INDIVIDUALIZED DOSING OF RADIOACTIVE TRACERS

FOR IMAGING

CROSS-REFERENCE TO RELATED APPLICATIONS

[0001] This application claims priority to U.S. Provisional Application Nos. 62/931,394, filed November 6, 2019, and to 62/958,934, filed January 9, 2020, each of which is incorporated herein by reference in its entirety.

FIELD OF THE INVENTION

[0002] The present invention is in the field of medicine. More particularly, the invention relates to radiopharmaceutical imaging of dopaminergic disorders.

BACKGROUND

[0003] Currently, imaging agents or tracers used for patient imaging are not dosed according to body weight and other customary parameters applied to other pharmaceutical formulations. For example, for brain imaging, no dose adjustment of the administered amount of radioactive imaging agent is currently made in practice or in the label of radioactive imaging agents approved by regulatory authorities. This means, in effect, that when undergoing an imaging exam, all patients will receive the same amount of radioactive tracer, resulting in a pre-set dose of radioactive exposure, irrespective of age, organ function, specific activity of enzymatic systems, and/or body weight.

[0004] However, internal pharmacokinetics play a major role in the ultimate saturation of the areas of interest to be imaged with a radio tracer. Specifically, a tracer used for brain imaging will be dependent on the general circulation of the patient to be imaged, cardiac output, his or her body weight, internal distribution spaces, metabolic activity, specificity of receptor binding, and internal metabolism of the tracer and associated molecules.

[0005] One of the reasons for this approach is that the manufacture of radioactive tracers is done in batches of a certain size and decay-time of the radioactivity. These parameters are calculated to coincide with an optimal dose of radioactivity manufactured at a radiopharmaceutical facility and then shipped and delivered to an imaging center where the patient at the time of imaging, for example, a SPECT brain imaging. Typically, a dose of tracer is manufactured, shipped, and provided in a fixed volume of aqueous or other solution, and then administered intravenously. The dose of administered radioactivity is calculated as a function of decay time between manufacture of the dose and time of administration. For the exam to be successful, a minimum dose of radioactivity is required, which is determined by the time between manufacture of the dose, not by the volume of the tracer to be administered. Therefore, all patients undergoing a SPECT or PET exam, for instance, will receive a radioactive dose of tracer that is not adjusted by body weight and other patient-specific parameters as it would be with other pharmaceutical compounds.

[0006] Unfortunately, if the administered dose is too high for a given patient, they may experience detrimental side-effects such as an increased life-time exposure of radiation which would expose the patient to unnecessary risk of adverse outcomes, mostly the induction of cancers and genetic mutations. Conversely, if the dose is too low, the resulting imaging quality and analysis may be incomplete and inaccurate, forcing a retest with another cycle of radioactivity exposure.

[0007] Thus, what is needed is an improved imaging method for dosing a patient with an individualized amount of a radioactive imaging agent that is accurate, efficient, and safe with minimal radiological exposure, reducing the overall lifetime dose of radioactivity a patient may receive through medical diagnostic procedures.

SUMMARY OF THE INVENTION

[0008] It has been discovered that by providing smaller amounts of pharmaceutical quantities of injectable radioactive tracers with dopamine transported specificities of greater than 1 : 2, it is possible to titrate the amount of radioactivity provided to a patient and provide an amount of radioactivity that allows for administration of the lowest possible dose that will result in a usable image for brain imaging, especially imaging of dopaminergic neurons, but also other neuronal functions. [0009] This discovery has been exploited to develop the present disclosure, which, in part, is methods of applying increasing doses of radioactive tracer, injected intravenously at timepoint t = 0 min and at dosing intervals of about 1 minute to about 5 minutes after the initial injection, until sufficient photon signals from the brain are received which will allow the operator of the SPECT camera to stop further injections of the radiotracer and thereby stop administration of subsequent doses which would not contribute to enhance imaging quality and readability of the image.

[0010] In one aspect, the disclosure provides a method of imaging the DAT receptors in a region of interest (ROI) in the body of a subject, comprising: administering a first packaging unit of radiolabeled tracer, the first packaging unit comprising a less than a number of counts sufficient to image the RO, and the radiolabeled tracer having a dopamine transporter specificity of greater than 1 : 2; acquiring the counts from the ROI starting at about 15 minutes after administration of the first packaging unit; administering a second packaging unit of radiolabeled tracer if the counts acquired after the administration of the first packaging unit are not sufficient to provide a complete image of the ROI, the second packaging unit comprising less than a number of counts sufficient to image the ROI, and the radiolabeled tracer having a dopamine transporter specificity of greater than 1 : 2; acquiring the counts starting at the time that the second packaging unit is administered; determining if the counts acquired are sufficient to provide a complete image of the ROI; and repeating the administration and acquiring steps if the counts acquired after administration of the second packaging unit are not sufficient to provide a complete image of the ROI.

[0011] In one embodiment, the amount of administered radiolabeled tracer in the packaging unit is determined from by the pharmacokinetic profile of the patient and measured by acquired counts in the ROI.

[0012] In certain embodiments, the packaging units contain at a pre-determined timepoint within the decay time of the tracer with an initial dose of about 0.25 mCi to about 0.5 mCi of radiolabeled tracer.

[0013] In some embodiments, the radioactive tracer is a radiolabeled tropane, and embodiments, the tropane comprises 2b -carbomethoxy- 3p-(4-iodophenyl) tropane beta- CIT); 2 -carbomethoxy-3 -(4-iodophenyl)-N-(3-fluoropropyl) nortropane (FP-CIT), TRODAT-1, or a derivative thereof. In certain embodiments, the radiolabeled tracer comprises ¹²³ I]-E-2P-carbomethoxy-3P-(4-fluorophenyl)-N-(3-iodo-E-a llyl) nortropane (DaT2020), [ ¹²³ I]-2b carbomethoxy- 3 -(4-iodophenyl)tropane ([ ¹²³ I]-beta-CIT); [ ¹²³ I]-2b- carbomethoxy-3P-(4-iodophenyl)-N-(3-fluoropropyl)nortropane ([ ¹²³ I]-FP-CIT); [ ¹²³ I]- altropane; and [ ⁹⁹ mTc] -TRODAT-1.

[0014] In some embodiments, the ROI sought to be imaged is the brain, kidney or cardiovascular system.

[0015] In particular embodiments, the counts are acquired by PET, SPECT, or an external sensor.

[0016] In some embodiments more than a first and a second packaging unit of radiolabeled tracer are administered to acquire a complete image.

[0017] In certain embodiments, the methods further comprising comparing the complete image obtained from the patient with a corresponding image of the ROI obtained from a control subject, the patient being afflicted with a dopaminergic disorder if the number of counts, pattern, and/or density of counts acquired to provide the image of the ROI is less than the number, density and pattern of counts acquired to provide an image of the ROI from the control subject which is not afflicted with the dopaminergic disorder.

[0018] In particular embodiments, the patient is determined to be afflicted with idiopathic Parkinson’s disease, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal degeneration (CBD), and vascular parkinsonism (VaP), among other rarer causes of parkinsonism), and Lewy body dementia, ADHD, clinical depression, anxiety, sleep disorders, obesity, sexual dysfunction, schizophrenia, pheochromocytoma, binge eating disorder, or diabetes.

[0019] In another aspect, the disclosure provides a method of dosing a patient with a radiolabeled tracer that specifically recognizes striatal DAT receptors and that has selectivity for a dopamine transporter versus a serotonin transporter of greater than 1 : 2 (dopamine : serotonin transporter) , to obtain an image of a region of interest within the body of the patient.

[0020] The method comprises administering a first packaging unit of radiolabeled tracer which comprises less than a number of counts sufficient to image the ROI, and which has a dopamine : serotonin transporter specificity of greater than 1 : 2. Counts are acquired from the ROI starting at about 1 minute to about 5 minutes after administration of the first packaging unit. If it is determined that the counts acquired are sufficient to provide a complete image of the ROI, then no additional packaging units are administered. If it is determined that the counts acquired are not sufficient to provide complete image of the ROI, then the administration and acquiring steps are repeated until the counts acquired are sufficient to provide a complete image of the ROI.

[0021] In yet another aspect, the disclosure provides a kit comprising multiple packaging units of a radiolabeled tracer that has a dopamine : serotonin transporter specificity of greater than 1 : 2, each packaging unit comprising a less than a number of counts sufficient to image a region of interest in a subject’s body.

[0022] In some embodiments, the kit provides one to 10 packaging units of radiolabeled tracer. In other embodiments, the kit provides 2 to 8 packaging units of radioactive tracer. In yet other embodiments, the kit provides 2 to 5 packaging units of radioactive tracer.

[0023] In some embodiments, each packaging units have from about 0.25 mCi to about 0.5 mCi radiolabeled tracer. In particular embodiments, the packaging units contain about 0.5 ml to about 2 ml, about 0.25 ml to 1 ml, about 0.5 ml to 0.75 ml, about 0.5 ml, or about 1 ml volume.

[0024] In certain embodiments, the radioactive tracer is a radiolabeled tropane, and in particular embodiments, the tropane comprises 2b -carbom ethoxy- 3P-(4-iodophenyl) tropane beta-CIT), 2P-carbomethoxy-3 -(4-iodophenyl)-N-(3-fluoropropyl)nortropane (FP-CIT), TRODAT-1, or a derivative thereof. In some embodiments, the radiolabeled tracer comprises ¹²³ I]-E-2P-carbomethoxy-3P-(4-fluorophenyl)-N-(3-iodo-E-a llyl) nortropane (DaT2020), [ ¹²³ I]-2b carbomethoxy- 3b-(4-iodophenyl)tropane ([ ¹²³ I]-beta-CIT); [ ¹²³ I]^-carbomethoxy- 3 -(4-iodophenyl)-N-(3-fluoropropyl)nortropane ([ ¹²³ I]-FP-CIT); [ ¹²³ I]-altropane, and/or [ ⁹⁹ mTc] -TROD AT - 1.

DESCRIPTION

[0025] The disclosures of these patents, patent applications, and publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed herein. The instant disclosure will govern in the instance that there is any inconsistency between the patents, patent applications, and publications and this disclosure.

[0026] Unless defined otherwise, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. The initial definition provided for a group or term herein applies to that group or term throughout the present specification individually or as part of another group, unless otherwise indicated.

[0027] “Altropane” refers to E-2P-carbomethoxy-3P-(4-fluorophenyl)-N-(3-iodo-E-allyl) nortropane

[0028] As used herein, “DaT2020” refers to E-2P-carbomethoxy-3P-(4-fluorophenyl)-N- (3-iodo-E-allyl) nortropane, or Altropane, in a solution suitable for IV injection. [0029] The term “tropane” as used herein refers to DaT2020 and its derivatives.

[0030] The terms “imaging agent” and “tracer” refer to molecules that can provide an image of a region of interest (ROI) in the body, and can be detected from outside the body. [0031] The terms “radioactive imaging agent and “radioactive tracer” refer to molecules labeled with a radionuclide used to image an ROI. [0032] The term “dopamine transporter specificity” refers to the ability of the radiolabeled tracer to bind dopamine receptors relative to its ability to bind serotonin receptors.

[0033] The term “packaging unit” refers to a set volume and set amount of radioactive tracer/ml and is in a syringe or other containing useful for administration.

[0034] The term “fractionated administration” means the administration of more than one bolus amounts of an imaging agent effective to image an ROI.

[0035] Multiple bolus administration” refers, e.g ., to the cumulated administration of two or more individual bolus injections of an imaging agent which are administered over an interval of time, i.e., at time point t = 0 min (initial intravenous injection), and then multiple injections at timepoints between about 1 minute and about 5 minutes following each other up to a timepoint of about 15 minutes after initial injection. The overall dose of, for example, 5 mCi, contained in about 5 ml of aqueous or nonaqueous vehicle suitable for IV administration, is divided into single bolus of, e.g. , about 1 ml, representing a fraction of the overall dose of radioactivity. The total dose of about ml represents the total dose that may be provided to a patient, but less than that dose may be enough to provide a complete image from that patient.

[0036] The present disclosure relates to methods of providing a radioactive tracer to a subject having an ROI to be imaged by PET, SPECT, external sensors, and the like, and to kits including multiple packaging units comprising a minimal amount of radiolabeled tracer which is less than useful or sufficient for obtaining a complete image of the ROI in the subject. Such methods are designed to reduce the overall exposure of patients to a radioactive tracer used for imaging an ROI.

[0037] In many areas of medicine, pharmacologically active substances are administered in chosen therapeutically effective amounts which take into consideration the clinical condition of the patient being treated, the patient’s metabolism, body weight, and age, and potentially other physical factors. In contrast, in the field of radio-diagnostics, especially in the field of diagnosing tremor disorders with radiopharmaceuticals measuring the activity of dopaminergic neurons, a standard dose of radiopharmaceutical (measured in amount of radioactivity) is provided to all patients, independent of patient characteristics. For example, especially in the field of diagnosing tremor disorders with radiopharmaceuticals measuring the activity of dopaminergic neurons ioflupane, used to measure the activity of dopaminergic neurons, is being administered at a dose of 5 mCi to 8 mCi per patient, independent of patient age, weight, metabolic parameters and other factors. Since ioflupane is a tracer that is less specific to dopaminergic neurons than, for example, altropane, ioflupane will slowly bind to dopaminergic neurons in the brain after having passed through general circulation during which it is also captured by other receptor types, specifically serotonin receptors. Therefore, the kinetics and receptor binding properties of ioflupane are not suitable for dosing titration in the early phases after injection.

[0038] The packaging units of radiolabeled tracer according to the disclosure allow for an up-titration of the effective dose of tracer effective to obtain a complete image of the ROI.

The administration of tracer in smaller aliquots, and hence lower levels of radioactivity, avoids unnecessary exposure to radiation for those patients whose pharmacokinetic parameters allow the administration of lower doses without loss of imaging quality, and therefore result in the administration of the lowest amount of tracer useful to obtain useful imaging results.

[0039] In addition, these “minimal” packaging units also account for individual patient pharmacokinetics, and when administered, reduces detrimental side-effects and potential related medical repercussions. Factors influencing patient pharmacokinetics include, but are not limited to, the existence of competitive receptors in vivo , body weight, metabolic activity, organ impairment, and receptor density and location that would sequester the tracer from the blood stream and would prevent it from reaching the dopaminergic neurons in the brain.

[0040] The tracer or imaging agent in the packaging unit is adhered or linked to a radionuclide that can be detected from outside of the body by various methods, and which has a dopamine transporter specificity of greater than about 1 : 2.

[0041] Receptor binding and ratios of selectivity can be derived according to the methods of Madras et al. (1998) SYNAPSE 29:93-104, Madras et al. (1998) SYNAPSE 29: 105-115, and Fischman et al. (1998) SYNAPSE 29: 128-141. In vitro receptor binding studies (Madras et al. (1998) SYNAPSE 29:93-104) also demonstrated that in Cynomolgus monkey striatal homogenates, Altropane exhibits good potency and selectivity for the dopamine transporter (IC50 = 6.62 ± 0.78 nM against 3H-WIN 35,428) versus the serotonin transporter (IC50 values = 181.9 ± 46 nM against [3H]citalopram) (Section 0). [ ¹²⁵ I] Altropane binding was linear as a function of tissue concentration, and a concentration of 0.3 nM bound rapidly and reversibly to striatal membranes. [ ¹²⁵ I] Altropane binding achieved equilibrium within 3 hours, was stable for at least 4 hours, and was still stable at 6-18 hours after the start of the assay.

[0042] Non-limiting exemplary imaging agents include tropanes such as 2b - carbomethoxy- 3P-(4-iodophenyl) tropane beta-CIT); 2P-carbom ethoxy-3 P-(4-iodophenyl)-N- (3-fluoropropyl) nortropane (Altropane), (FP-CIT), TRODAT-1, and derivatives thereof. Useful imaging agents are those with a high specificity for dopaminergic neurons, low capture rate by other receptors (serotonin receptors inside other tissues of the body, especially in the lung), and a fast binding to these dopaminergic neurons in the ROIs, e,g ., in the brain (in the case of tremor disorders in the substantia nigra of the putamen), are suitable for up-titration during image acquisition.

[0043] Useful radionuclides to be linked to the imaging agent include those whose emitted counts and thus patterns, levels, and/or intensity can be acquired by PET or SPECT. Alternatively, the pattern, level, and/or intensity of tracer binding to DAT can be determined by the data captured by the sensors and sent, e.g., to a data reader attached to a computer. Useful radionuclides include, but are not limited to with ¹²³ I, ¹²⁴ I, ¹²⁵ 1, ^99m Tc, ¹⁸ F or ^117m Sn.

The isotope can be located at any position on pre- Altropane, or a derivative thereof, and can be directly linked or indirectly linked via a linker (see, U.S. Patent No. 8,574,545). One suitable position is the free terminus of the haloallyl moiety.

[0044] An imaging agent labeled with ¹²³ I, ¹²⁵ 1, ^99m Tc, or ^117m Sn, emits counts that can be acquired by SPECT. Imaging agents radiolabeled with ¹⁸ F, ¹²⁴ I, or ^U C, emit counts that can be are acquired by PET.

[0045] External devices that are located on the surface or in close proximity to the ROI of a patients can also detect photons and protons emitted from ROI, depending on their specifications and are included in this disclosure. For example, if the ROI is a region of the brain the external device is placed on the head/skull of the patient closet to that ROI. Radiolabeled Altropane and its radiolabeled derivatives may be generated by the user through any known or developed radiolabeling procedure. For example, to prepare Altropane, a reaction between a haloallyl Sn precursor (pre- Altropane) and a radionuclide under oxidative conditions is allowed. Other standard methods of radiolabeling can be used as well. For radiolabeling, Altropane in lyophilized form is useful, however, it can also be in aqueous form.

[0046] Non-limiting examples of useful SPECT-readable tracers for DAT detection according to the disclosure include [ ¹²³ I]-E-2P-carbomethoxy-3P-(4-fluorophenyl)-N-(3-iodo- E-allyl) nortropane (DaT2020), [ ¹²³ I] -2b carbomethoxy- 3 -(4-iodophenyl)tropane ([ ¹²³ I]-beta- CIT); [ ¹²³ I]-2P-carbomethoxy-3P-(4-iodophenyl)-N-(3-fluoropropyl )nortropane ([ ¹²³ I]-FP- CIT); [ ¹²³ I]-altropane; and [ ⁹⁹ mTc]-TRODAT-l. Among these, [ ¹²³ I]-FP-CIT (DaTscan) achieves stable binding 3 hours post-injection and remains stable for 3 hours, has a half-life of 13.2 hr, emits gamma rays with an energy of 159 keV, and is FDA approved. These are also described in U.S. Patent Nos. 5,493,026, 8,084,018, 8,574,545, 8,986,653, and PCT International Application No. PCT/US2015/037340.

[0047] A useful amount of radiolabeled tracer in the packaging unit is that amount that provides less than that need to provide a full image of the ROI, and which can be used for fractionated administration or up-titration. For example, a useful range includes about 0.25 mCi to about 8 mCi, about 0.5 mCi to about 5 mCi, about 1 mCi to about 5 mCi, or about 2 mCi to about 4 mCi.

[0048] The method according to the disclosure may be used for imaging any ROI. For example, any organ that has DAT receptors may be imaged, such as, but not limited to, in the brain, the caudate-putamen, nucleus accumbens and olfactory tubercle in the substantia nigra and ventral tegmental area, the pituitary, the central nervous system, specifically in the hippocampal dentate gyrus and subventricular zone, the pancreas, the kidney and vasculature nephron in the kidney, with proximal tubule epithelial cells showing the highest density. [0049] A useful exemplary tracer is Altropane or DaT2020, labeled with Iodine 123, which can be commercially obtained, or radiolabeled derivatives thereof.

[0050] For administration, the radiolabeled imaging agent can be formulated for injection in a physiologically acceptable carrier solution e.g., such as an aqueous or non-aqueous solution. One exemplary, nonlimiting I. V. formulation useful in the method of the disclosure is Dat2020 shown in Table 1.

Table 1. Content of DaT2020 for Intravenous Injection (per mL

DaT2020 32 - 44 MBq (0.5 - 1.5 mCi) ¹

Ethanol, USP 0.005 - 0.022 mL ²

Sodium Hydroxide, ACS 0.025 - 0.51 mg

Acetic Acid, USP 2.5 - 4.0 mg

Sodium Chloride Injection, USP (0.9%) 0.5 - 1.2 mL

Sterile Water for Injection, USP 0.001 - 0.02 mL

ACS = American Chemical Society; USP = United States Pharmacopeia. lAt calibration/expiration time (on the day after manufacture)

² Range of ethanol content based on the dilution required to adjust radioactivity concentration during manufacture.

[0051] The imaging method according to the disclosure comprises administering a first packaging unit of radiolabeled tracer to the subject. The first and additional packaging units each comprise a less than a number of counts sufficient to image the ROI, and each have a dopamine : serotonin transporter specificity of greater than about 1 : 2. Counts are acquired from the ROI starting at about 15 minutes after administration of the first packaging unit. A second is administered if the counts acquired after the administration of the first packaging unit are not sufficient to provide a complete image of the ROI. Counts are acquired starting at the time that the second packaging unit is administered, and these counts are sufficient to provide a complete image of the ROI, then no additional packaging units are administered. If these counts are not sufficient to provide a complete image, then additional packaging units are administered one by one and counts acquired after each administration to determine if a complete image has been provided. [0052] The present method is different than the methods used under existing dosing schemes, which are not individualized, and during which a total dose of 5 mCi would be administered in one 5 ml intravenous bolus of solution containing 5 mCi of radioactivity. The present packaging units, containing an aliquot of the overall dosage of radioactivity and an aliquot of the overall volume in solution of such dose of radioactivity, can be administered in succession through an indwelling catheter or other suitable venous access line.

[0053] The content of the first sub-unit is administered at time t = 0 while the patient is in the SPECT or PET camera, or is exposed to any other suitable counting device. Emitted photons, in the case of SPECT, are counted at about one minute to 5 minutes after administration or once they passed general circulation and arrived at the dopaminergic neuron, from which they would then emit photons which are be picked up by the camera. If the signal after the first injection is too weak to be picked up by the camera, a second injection of the aliquot of the volume (and radioactivity) of the total dose will be administered. If insufficient counts after the second injection are acquired after an appropriate waiting time, additional injections are conducted in appropriate timely spacing until the desired count of emitted photons is achieved.

[0054] The number, pattern, and/or density of counts of the image acquired from the patient can also be measured and compared with the number, pattern, and/or density of counts of the image obtained from an age-matched control subject which is not afflicted with a dopaminergic disorder. The patient is afflicted with a dopaminergic disorder if the counts, density, and/or pattern of counts acquired is less than that acquired from the control subject.

[0055] For each patient, an individualized imaging procedure is developed based on the above-mentioned pharmacokinetic parameters. Then, a number of packaging units eventually satisfying the procedure (i.e., enabling the acquisition of a “complete” image) are administered one-by-one, or up-titrated, during the imaging procedure. It is possible that an individual is completely does after administration of one packaging unit if, e.g ., that individual has certain physiological characteristics, e.g. , is very small, light-weight, and elderly.

[0056] For example, the dose administered is in less than 5 ml aliquots, e.g. , in 0.25 ml, 0.5 ml, 1 ml, 1.5 ml, or 2 ml titration steps or packaging units, each step provided in single syringes or other useful application containers. The tracer content of the syringes or containers is manufactured in the same batch and therefore is subject to the same radioactive decay dynamics, depending on the radionuclide used.

[0057] The procedure is initiated by injection of one, or under certain circumstances, several smaller than 5 ml doses as estimated by the patient parameters. The injection is done under SPECT, PET, or external sensor device control such that the patient is in the camera or in contact with the device during injection. Once sufficient counts are detected by the camera/device and appropriate algorithms to result in a “complete” image, additional administration of the radioactive tracer may be unnecessary for sufficient imaging quality.

[0058] Any remaining packaging units, which ordinarily have been produced under the same batch and transported to the imaging facility in the same shipment, and thus have been exposed to the same radioactive decay, can be used for other subjects scheduled for the same exam at the same center in close timely proximity.

[0059] The present methodology using these packaging units are useful for many diagnostic and imaging methods that aid in differential diagnosis, leading to appropriate treatment of conditions where the functioning or dysfunctioning of DAT is a biomarker. For example, dysfunctions of DAT resulting in dopaminergic disorders are known in the brain and CNS, as well as outside of the CNS, including pancreas, kidney, gastrointestinal tract, and cardiovascular system. The present method can distinguish non-dopaminergic conditions, such as, but not limited to, non-parkinsonian or essential tremor and non- Alzheimer dementia, as well as multiple sclerosis, chronic kidney disease, stroke, traumatic brain injury, drug or alcohol use, hypoglycemia, lack of sleep, lack of vitamins, increased stress, magnesium and/or thiamine deficiencies, liver failure, mercury poisoning, and drug or alcohol addiction or withdrawal, from a dopaminergic disorder displaying similar clinical manifestations. Such dopaminergic disorders include, but are not limited to, parkinsonian syndromes including idiopathic Parkinson’s disease, progressive supranuclear palsy (PSP), multiple system atrophy (MSA), corticobasal degeneration (CBD), and vascular parkinsonism (VaP), among other rarer causes of parkinsonism), and Lewy body dementia, ADHD, clinical depression, anxiety, sleep disorders, obesity, sexual dysfunction, schizophrenia, pheochromocytoma, binge eating disorder, and diabetes and other disorders resulting from DAT dysfunction outside of the CNS. [0060] These methods can also be used in clinical trials designed to evaluate the efficacy of new treatments for DAT dysfunction to stratify subjects according to disease stage. These methods are also useful for monitoring the effectiveness of treatments for and progression of DAT dysfunction over time.

[0061] Reference will now be made to specific examples illustrating the disclosure. It is to be understood that the examples are provided to illustrate exemplary embodiments and that no limitation to the scope of the disclosure is intended thereby.

EXAMPLE 1

SPECT Imaging of Parkinson’s Disease with -Carbomethoxy-3B-(4-fluorophenvD-N-(3-iodo-E-allvD Nortropane

[0062] A clinical study is conducted that assesses the diagnostic information on dopamine activity in the striatum that can be read from SPECT images using altropane, representative of a tracer with fast distribution and high receptor affinity for dopaminergic neurons in the brain. The study is conducted in patients with early and late Parkinson’s Disease (PD) and in healthy volunteers (HV).

[0063] Subjects appropriate for each of three cohorts (late PD, HV, and early PD) are selected as follows. Late PD subjects have a Modified Hoehn and Yahr score of between 3 and 5 during “ON state”. An even spread of late stage PD patients within this range are used. Early PD have a Modified Hoehn and Yahr score of between 1 and 2.5 during “ON state”. An even spread of early parkinsonism patients within this range are used.

[0064] The inclusion/exclusion and cohort criteria are designed to ensure that study subjects are stratified, as reliably as clinically possible, into early- or late PD patients or are healthy. Subjects > 40 years of age are included in the study, as the occurrence of PD in patients less than 40 years of age is unusual. The inability to lie supine for 1 hour excludes subjects who are unsuited for SPECT scanning procedures.

[0065] The drug substance or tracer, Altropane, [ ¹²³ I]-2p-carbomethoxy-3P-(4- fluorophenyl)-N-(3-iodo-E-allyl) nortropane, is made according to known methods, with no carrier added. Alternatively, the tracer is commercially available from LikeMinds. The chemical mass of drug substance in a 3 mCi to 5 mCi (111 to 185 MBq) dose is not more than 16 ng. The radioactive isotope of the drug substance, [ ¹²³ I], emits a 159 keV gamma ray which is readily detected by suitable SPECT cameras. The radioisotope has a half-life of 13.2 hours. The molecular formula is CisEbiFINCk. The anhydrous formula weight is 425 Da.

[0066] The drug substance is manufactured and handled according to the applicable Good Manufacturing Practice (GMP) at a qualified production facility. Before release, each batch of investigational product is assessed by a number of quality control tests according to methods approved by the sponsor. The batch produced meets pre-specified criteria for color, clarity, radionuclidic identity and purity, radiochemical identity and purity, chemical purity, radioactive concentration, total vial radioactivity, pH, bacterial endotoxin level, and autoclave requirements. [0067] The final product is formulated as a sterile solution for intravenous injection. The drug substance is provided in a formulation suitable for human IV administration. It contains excipients previously approved by the FDA for other intravenously delivered products. The drug substance is provided in a clear, colorless, sterile solution in 5 single-use pre-filled syringes, each of which containing approximately 1 mCi at the timepoint of patient injection.

[0068] The subject packaging units are prepared from a production batch in a way that at the timepoint of administration, the volume is about 0.5 ml and contains 1 mCi of Altropane in solution. [0069] Trial participants are administered Altropane in solution under the direct supervision of a nuclear medicine physician or designee. For administration of Altropane in solution, access into a large vein ( e.g ., antecubital vein) is established using a suitable intravenous (IV) catheter that does not contain silicone. To avoid extravasation of Altropane in solution, correct localization of the catheter is ensured by a test injection of normal saline prior to injection.

[0070] While being placed in the SPECT camera, with the camera in “on” mode, i.e., collecting emitted photons from the subject’s ROI (head), each study participant receives an initial single IV injection of Altropane in a solution with a total activity dose amounting to about 1 mCi. Altropane in solution is administered manually via slow IV injection, followed by a 10 mL saline flush.

[0071] The exact radioactive dose administered is determined by calculating the difference between the radioactivity in the syringe and delivery system immediately before and after injection. After the dose is delivered, the syringe is filled with a volume of saline equal to the administered dose volume and the syringe is recounted under the same conditions as used to determine the dose; separately, the delivery system is placed in a suitably sized plastic container and counted in the dose calibrator using the same parameters as used for the dose. Measured radioactivity values and times of measurement are documented in the source documents and recorded in the eCRF, as well as the total injected volume.

[0072] Three minutes after the injection of the first dose, and collection of initial counts by the SPECT camera, a second injection of another dose of Altropane amounting to 1 mCi is administered During the next 3 min. photon counts are collected by the SPECT camera and extrapolated with appropriate algorithms which predicts the availability or non-availability of sufficient counts to obtain an interpretable image. If an interpretable image is obtained, based on the count of photons emitted from the ROI after the first or second bolus, further injections are discontinued and the patient remains in the camera until t = 45 min or until all counts have been collected and the image has been constructed.

[0073] If the injection of 2 mCi, spaced over 3 minutes as two boli is sufficient to arrive at a readable image, this subset of patients is spared from exposure to another 3 mCi, an amount which would have been administered under the current treatment protocols. Another subset of patients is administered and requires he full dose of 5 mCi to obtain a full SPEC image.

EQUIVALENTS

[0074] Those skilled in the art will recognize, or be able to ascertain, using no more than routine experimentation, numerous equivalents to the specific embodiments described specifically herein. Such equivalents are intended to be encompassed in the scope of the following claims.