety or a further-reactable moiety, which further-reactable moiety comprises a functional group suitable for attaching the compound of formula (HI) to a tracer moiety; and L is a linking group. Typically, in the compound of formula (ITI) of the invention, Y is ¹⁸ F.

The invention also provides novel compounds of formula (IQ)

O

X H (III) wherein

Y is F;

L is a linking group; and

X is a tracer moiety comprising: an oligopeptide, a polypeptide, a protein, a sugar, a lipid, a fatty acid, a nucleo base, a nucleoside, a nucleotide, or a nucleic acid; a ligand capable of binding to a tumour receptor, selected from bombesin, octreotide, lanreotide, pentetriotide, somatostatin, a somatostatin analogue, estradiol, trastuzumab, cetuximab, testosterone, a peptide secreted by an endocrine cell, tamoxifen, flutamide, an antioestrogen, an antiandrogen, a steroid, a progestin, an androgen, fulvestrant, metaiodobenzylguanidine, 3,4-dihydroxyphenylalanine, erlatinib, epidermal growth factor, transforming growth factor, ¹⁸ F-FDHT, ll-β-methoxy-17-α- ¹²³ I- iodovinylestradiol, ¹⁸ F-FES, 21- ¹⁸ F-fluoro-16-α-ethyl-19-norprogesterone, N-(4-(6,7- dimethoxy-3,4-dihydroisoquinolin-2- ¹ H-yl-)butyl), 2-(2- ¹⁸ F-fluoroethoxy)-5- methylbenzamide, ⁿ C-gefitinib, ^m In-octreatide, ⁶⁸ Ga-DOTA-octreotide, ⁶⁴ Cu- 82

TETA-octreotide, ¹¹¹ In-DTPA-EGF, ⁶⁸ Ga-DOTA-EGF, Cy5.5-EGF, ¹⁸ F-galacto- RGD, RGD-USPIO, RGD-Cy5.5, [ ^{π 1} In-DTPA-PrOl, Tyr4]bombesin, ⁶⁴ Cu-DOTA- [Lys3]bombesin, Bombesin-CLIO (Cy5.5), ⁶⁸ Ga-DOT A-F(ab') ₂ -trastuzumab, ¹¹¹ In-DTP A-trastuzumab, Polylactic acid nanoparticle-trastuzumab, RhodG- trastuzumab, (Avidin-Gd)-biotinylated anti-HER2/neu monoclonal antibody, ⁶⁴ Cu- DOTA-cetuximab and Cy5.5-cetuximab; or a metal complex, [M], which comprises a metal, M, and one or more ligands, as defined herein; or

X is a further-reactable moiety, which further-reactable moiety comprises a functional group suitable for attaching the compound of formula (UT) to a tracer moiety, which further-reactable moiety is a group of formula (XII)

wherein L ² is an unsubstituted or substituted C _1-20 alkylene group or an unsubstituted or substituted arylene group; or X is a group of formula (X)

R ⁶

R ⁵ (X) wherein

R ⁵ is selected from hydrogen, unsubstituted or substituted C _1-10 alkyl, or a group of formula alk-R ¹⁶ , wherein alk is an unsubstituted or substituted C _1-10 alkylene group and R ¹⁶ is selected from hydroxyl, thiol, C _1-6 alkylthio, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, carboxyl, amido, amino, -NH ₃ ⁺ and -N(H)-C(=NH ₂ ⁺ )-NH ₂ ; R ⁶ is hydrogen; provided that R ⁵ and R ⁶ may together form a propylene group; R ⁷ is an amino acid, a dipeptide, an oligopeptide, a polypeptide, a protein, a tracer moiety as defined in any one of claims 16 to 28, or a group of formula (XI) 83

wherein

R ⁸ is selected from hydrogen, unsubstituted or substituted C _1-10 alkyl, or a group of formula alk-R ¹⁶ , wherein alk is an unsubstituted or substituted C _1-10 alkylene group and R ¹⁶ is selected from hydroxyl, thiol, C _1-6 alkylthio, unsubstituted or substituted aryl, unsubstituted or substituted heteroaryl, carboxyl, amido, amino,

R ⁹ is hydrogen, provided that R ⁸ and R ⁹ may together form a propylene group;

R ¹⁰ is hydrogen or an amino protecting group; provided that R ¹⁰ and the R ⁹ substituent bonded to the same nitrogen atom as R ¹⁰ may together form an amino protecting group; and n is an integer of from 1 to 100; provided that R ⁶ and R ⁷ may together form an amino protecting group; or

X is a group of formula (XIII)

wherein R ⁷ is hydrogen, an amino protecting group, an amino acid, a dipeptide, an oligopeptide, a polypeptide, a protein, a tracer moiety as defined herein, or a group of formula (XI) as defined above; or X is a group of formula -L ⁹ -Ar, wherein Ar is unsubstitutued or substituted aryl or unsubstitutued or substituted heteroaryl, and L ⁹ is an unsubstituted C _2-20 alkylene group; provided that X does not comprise oxytocin.

The invention also provides a combination product, as defined herein, for medical imaging comprising (a) a compound of formula (I); and (b) a compound of formula (II). 84

Typically, in the combination product of the invention, the detectable label is as further defined hereinbefore. Similarly, the or each fluorous group, where present in the compound of formula (I), maybe as further defined hereinbefore. Typically, in the combination product of the invention at least one of R ³ and R ⁴ in the compound of formula (I) is a said fluorous group.

Typically, in the compound of formula (HI) or combination product of the invention:

X is any tracer moiety as defined herein; or

X is a further-reactable moiety, wherein the further-reactable moiety is a group o f formula (XII)

wherein L ² is an unsubstituted or substituted C _1-20 alkylene group or an unsubstituted or substituted arylene group; or

X is a group of formula (X), (XH) or (XIH) as defined herein; or X is selected from:

wherein [M] is a group of formula (IX)

wherein M, R ¹ \ R ¹² , R ¹³ , R ¹⁴ and R ¹⁵ are as defined herein. 85

Typically, in the compound of formula (III) or combination product of the invention L is an unsubstituted or substituted arylene group, an unsubstituted or substituted heteroarylene group, or an unsubstituted or substituted Cj _-20 alkylene group, which C _1-20 alkylene group is optionally interrupted by N(R"), O, S, C(O), C(O)N(R") or arylene, wherein R" is H, C _1-6 alkyl or aryl.

Typically, in the compound of formula (HI) of the invention, Y is ¹⁸ F.

Typically, in the combination product of the invention: Y is F. More typically in the combination product, Y is ¹⁸ F.

The present invention will be further illustrated in the Examples which follow:

EXAMPLES

Experimental details 1H NMRs were reported on Bruker DPX 200, DPX 400, AV 400 and AV 500 spectrometers, at a frequency of 200, 400 and 500 MHz respectively. ¹³ C NMRs were recorded on Bruker AV 400 and AV 500 spectrometers at a frequency of 100 or 125 MHz respectively. Mass spectra (m/z) were obtained on a Bruker MicroTOF in Electrospray (ESI). Analytical thin layer chromatography (TLC) was performed on Merck Silica 60 F ₂₅₄ plates. Crude reaction mixtures were analysed by TLC and HPLC. HPLC analysis was performed with a Gilson 322 or Dionex Ultimate 3000 systems, equipped with a Nal/PMT radiodetector and a UV-detector. Radio-TLC was performed on Macherey-Nagel Polygram Silica Plates and eluted with EtOAc or 95% aq. MeCN. Analysis was performed with a plastic scintillator/PMT detector. FSPE separation was carried out using pre-assembled Waters Sep-Pak cartridges (Waters, Milford, MA) and FluoroFlash Silica gel (Fluorous Technologies Inc., Pittsburgh, PA) (Angew. Chem. Int. Ed. 2009, 48, 586-589). Pre-assembled Sep-Pak C ₁₈ SPE cartridges (Waters, Milford, MA) were used in the same way. [ ¹⁸ F]Fluoride was produced by the cyclotron of PETNET Solutions at Mont Vernon Hospital (UK) via the ¹⁸ O(p,n) ¹⁸ F reaction and delivered as [ ¹⁸ F]fluoride in [ ¹⁸ O]water (1-2 GBq, 1- 3 mL). This target solution was passed through a QMA anion exchange resin cartridge (20 mg, Waters). [ ⁾⁸ F]Fluoride adsorbed on the resin was eluted into a 86 reaction vial with a solution of Kryptofix 222 (15 mg) and K ₂ CO ₃ (3 mg) in 1 mL acetonitrile/water (8:2). Excess water was removed under N ₂ stream at 100-110°C, and the resulting complex was dried an additional 3 times by azeotropic distillation with 0.5 mL acetonitrile each under N ₂ stream. The resulting dry complex of K ¹⁸ F/Kryptofix 222 was further dissolved by anhydrous acetonitrile (2-4 mL) and dispensed into reaction vials containing the precursor for nucleophilic fluorination.

(Diphenylphosphino)methanethiol

Phosphine 1 (2.2g, 7.8 mmol) was dissolved in methanol (25 mL) and sodium methoxide (527 mg, 9.75 mmol) was added. The reaction mixture was then stirred for 30 minutes and subsequently concentrated to dryness. The residue was dissolved in DCM (25 mL), washed with 2M HCl (10 mL) and brine (25 mL), dried over MgSO ₄ and concentrated. The crude mixture was purified by flash chromatography in neutral alumina (25 % EtOAc in hexane) to afford the desired product as a viscous, colourless oil (71 %, 1.1 g); δ _H (200 MHz, CDCl ₃ ) 1.38 (IH, t, J= 7.5 Hz), 3.00 (2H, d, J= 7.8 Hz), 7.26-7.33 (6H, m), 7.38-7.41 (4H, m); δ _c (100 MHz, CDCl ₃ ) 20.7, 128.1, 128.5, 128.9, 132.5 (d, J= 17.1 Hz); m/z (ESI) 246. (Soellner MB, Nilsson BL, and Raines RT. Staudinger Ligation of a-Azido Acids Retains Stereochemistry. The Journal of Organic Chemistry 2002;67:4993-6.)

General Procedure for Coupling of Acids to Thiols

Ph 87

(Diphenylphosphino)methanethiol (416 mg, 1.8 mmol) was dissolved in DCM (20 niL), to which DCC (408 mg, 1.98 mmol), DMAP (1 crystal) and then 4-formyl benzoic acid (270 mg, 1.8 mmol) were added. The reaction was stirred for 16 hours at room temperature, during which time, a white precipitate formed. The reaction mixture was passed through Celite® and concentrated to dryness. The residue was purified by flash chromatography (40 % EtOAc in hexane) to afford the desired product as a viscous, yellow oil (typical yield, 62 %). (Soellner MB, Nilsson BL, and Raines RT. Staudinger Ligation of a-Azido Acids Retains Stereochemistry. The Journal of Organic Chemistry 2002;67:4993-6.)

General Procedure for Deprotection of Phosphino(borane)s to Phosphines

X Phosphino(borane) X (120 mg, 0.32 mmol) was dissolved in toluene (2 mL) and DABCO (79 mg, 0.70 mmol) was added. The reaction mixture was stirred at 60 ⁰ C for 1 hour, at which point it was cooled to room temperature and concentrated to dryness. The residue was purified by flash chromatography in silica gel (25 % EtOAc in hexane) to afford the desired product as a viscous, yellow oil (typical yield, 93 %). (Soellner MB, Nilsson BL, and Raines RT. Staudinger Ligation of a-Azido Acids Retains Stereochemistry. The Journal of Organic Chemistry 2002;67:4993-6.)

Characterising Data for Phosphine Products

Product 1

δ _H (200 MHz, CDCl ₃ ) 1.94 (3H, s), 2.94 (IH, dd, J= 14.0, 7.5 Hz), 3.09 (IH, dd, J= 14.0, 5.2 Hz), 3.42-3.61 (2H, m), 4.91-5.03 (IH, m), 5.72 (IH, d, J = 8.2 Hz), 7.05- 7.12 (2H, m), 7.22-7.29 (3H, m), 7.34-7.49 (1OH, m); δ _c (100 MHz, CDCl ₃ ) 23.0, 25.6 (d, J= 24.5 Hz), 38.0, 59.6, 127.0, 128.47, 128.49, 128.8 (d, J= 36.0 Hz), 129.1 (d, J= 9.8 Hz), 132.6 (d, J= 19.4 Hz), 135.5, 169.9, 198.9; δ _P (162 MHz, CDCl ₃ ) -44.7.

Product 2

δ _H (400 MHz, CDCl ₃ ) 3.74 (2H, d, J= 3.8 Hz), 7.29-7.55 (1OH, m), 7.80-8.10 (4H, m); δ _c (100 MHz, CDCl ₃ ) 31.5, 127.9, 128.9, 129.0, 129.8, 130.2, 131.9, 132.4, 132.5, 191.3; δ _P (162 MHz, CDCl ₃ ) -47.6; mlz (ESI) C ₂₂ H ₁₇ O ₂ PS (M+H ⁺ ) calc. 365.0760, found 365.0755.

Product 3

89

δ _H (400 MHz, CDCl ₃ ) 1.91 (3H, s), 3.26 (2H, t, J= 6.1 Hz), 3.50 (3H, ddd, J= 28.6, 13.6, 3.8 Hz), 5.05 (IH, dt, J= 8.6, 5.6 Hz), 6.90 (IH, d, J= 2.3 Hz), 7.14 (IH, td, J = 7.1, 1.0 Hz), 7.22 (IH, td, J= 8.1, 1.0 Hz), 7.35-7.46 (HH, m), 7.54 (IH, d, J= 7.5 Hz); δ _c (100 MHz, CDCl ₃ ) 23.2, 25.8 (d, J= 23.8 Hz), 28.0, 59.4, 109.4, 111.3, 118.4, 119.9, 122.3, 123.2, 127.8, 128.6 (d, J= 6.7 Hz), 129.2 (d, J= 5.7 Hz), 132.1 (d, J= 19.1), 132.7 (d, J= 19.1), 136.0, 136.7 (d, J= 14.3), 169.8, 199.5; δ _P (162 MHz, CDCl ₃ ) -15.6; m/z (ESI) C ₂₆ H ₂₆ N ₂ O ₂ PS (M+H ⁺ ) calc. 461.1447, found 461.1450.

Product 4

δ _H (400 MHz, CDCl ₃ ) 1.55-1.79 (4H, m, (CH ₂ J ₂ ), 2.54 (2H, t, J= 6.6 Hz, CH ₂ CH ₂ CO), 2.59 (2Η, t, J= 7.6 Hz, PhCH ₂ CH ₂ ), 3.53 (2H, dd, J= 3.8, 1.0 Hz, SCH ₂ P), 7.12-7.22 (3Η, m, Ph), 7.25-7.29 (3H, m, Ph), 7.33-7.38 (5H, m, Ph), 7.40- 7.48 (4H, m, Ph); δ _c (100 MHz, CDCl ₃ ) 25.2, 25.3, 25.5, 30.6, 35.5, 43.6, 125.8, 128.3, 128.4, 128.5, 128.6, 128.7, 129.1, 131.1 (d, J= 9.5 Hz), 132.7, 132.8, 136.7 (d, J= 13.4 Hz), 141.9, 198.1; δ _P (162 MHz, CDCl ₃ ) -14.8; m/z (ESI) C ₂₄ H ₂₆ OPS ([M+H] ⁺ ) calc. 393.1436, found 393.1440.

Procedure for Imine Condensation

Phosphine 2 (20 mg, 0.06 mmol) was added to a suspension of ZnATSA/M (16 mg, 0.06 mmol) in methanol (2 mL) and the reaction mixture was heated to reflux for 4 90 hours. During the reaction, the solution went orange/yellow. The mixture was cooled and a precipitate was formed upon dropwise addition of diethyl ether (20 mL). The precipitate was collected and washed with copious amounts of diethyl ether (5 x 20 mL) and then dried in vacuo to give the desired product (18 mg, 45 % yield) as an orange solid.

Product 5

δ _H (400 MHz, DMSO-D ₆ ) 2.23 (3H, s), 2.28 (3H, s), 2.82-2.88 (3H, m), 3.82 (2H, d, J= 3.5 Hz), 7.38-7.44 (6H, m), 7.47-7.54 (4H, m), 7.73 (2H, d, J= 8.6 Hz), 7.90 (2H, d, J= 8.6 Hz), 8.13 (IH, s); δ _c (125 MHz, DMSO-D ₆ ) 14.1, 23.2, 25.8, 48.6, 126.6, 127.4, 127.6, 128.7, 128.8, 128.9, 129.3, 130.8 (d, J= 9.5 Hz), 132.5 (d, J= 19.1 Hz), 136.7, 136.8, 140.6; δ _P (162 MHz, DMSO-D ₆ ) 61.9; mlz (ESI) C ₂₈ H ₂₇ N ₇ OPS ₃ Zn (M-H ⁺ ) calc. 668.0474, found 668.0463.

General Procedure for the Staudinger Ligations

Phosphine Y (20 mg, 0.06 mmol) was dissolved in a mixture of THF and H ₂ O (3:1, 2 mL) and 2-fluroethylazide (0.06 mmol in a solution of THF) was added. The reaction mixture was heated to 8O ⁰ C for up to 30 minutes, at which point TLC demonstrated the consumption of the starting material and formation of a new product. The 91 reaction mixture was concentrated to dryness and the residue purified by flash chromatography in silica gel (10 % MeOH in DCM) which afforded the desired product as an oil (typical yield, 82 %). (Nilsson BL, Kiessling LL, and Raines RT. High- Yielding Staudinger Ligation of a Phosphinothioester and Azide To Form a Peptide. Organic Letters 2001;3:9-12.)

Characterising Data for Fluorine-Labelled Products

Product 6

δ _H (400 MHz, CDCl ₃ ) 2.01 (3H, s, OAc), 2.99 (IH, dd, J= 13.4, 8.1 Hz, CHCHH), 3.13 (IH, dd, J= 13.6, 6.1 Hz, CHCHH), 3.40-3.55 (2Η, m, NHCH ₂ CH ₂ ), 4.21-4.48 (2H, m, CH ₂ CH ₂ F), 4.62 (1Η, dt, J= 16.2, 7.8 Hz, CHCH ₂ ), 5.90-5.98 (IH, m, NH), 6.15 (IH, d, J= 7.3 Hz, NH), 7.22 (2H, d, J= 8.1 Hz, Ph), 7.28-7.35 (3H, m, Ph); δ _c (100 MHz, CDCl ₃ ) 23.2, 38.6, 39.8 (d, J= 20.0 Hz), 53.4, 54.7, 81.9 (d, J= 167.9 Hz), 127.2, 128.8, 129.2, 136.4, 170.0, 171.0; δ _F (377 MHz, CDCl ₃ ) -224.0; mlz (ESI) C ₁₃ H ₁₈ FN ₂ O ₂ ([M+H] ⁴ ) calc. 251. U91, found 251.1201.

Product 7

δ _H (400 MHz, CDCl ₃ ) 3.79 (2H, d, J= 28.0 Hz, NHCH ₂ CH ₂ ), 4.60 (2H, d, J= 47.1 Hz, CH ₂ CH ₂ F), 6.92 (1Η, br s, NH), 7.94 (4Η, app. s, Ph), 10.06 (IH, s, CHO); 92

δ _c (100 MHz, CDCl ₃ ) 40.6 (d, J= 19.0 Hz), 82.5 (d, J= 168.2 Hz), 127.8, 129.8, 138.3, 139.2, 166.7, 191.6; δ _F (377 MHz, CDCl ₃ ) -223.9; mlz (ESI) C ₁₀ H ₁₁ FNO ₂ ([M+H] ⁺ ) calc. 196.0168, found 196.0776.

Product 8

δ _H (400 MHz, CDCl ₃ ) 2.08 (3H, s, OAc), 3.07 (IH, dd, J= 12.9, 7.6 Hz, CHCHH), 3.37 (V ₂ H, t, J= 3.8 Hz, NHCH ₂ CH ₂ F), 3.41 (IH, at, J= 5.6, 3.7 Hz, NHCH ₂ CH ₂ F), 3.46 (V ₂ H, t, J= 3.8 Hz, NHCH ₂ CH ₂ F), 3.57 (IH, dd, J= 12.7, 7.9 Hz, CHCHH), 4.35 (2Η, dt, J= 46.2, 3.9 Hz, CH ₂ CH ₂ F), 4.58 (1Η, s, NH), 4.93 (1Η, t, J= 7.7 Hz, NHCHCO), 5.07 (1Η, s, NH), 7.04 (1Η, s, Ar), 7.18-7.24 (3Η, m, Ar), 7.32-7.36 (2H, m, Ar) ; δ _c (100 MHz, CDCl ₃ ) 22.8, 30.5, 40.5 (d, J= 27.0 Hz), 54.7, 82.6 (d, J= 168.4 Hz), 108.5, 111.6, 119.5, 120.1, 121.7, 123.4, 128.0, 137.3, 172.6, 174.0.; δ _F (377 MHz, CDCl ₃ ) -222.0; mlz (ESI) C ₁₅ H ₁₉ FN ₃ O ₂ ([M+Hft calc. 292.1456, found 292.1460.

Product 9

δ _H (400 MHz, CDCl ₃ ) 1.61-1.75 (4H, m, (CH ₂ J ₂ ), 2.23 (2H, t, J= 6.6 Hz, CH ₂ CH ₂ CO), 2.64 (2Η, t, J= 7.2 Hz, PhCH ₂ CH ₂ ), 3.57 (2H, dq, J= 28.1, 5.1 Hz, NHCH ₂ CH ₂ ), 4.50 (2H, dt, J= 47.3, 4.8 Hz, CH ₂ CH ₂ F), 5.77 (1Η, s, NH), 7.15-7.21 (3Η, m, Ph), 7.26-7.31 (2H, m, Ph); δ _c (100 MHz, CDCl ₃ ) 25.2, 31.0, 35.5, 36.5, 39.7 (d, J= 22.5 Hz), 54.1, 82.9 (d, J= 166.2 Hz), 125.8, 128.3, 128.4, 173.0; 93

δ _F (377 MHz ₅ CDCl ₃ ) -224.3; mlz (ESI) C ₁₃ H ₁₉ FNO ([M+H] ⁺ ) calc. 224.1445, found 224.1440.

Product 10

δ _F (376.56 MHz, DMSO-D ₆ ) - 221.5; mlz (ESI) C ₁₀ H ₁₁ FNO ₂ (MH-H ⁺ ) calc. 194.0623, found 194.0626.

Radiochemical Procedures

O _N P Kryptofix 222, K ₂ CO ₃ , ¹⁸ F C8 ^F 17 "° 15 mins, 12O ⁰ C

In a sealed reaction vial, 0.3 mL of K ¹⁸ F/Kryptofix 222 in anhydrous MeCN (20-100 MBq) was added to 2-azidoethyl lH,lH,2H,2H-perfluorodecane-l-sulfonate (10 mg) and heated for 15 minutes at 120°C. Determination of the radiochemical yield was by a further reaction. An aliquot (10 μL) of the crude reaction mixture was combined with 7V-propargylbenzamide (5 mg), CuSO _4(aq) (50 μL) and sodium ascorbate _(aq) (50 μL) and heated for 15 minutes at 80°C. Analysis by ΗPLC (Zorbax SB, C 18, 250 x 4.6 mm, MeCN/Η ₂ 0 gradient, 1 mL/min) gave a retention time of 6.70 minutes. Comparison with the cold reference HPLC trace confirmed the product to be successfully labelled [ ¹⁸ F]iV-benzyl-3-[l-(2-fluoroethyl)-lH-[l,2,3]triazol-4- yl]propionamide. Analysis by radio-TLC (acetonitrile: water 95:5) indicated an 84 % RCY. (Glaser, M.; Arstad, E. Bioconjugate Chem. 2007, 18, 989-993.) Purification was carried out by FSPE as described in the General Procedures. (Bejot R.; Fowler T.; Carroll L.; Boldon S.; Moore J. E.; Declerck J.; V., G. Angewandte Chemie International Edition 2009, 48, 586-589.) 94

General Procedure for 18τ F-Staudinger Ligations

In a sealed reaction vial, the FSPE purified solution of 2-[ ¹⁸ F]fluoroethylazide (20- 100 MBq) in MeCN/H ₂ 0 (7:3, 0.1 mL) was reacted with Z (5 mg) in THF:H ₂ O (4:1, 0.2 mL), and heated for 15 minutes at 8O ⁰ C. Analysis by reverse-phase HPLC (Vydac, 3OθA, C18, 100 mm x 4.6 mm, MeCN/H ₂ O gradient, 1 mL/min). Comparison with a cold reference HPLC trace confirmed this to be the desired labelled product. The conversion of 2-[ ¹⁸ F]fluoroethylazide was complete according to HPLC analysis and no side-products were noted by TLC analysis (MeCN:H ₂ O, 95:5).

HPLC Retention Times for ¹⁸ F Labelled Products Product 6

Retention Time (1) = 10.2 minutes. Analysis by reverse-phase HPLC (Vydac, 3OθA, C 18, 100 mm x 4.6 mm, MeCN/H ₂ O gradient, 1 mL/min).

Retention Time (2) = 5.7 minutes (Phenomenex NX 5u C18 column (150x4.60 mm) at room temperature using a gradient of acetonitrile/water (1 mL/min) as the mobile phase.) 95

Product 7

Retention Time (1) = 10.1 minutes. Analysis by reverse-phase HPLC (Vydac, 3OθA, C 18, 100 mm x 4.6 mm, MeCN/H ₂ 0 gradient, 1 mL/min).

Retention Time (2) = 5.5 minutes (Phenomenex NX 5u C18 column (150x4.60 mm) at room temperature using a gradient of acetonitrile/water (lmL/min) as the mobile phase.

Product 8

Retention Time (1) = 9.8 minutes. Analysis by reverse-phase HPLC (Vydac, 300A, C 18, 100 mm x 4.6 mm, MeCN/H ₂ O gradient, 1 mL/min).

Retention Time (2) = 5.6 minutes (Phenomenex NX 5u C18 column (150x4.60 mm) at room temperature using a gradient of acetonitrile/water (1 mL/min) as the mobile phase.

Product 9

96

Retention Time = 7.7 minutes (Phenomenex NX 5u C18 column (150x4.60 mm) at room temperature using a gradient of acetonitrile/water (lmL/min) as the mobile phase.

Modified ¹⁸ F Labelling Procedure for Zn-Complex

In a sealed reaction vial, the FSPE purified solution of 2-[ F]fluoroethylazide (20- 100 MBq) in MeCN/H ₂ O (7:3, 0.05 mL) was reacted with (3 mg) in DMF:H ₂ O (6:1, 0.12 mL) and heated for 15 minutes at 80°C. Analysis by reverse-phase HPLC (Vydac, 3OθA, Cl 8, 100 mm x 4.6 mm, MeCN/H ₂ O gradient, 1 rnL/min). Comparison with a cold reference HPLC trace confirmed this to be the desired labelled product. The conversion of 2-[ ¹⁸ F]fluoroethylazide was complete according to HPLC analysis and no side-products were noted by TLC analysis (EtOAc :MeOH, 90:10).

Retention Time = 9.9 minutes

Preparation of a Fluorous Variant (£)-l-Bromo-4-(3,3,4,4,5,5,6,6,6-nonafluorohex-l-en-l-yl)be nzene

A solution of 3,3,4,4,5,5,6,6,6-nonafluorohex-l-ene (3.5 mL, 20.2 mmol) in methanol (10 mL) was added dropwise to a stirred solution of 4- bromobenzenediazonium tetrafluoroborate (5.46 g, 20.2 mmol) and palladium(π) acetate (0.023 g, 0.10 mmol) in methanol (10 mL) at room temperature under 97

nitrogen. The resulting mixture was stirred at 40 ⁰ C until the bubbling ceased. The reaction mixture was extracted into DCM, washed successively with water (30 mL) and brine (30 mL) and then concentrated in vacuo. The residue was dissolved in pentane, filtered through silica gel and evaporated to afford desired product (E)-I- bromo-4-(3,3,4,4,5,5,6,6,6-nonafluorohex-l-en-l-yl)benzene as an oil; 6 _H (400 MHz, CDCl ₃ ) 6.14-6.24 (IH, m, CF ₂ CH), 7.12 (1Η, d, J= 16.0 Hz, CH=CH), 7.35 (2Η, dd, J= 8.3, 2.8 Hz, Ar-H), 7.55 (2Η, dd, J= 8.3, 3.2 Hz, Ar-H); δ _c (100 MHz, CDCl ₃ ) 115.0 (t, J= 23.2 Hz), 124.5, 129.1, 132.2, 132.4, 138.6 (t, J= 9.6 Hz); δ _F (377 MHz, CDCl ₃ ) -80.0 (3F, t, J= 9.5 Hz), -111.5, -124.1, -125.8; mlz (ΕSI) C ₁₂ H ₇ F ₉ Br ([M+H] ⁺ ) calc. 400.9587, found 400.9605.

l-Bromo-4-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)benzene

A solution of (E)-l-bromo-4-(3,3,4,4,5,5,6,6,6-nonafluorohex-l-enyl)benzen e (1 g, 2.49 mmol) in DCM (10 mL) under 5 bar H ₂ was stirred with Rh/C catalyst at 30 ⁰ C for 24 hours. The reaction was monitored by GCMS analysis and upon consumption of the starting material, the mixture was filtered through a plug of Celite® and concentrated in vacuo to yield the desired product l-bromo-4-(3,3,4,4,5,5,6,6,6- nonafluorohexyl)benzene as a colourless oil; δ _H (400 MHz, CDCl ₃ ) 2.34-2.37 (2H, m, CF ₂ CH ₂ ), 2.86-2.90 (2Η, m, CH ₂ Ar), 7.07-7.11 (2Η, m, Ar-H), 7.43-7.46 (2Η, m, Ar-H); δ _c (100 MHz, CDCl ₃ ) 25.9, 32.6 (t, J= 22.4 Hz), 120.6, 130.0, 131.9, 138.0; δ _F (377 MHz, CDCl ₃ ) -81.0 (3F, t, J= 9.5 Hz), -114.9, -124.5, -126.1; mlz (ΕSI) C ₁₂ H ₉ F ₉ Br ([M+H] ⁺ ) calc. 402.9744, found 402.9758.

jB/s(4-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)phenyl)phosphin e oxide

98

To a stirred solution of l-bromo-4-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)benzene (3 g, 7.4 mmol) in Et ₂ O (52 mL) at -78 ⁰ C under argon was added tBuLi (1.6 M solution in Et ₂ O, 9.3 mL, 14.9 mmol) carefully. The resulting mixture was slowly warmed to 0 ⁰ C (> 30 mins) before the addition of dichloro(diethylamino)phosphine (0.97 mL, 6.7 mmol) dropwise. The reaction mixture was stirred at 0 ⁰ C for 16 hours, then concentrated hydrochloric acid (0.99 mL, 11.9 mmol) was added the mixture warmed to room temperature for 4 hours. The reaction was quenched by the addition ofH ₂ O (20 mL) and the aqueous layer extracted with Et ₂ O (100 mL). The combined organic layer was washed with brine (100 mL), dried (MgSO ₄ ) and concentrated in vacuo. Purification by silica column chromatography (97:3 DCM:MeOH) afforded the desired product fos(4-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)phenyl)phosphine oxide as a solid; δ _H (400 MHz, CDCl ₃ ) 2.30-2.46 (4H, m, CF ₂ CH ₂ ), 2.92-3.05 (4H, m, CH ₂ Ar), 7.38 (4Η, dd, J= 5.0, 2.7 Hz, Ar-H), 7.47 (V4Η, d, J= 481.8 Hz, P-H), 7.61- 7.74 (4Η, m, Ar-H), 8.68 (V ₂ R, d, J= 481.8 Hz, P-H); mlz (ESI) C ₂₄ H ₁₇ F ₁₈ NaOP ([M+Hft calc. 111.0622, found 717.0628.

(jB/s(4-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)phenyl)phospho nio)trihydroborate

To a stirred solution of tø(4-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)phenyl)phosphine oxide (1.86g, 2.7 mmol) in THF (56 mL) under argon was added H ₂ O (0.48 mL, 26.8 mmol). The mixture was allowed to homogenise and then cooled to 0 ⁰ C before the slow addition of BH ₃ SMe ₂ (2 M solution in Et ₂ O, 26.8 mL, 53.6 mmol) [Note: evolution of gas]. The resulting mixture was allowed to warm to room temperature and stirred for 5 hours, after which it was concentrated in vacuo and the residue purified using silica column chromatography (98:2 Hexane:EtOAc) to afford the desired product (όzs(4-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)phenyl)phosphonio ) trihydroborate as a solid; δ _H (400 MHz, CDCl ₃ ) 0.45-1.57 (3H, m, BH ₃ ), 2.27-2.46 (4Η, m, CF ₂ CH ₂ ), 2.88-3.03 (4Η, m, CH ₂ Ar), 5.76-5.88 ( ¹ AH, dm, J= 379.3 Hz, P- 99

H), 6.72-6.88 (V ₂ H, dm, J= 379.3 Hz, P-H), 7.33 (4Η, d, J= 6.8 Hz, Ar-H), 7.58- 7.68 (4Η, m, Ar-H); δ _c (100 MHz, CDCl ₃ ) 26.4, 32.4 (t, J= 22.0 Hz), 124.6 (d, J _C-P = 57.5 Hz), 129.2 (d, J _c-P = 11.2 Hz), 133.4 (d, J _c-P = 9.6 Hz), 143.2 (d, J _c-P = 2.4 Hz); δ _F (377 MHz, CDCl ₃ ) -81.1, -114.8, -124.5, -126.1; δ _P (162 MHz, CDCl ₃ ) -0.1; m/z (ESI) - MS was unobtainable due to decomposition.

(((Acetylthio)methyl)ftw(4-(3,3,4,4,5,5,6,6,6- nonafluorohexyl)phenyl)phosphonio) -trihydroborate

To a stirred solution of (όw(4-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)phenyl)phosphonio) trihydroborate (500 mg, 0.72 mmol) in DMF (2.5 mL) at 0 ⁰ C under argon was added sodium hydride (60 % in mineral oil, 43 mg, 1.1 mmol). The resulting mixture was stirred at 0 ⁰ C until bubbling ceased. A solution of S-(bromomethyl) ethanethioate (183 mg, 1.1 mmol) in DMF (0.5 mL) was added dropwise and the reaction mixture allowed to warm to room temperature and stirred overnight. The mixture was then concentrated in vacuo and purified using silica column chromatography (96:4 Hexane:Et ₂ O) to afford the desired product (((acetylthio)methyl)tø(4- (3,3,4,4,5,5,6,6,6-nonafluorohexyl) phenyl)phosphonio)trihydroborate as an oil; δπ (400 MHz, CDCl ₃ ) 0.48-1.48 (3H, m, BH ₃ ), 2.26 (3Η, s, CH ₃ ), 2.30-2.47 (4Η, m, CF ₂ CH ₂ ), 2.91-3.01 (4Η, m, CH ₂ Ar), 3.70 (2Η, dd, J= 6.7, 2.7 Hz, PCH ₂ S), 7.28- 7.37 (4Η, m, Ar-H), 7.60-7.71 (4Η, m, Ar-H); δ _c (100 MHz, CDCl ₃ ) 23.7 (d, J _c-P = 36.0 Hz), 26.4, 30.0, 32.3 (t, J= 22.0 Hz), 125.9 (d, J _c-P = 56.7 Hz), 128.9 (d, J _c-P = 11.2 Hz), 132.9 (d, J _c-P = 9.6 Hz), 143.3 (d, J _C-P = 1.6 Hz), 193.2; δ _F (377 MHz, CDCl ₃ ) -81.1, -114.8, -124.5, -126.1; δ _P (162 MHz, CDCl ₃ ) 18.2; m/z (ESI) C ₂₇ H ₂₄ BF ₁₈ NaOPS ([M+H] ⁺ ) calc. 803.09SZ, found 803.0983.

(5)-6-Benzyl-2,2-όw(4-(3,3,4,4,5,5,6,6,6-nonafluorohexyl )phenyl)-5,8-dioxo-4- thia-7-aza-2-phospha-l-boranonan-2-ium-l-uide 100

To a stirred solution of (((acetylthio)methyl)όz5'(4-(3,3,4,4,5,5,6,6,6-nonafluorohe xyl) phenyl)phosphonio)trihydroborate (400 mg, 0.51 mmol) in degassed MeOH (2.4 mL) at room temperature under argon was added sodium methoxide (36 mg, 0.67 mmol). The reaction was followed by TLC and upon consumption of starting material, the mixture was quenched by the addition of 1 N HCl (2 mL). The resulting mixture was extracted with EtOAc (15 mL) and the combined organic layer was washed with brine (20 mL), dried over Na ₂ SO ₄ and concentrated in vacuo. The residue was re-dissolved in DCM (3.2 mL) under argon and 7V-acetylphenylalanine (116 mg, 0.56 mmol), DCC (121 mg, 0.59 mmol) and DMAP (3 mg, 0.03 mmol) were added sequentially. The reaction mixture was stirred at room temperature overnight. The reaction mixture was then filtered through a plug of Celite® and the filtrate concentrated in vacuo. Purification by silica column chromatography (90:10 Hexane:EtOAc) afforded the desired product (iS)-6-benzyl-2,2-&w(4-

(3,3,4,4,5,5,6,6,6-nonafluorohexyl)phenyl)-5,8-dioxo-4-th ia-7-aza-2-phospha-l- boranonan-2-ium-l-uide as a solid; δ _H (400 MHz, CDCl ₃ ) 0.54-1.47 (3H, m, BH ₃ ), 1.92 (3Η, s, CH ₃ ), 2.28-2.46 (4Η, m, CF ₂ CH ₂ ), 2.79-2.86 (1Η, m, CHΗPh), 2.90- 3.08 (5Η, m, CH ₂ Ar and CΗHPh), 3.58-3.67 (1Η, m, PCHΗS), 3.71-3.81 (1Η, m, PCΗHS), 4.83-4.92 (1Η, m, CHCH ₂ Ph), 5.63 (IH, d, J= 8.1 Hz, NH), 7.00-7.08

(2Η, m, Ph-H), 7.23-7.29 (3Η, m, Ph-H), 7.30-7.39 (4Η, m, Ar-H), 7.60-7.71 (4Η, m, Ar-H); δ _c (100 MHz, CDCl ₃ ) 23.0, 23.5 (d, ¹ J _0P = 35.1 Hz), 26.4, 32.3 (t, ³ J _CF = 22.0 Hz), 37.7, 59.5, 125.8, (d, ¹ J _0P = 56.3 Hz), 125.9 (d, ¹ Jc _P = 56.3 Hz), 127.4, 128.8, 128.9, 129.0, 129.0, 132.9 (d, ³ J _CP = 9.8 Hz), 133.0 (d, ³ J _CP = 9.8 Hz), 135.0, 143.3 (d, ⁴ Jc _P = 2.4 Hz), 143.4 (d, ⁴ J _CP = 2.4 Hz), 169.9, 198.1; δ _F (377 MHz, CDCl ₃ ) -81.0, -114.8, -124.4, -126.0; δ _P (162 MHz, CDCl ₃ ) 18.4; m/z (ESI) C ₃₆ H ₃₃ BF ₁₈ NNaO ₂ PS ([M+H] ⁺ ) calc. 950.1674, found 950.1667. 101

(5)-S-((5/s(4-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)phenyl)p hosphino)methyl) 2- acetamido-3-phenyIpropanethioate

A solution of (5)-6-benzyl-2,2-δw(4-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)ph enyl)-5,8- dioxo-4-thia-7-aza-2-phospha-l-boranonan-2-ium-l-uide (103 mg, 0.11 mmol) and DABCO (12 mg, 0.22 mmol) in toluene (1.1 mL) under Argon was stirred at 60 ⁰ C for 5 hours. The reaction mixture was then concentrated in vacuo and purified using silica column chromatography (under a stream of nitrogen) to afford the desired product as an oil. By ¹ H and ³¹ P NMR recorded immediately, ratio of oxidised product P=O to desired product found to be 30:70; δ _H (400 MHz, CDCl ₃ ) 1.92 (IH, s, CH ₃ (P=O)), 1.94 (2H, s, CH ₃ (P)), 2.28-2.47 (4Η, m, CF ₂ CH ₂ ), 2.80 (0.3Η, dd, J=

14.5, 7.6 Hz, CHHPh(P=O)), 2.88-3.06 (5H, m, CH ₂ Ar; CHHPh(P=O) and CHHPh(P)), 3.10 (0.7Η, dd, J= 14.4, 6.1 Hz, CHHPh(P)), 3.45 (0.7H, dd, J= 14.3, 3.3 Hz, PCHHS), 3.51 (0.7H, dd, J= 14.3, 3.3 Hz, PCHHS), 3.65 (0.3Η, dd, J= 14.8, 8.9 Hz, P(O)CHHS), 3.83 (0.3H, dd, J= 14.8, 8.6 Hz, P(O)CHHS), 4.86-4.93 (0.7Η, m, CHCH ₂ Ph(P)), 4.94-5.01 (0.3H, m, CHCH ₂ Ph(P=O)), 5.65-5.73 (IH, m, NH), 6.98-7.12 (2Η, m, Ph-H), 7.19-7.31 (5Η, m, Ph-H and Ar-H), 7.32-7.43 (4Η, m, Ar-H), 7.68-7.79 (2Η, m, Ar-H); δ _c (100 MHz, CDCl ₃ ) 23.0, 23.1, 26.4, 26.5, 32.3,

37.6, 38.2, 59.5, 59.7, 127.2, 127.3, 128.6, 128.7, 128.8, 128.9, 129.0, 129.3, 131.6, 131.7, 133.1, 133.3, 135.3, 144.0, 170.0; δ _F (377 MHz, CDCl ₃ ) -81.0, -114.8, -124.4,

-126.0; δ _P (162 MHz, CDCl ₃ ) -16.9 (0.7P, P), 28.7 (0.3P, P=O); m/z (ESI) C ₃₆ H ₃₀ Fi ₈ NNaO ₂ PS ([M+H] ⁺ ) calc. 936.1340,/oum/ 936.1336.

Preparation of Product 6 using ¹⁹ F

102

To a stirred solution of (S)-S-((bis(4-(3,3,4,4,5,5,6,6,6-nonafluorohexyl)phenyl)- phosphino)methyl) 2-acetamido-3-phenylpropanethioate (120 mg, 0.13 mmol) in H ₂ O (0.1 mL) and THF (6 μL) under Argon was added 2-fluoroethylazide (0.33 M in THF, 394 μL). The resulting mixture was heated to 80 ⁰ C for 30 min. Purification by HPLC gave 32 mg of the desired product 6 in a 29 % yield. In another experiment, purification of product 6 was effected using FSPE instead of HPLC, to produce the purified product 6 in a similar yield.

Preparation of Product 6 using ¹⁸ F

In a sealed reaction vial, the FSPE purified solution of 2-[ ¹⁸ F]Fluoroethylazide (20- 100 MBq) in MeCN/H2θ (7:3, 0.5 mL) was mixed with a thiophosphane (1 mg) in either 300 μL THFrBbO (4:1) or 300 μL DMF:H2θ (6:1) and heated for 15 minutes at 120 ⁰ C. Analysis by reverse-phase HPLC gave a retention times that correlated to the cold reference compounds, with > 95 % conversion from [ ¹⁸ F]2-fluoroethylazide to the product in each case. In another experiment, purification was effected using FSPE instead of HPLC.