NEW DEUTERIUM-SUBSTITUTED POSITRON EMISSION TOMOGRAPHY (PET) IMAGE AGENTS AND THEIR PHARMACOLOGICAL APPLICATIONS

Description

BACKGROUND OF THE INVENTION

[0001] Deuterium (D) is a stable isotope of hydrogen (H). While the differences in the physical and chemical properties between hydrogen and deuterium are relatively small (Meanwell, J. Med. Chem. 2011, 54:2529-91), deuterated compounds can have significant effects on biological and chemical processes that were developed optimally for hydrogen. The deuterium substitution is slightly less lipophilic than hydrogen, ΔlogP = - 0.006 and the molar volume of deuterium is smaller than hydrogen by 0.140 cm 3< / mol per atom. The carbon-deuterium (C-D) bonds are shorter than carbon hydrogen (C-H) bonds by 0.005 Å, therefore the activation energy for breaking a C-D vs C-H bond is significantly higher. Functionally, this reduces the cleavage rate for C-D bonds 6.7 times over C-H bonds (Kuchar, Molecules 2015, 20:16186-220), which can have a profound effect on drug pharmacokinetic properties.

[0002] Recent reports on deuterium substituted active pharmaceuticals have demonstrated benefits of the deuterium's kinetic isotope effect on the safety and clearance of drug substances and creation of new drugs through deuterated versions of existing molecules (Gant, J. Med. Chem. 2014, 57:3595-611). Some examples, such as tetrabenazine (NITOMAN or XENAZINE), deuterated tetrabenazine (SD-809, AUSTEDO), dextromethorphan, and D6-dextromethorphan (AVP-786) are shown below.

[0003] Deuterated tetrabenazine (SD-809) was recently approved by the FDA for treatment of chorea associated with Huntington's disease. Another example is AVP-786, deuterated dextromethorphan, which is designed to treat agitation in patients with Alzheimer disease (Garay, Expert Opin. Investig. Drugs 2017, 26:121-32).

[0004] The ability to moderate drug metabolism through hydrogen to deuterium substitution provides a novel approach in solving common complications of imaging agents-a lack of suitable resident time in vivo. In the past few decades there have been reports on using hydrogen to deuterium substitution to improve in vivo PET imaging agents (Kuchar, Molecules 2015, 20:16186-220; Guengerich, J Labelled Comp Radiopharm 2013, 56:428-31). A purpose of substituting deuterium for hydrogen is to slow down the in vivo metabolism to reduce the loss of radioactive tracer while maintaining binding capability for a specific enzyme or receptor binding site. One example is the use of 11< C-L-deprenyl-D2 (instead of 11< C-L-deprenyl) for mapping MAO-B enzyme (monoamine oxidase-B; amine oxygen oxidoreductase-B) activity in the brain (Fowler, J. Nucl. Med. 1995, 36:1255-62; Logan, Nucl. Med. Biol. 2000, 27:43-9).

[0005] Another example of hydrogen to deuterium substitution for developing PET tracers is the tetra-deuterated 18< F-fluoro-reboxetine-D4, which improved the in vivo stability of the deuterated PET tracers by retarding in vivo metabolism (Lin, Nucl. Med. Biol. 2005, 2:415-22; Ding, Curr. Pharm. Des. 2006, 12:3831-45). In addition, 11< C-choline, 11< C-D4-choline, 18< F-fluoroethyl-choline and 18< F-fluoroethyl-D4-choline have been compared in patients, to study tumor metabolic activity (Beauregard, Cancer Imaging 2016, 16:41; Nitsch, J. Nucl. Med. 2016, 57:38s-42s; Smith, Nucl. Med. Biol. 2011, 38:39-51; Witney, Clin. Cancer Res. 2012, 18:1063-72). Fluorinated deuterium-containing compounds that are useful for imaging with PET or SPECT (single photon emission tomography) are also mentioned in US 2008 / 050312 A1.

[0006] There exists a need to develop improved PET imaging agents, for example, using hydrogen to deuterium substitution, for evaluating conditions such as Parkinson"s Disease, Alzheimer Disease, and serotonin transporter binding of specific serotonin reuptake inhibitor (SSRI) for treatment of depression.BRIEF SUMMARY OF THE INVENTION

[0007] The present disclosure provides deuterium substituted tetrabenazine derivatives labeled with 18< F as PET imaging agents for diagnosis of Parkinson's disease. Non radioactive deuterated derivatives provide drugs targeting vesicular monoamine transporter 2 for therapy of movement disorders.

[0008] In one embodiment, the present disclosure provides a compound having Formula I-A: or a pharmaceutically acceptable salt thereof, wherein: R 1< is C 1-4 alkyl and is optionally substituted with one or more deuterium atoms; and X is 18< F or 19< F; Y is -(CD 2 ) 3 - ,

[0009] The present disclosure also provides deuterium substituted compounds as a PET imaging agent for diagnosis of Alzheimer disease.

[0010] In one embodiment, the present disclosure relates to a pharmaceutical composition comprising a deuterium substituted compound disclosed herein and a pharmaceutically acceptable carrier.

[0011] In one embodiment, the present disclosure relates to a method for imaging in a subject, comprising administering a radiolabeled compound disclosed herein to the subject; and obtaining an image of the subject or a portion of the subject.

[0012] In one embodiment, the present disclosure relates to a method of in vivo imaging, comprising administering an effective amount of a radiolabeled compound disclosed herein to a subject and detecting the pattern of radioactivity of the compound in the subject.DETAILED DESCRIPTION OF THE INVENTION

[0013] The present disclosure provides novel deuterium substituted PET imaging agents for evaluating Parkinson's Disease, Alzheimer Disease, and for determining specific serotonin reuptake inhibitor (SSRI) activity for treatment of depression.

[0014] As used herein, "a," "an," or "the" means one or more unless otherwise specified.

[0015] The term "or" can be conjunctive or disjunctive.

[0016] Open terms such as "include," "including," "contain," and "containing" mean "comprising."

[0017] The term "about," as used herein, is intended to qualify the numerical values which it modifies, denoting such a value as variable within a margin of error. The term "about" should be understood to mean that range which would encompass the recited value and the range which would be included by rounding up or down to that figure as well, taking into account significant figures. The term "about" as used herein, includes the recited number ±10%. For example, "about 10" means 9 to 11.

[0018] When ranges of values are disclosed, and the notation "from n 1 . . . to n 2 " or "n 1 -n 2 " is used, where n 1 and n 2 are the numbers, then unless otherwise specified, this notation is intended to include the numbers themselves and the range between them. This range may be integral or continuous between and including the end values.

[0019] The term "deuterium enrichment" refers to the percentage of incorporation of deuterium at a given position in a compound in the place of hydrogen. For example, deuterium enrichment of 1% at a given position means that 1% of molecules in a given sample contain deuterium at the specified position. Because the naturally occurring distribution of deuterium is about 0.0156%, deuterium enrichment at any position in a compound synthesized using non-enriched starting materials is about 0.0156%. The deuterium enrichment can be determined using conventional analytical methods known to one of ordinary skill in the art, including mass spectrometry and nuclear magnetic resonance spectroscopy.

[0020] The term "deuterium enrichment factor," as used herein, means the ratio between the isotopic abundance and the natural abundance of deuterium. For example, a position designated as having deuterium can have a minimum isotopic enrichment factor of at least 3340 (50.1% deuterium incorporation) at each atom designated as deuterium in a compound disclosed herein.

[0021] In some embodiments, a compound of the present disclosure has an isotopic enrichment factor for each designated deuterium atom of at least 3500 (54.6% deuterium incorporation at each designated deuterium atom), at least 4000 (62.4% deuterium incorporation), at least 4500 (70.2% deuterium incorporation), at least 5000 (78% deuterium), at least 5500 (85.8% deuterium incorporation), at least 6000 (93.6% deuterium incorporation), at least 6090 (95% deuterium incorporation), at least 6218 (97% deuterium incorporation), at least 6346 (99% deuterium incorporation), or at least 6378 (99.5% deuterium incorporation).

[0022] The term "is / are deuterium," when used to describe a given position in a compound disclosed herein or the symbol "D," when used to represent a given position in a drawing of a compound, means that the specified position is enriched with deuterium above the naturally occurring distribution of deuterium. In some embodiments, deuterium enrichment is at least about 1%, at least about 5%, at least about 10%, at least about 20%, at least about 50%, at least about 70%, at least about 80%, at least about 90%, at least about 95%, at least about 97%, at least about 98%, or at least about 99% of deuterium at the specified position.

[0023] The deuterated compounds disclosed herein can be prepared using commercially available deuterium-containing starting materials. Many deuterium-containing starting materials have >99% deuterium enrichment at the specified position.

[0024] Some of the compounds disclosed herein contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. The invention is meant to encompass the compounds in all such possible forms, as well as their racemic and resolved forms and mixtures thereof.

[0025] Certain compounds disclosed herein are labeled with a radioactive fluorine atom 18< F. Certain other compounds disclosed herein contain the stable isotope of fluorine, 19< F, which is used interchangeably with F herein.

[0026] As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, and allergic response, and are commensurate with a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, S. M. Berge et al., describe pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 1977, 66, 1-19.

[0027] The term "pharmaceutically acceptable salts" embraces salts with inorganic and organic acids, and inorganic and organic bases. The pharmaceutically acceptable salts include, metal salts such as sodium salt, potassium salt, cesium salt ; alkaline earth metals such as calcium salt, magnesium salt; organic amine salts such as triethylamine salt, pyridine salt, picoline salt, ethanolamine salt, triethanolamine salt, dicyclohexylamine salt, N,N'-dibenzylethylenediamine salt; inorganic acid salts such as hydrochloride, hydrobromide, phosphate, sulphate; organic acid salts such as citrate, lactate, tartrate, maleate, fumarate, mandelate, acetate, dichloroacetate, trifluoroacetate, oxalate, formate; sulfonates such as methanesulfonate, benzenesulfonate, p-toluenesulfonate; and amino acid salts such as arginate, asparginate, glutamate.

[0028] The term "treating" or "treatment" refers to administering a therapy in an amount, manner, or mode effective to improve a condition, symptom, or parameter associated with a disorder or to slow or prevent progression of a disorder, to either a statistically significant degree or to a degree detectable to one skilled in the art. An effective amount, manner, or mode can vary depending on the subject and may be tailored to the subject. A subject includes a human or an animal.Deuterated 18< F-FP-DTBZ ( 18< F-AV-133) as a vesicular monoamine transporter 2 (VMAT2) imaging agent

[0029] Fluoroalkyl derivatives of dihydroxy-tetrabenazine have been prepared and tested as imaging agents for vesicular monoamine transporter 2 (VMAT2) in the brain (Goswami, Nucl. Med. Biol. 2006, 33:685-94; Kilbourn, Nucl. Med. Biol. 2007, 34:233-7). PET imaging using 11< C-dihydrotetrabenazine, ( 11< C-DTBZ) is useful to map the distribution VMAT2 in neurons. The 18< F labeled FP-DTBZ ( 18< F-FP-(+)-DTBZ, 18< F-AV-133), with a longer physical half-life, has also been developed. In the past few years, several reports have described the clinical usefulness of 18< F-AV-133 as a VMAT2 imaging agent. Results of human clinical studies for 18< F-AV-133 / PET have suggested that it is a useful agent in assisting diagnosis and monitoring of Parkinson's disease.

[0030] In relation to the discovery of the effects of deuterium on metabolic clearance, an additional area of use for 18< F-AV-133 / PET that demonstrated this effect, was in visualizing beta cells within the pancreas. It was proposed that the VMAT2 binding in the pancreas may be a useful indicator for measuring beta cell mass, which is significantly reduced in patients with diabetes (Kung, J. Nucl. Med. 2008, 49:1171-6; Raffo, J. Endocrinol. 2008, 198:41-9; Harris, J. Mol. Med. 2008, 86:5-16; Harris, Nucl. Med. Biol. 2013, 40:60-4; Freeby, Islets 2012, 4:393-7).

[0031] Both of 11< C-DTBZ and 18< F-FP-DTBZ have been tested in humans as vesicular monoamine transporter 2 (VMAT2) imaging agents for diagnosis of Parkinson's disease. 18< F-FE-DTBZ has also been investigated as a potential pancreas imaging agent.

[0032] In an effort to develop additional VMAT2 imaging agents specifically targeting beta cells, similar derivatives, 18< F-fluoroethyl-DTBZ (FE-DTBZ) and the corresponding deuterated 18< F-fluoroethyl-DTBZ-D4 ( 18< F-FE-D4-DTBZ-D4), have been prepared for imaging VMAT2 in the pancreas (Eriksson, Nucl. Med. Biol. 2010, 37:357-63; Jahan, EJNMMI Res 2011, 1:33).

[0033] Of additional note to these studies, there may be side products produced during the preparation of 18< F-FP-DTBZ. It is likely that one of the impurities was derived from a nucleophilic substitution of the fluoride ion that induced an elimination reaction instead. The elimination reaction likely occurred by breaking the C-H bond first, which led to the elimination reaction. Without wishing to be bound by theory, it is believed that substituting the hydrogen atoms with deuterium on the 18< F propyl group can reduce the elimination reaction, and thus improve the labeling reaction (Scheme 1). In addition, the deuterium atoms on the fluoropropyl group can provide the compounds with better in vivo stability for imaging VMAT2 binding sites in the brain of Parkinson's patients.

[0034] The present disclosure provides deuterium substituted tetrabenazine derivatives as a PET imaging agent for diagnosis and therapy of Parkinson's disease.

[0035] In one embodiment, the present disclosure provides a compound having Formula I-A: or a pharmaceutically acceptable salt thereof, wherein: R 1< is C 1-4 alkyl and is optionally substituted with one or more deuterium atoms; and X is 18< F or 19< F; Y is -(CD 2 ) 3 -.

[0036] One embodiment of the present disclosure provides a compound of Formula I-A wherein R 1< is C 1-4 alkyl that can be deuterated or non-deuterated. In some embodiments, R 1< is -CH 3 , -CD 3 , -CH 2 CH 3 , -CD 2 CD 3 , -CD 2 CH 3 , -CH 2 CD 3 , -CH(CH 3 ) 2 , -CD(CD 3 ) 2 , -CH(CD 3 ) 2 , -CD(CH 3 ) 2 , -CH 2 CH(CH 3 ) 2 , -CD 2 CH(CH 3 ) 2 , -CH 2 CD(CH 3 ) 2 , -CH 2 CH(CD 3 ) 2 , -CD 2 CD(CH 3 ) 2 , -CD 2 CH(CD 3 ) 2 , -CH 2 CD(CD 3 ) 2 , or -CD 2 CD(CD 3 ) 2 . In some of these embodiments, R 1< is -CD 3 , -CD 2 CD 3 , -CD 2 CH 3 , -CH 2 CD 3 , -CD(CD 3 ) 2 , -CH(CD 3 ) 2 , -CD(CH 3 ) 2 , -CD 2 CH(CH 3 ) 2 , -CH 2 CD(CH 3 ) 2 , -CH 2 CH(CD 3 ) 2 , -CD 2 CD(CH 3 ) 2 , -CD 2 CH(CD 3 ) 2 , -CH 2 CD(CD 3 ) 2 , or -CD 2 CD(CD 3 ) 2 . In some embodiments, R 1< is -CH 3 or -CD 3 . In some embodiments, R 1< is -CD 3 .

[0037] In some embodiments, the compound of Formula I-A has the following formula: or a pharmaceutically acceptable salt thereof, wherein X, Y, and R 1< are as defined herein.

[0038] In some embodiments, the compound of Formula I-A has the following formula: or a pharmaceutically acceptable salt thereof, wherein X is 18< F or 19< F.

[0039] In some embodiments, the compound of Formula I-A has the following formula: or a pharmaceutically acceptable salt thereof, wherein X is 18F or 19F.

[0040] In one embodiment, the compound of Formula I-A is: or a pharmaceutically acceptable salt thereof.

[0041] In one embodiment, the compound of Formula I-A is: or a pharmaceutically acceptable salt thereof.

[0042] In one embodiment, the compound of Formula I-A is: or a pharmaceutically acceptable salt thereof.

[0043] In one embodiment, the compound of Formula I-A is: or a pharmaceutically acceptable salt thereof.

[0044] The present disclosure provides a method for imaging in a subject comprising administering an effective amount of a compound of Formula I-A or a pharmaceutically acceptable salt thereof to the subject and obtaining an image of the subject or a portion of the subject. In some embodiments, the method comprises; administering an effective amount of a compound of Formula I-A disclosed herein wherein X is 18< F.

[0045] The present disclosure also provides a compound of Formula I-A or a pharmaceutically acceptable salt thereof for use in a method for treating Parkinson's disease in a subject in need thereof comprising administering a therapeutically effective1 amount of a compound of Formula I-A or a pharmaceutically acceptable salt thereof to the subject. In some embodiments, in the compound of Formula I-A X is 19< F.

[0046] Certain compounds disclosed herein may possess useful VMAT2 inhibiting activity. Other embodiments provide a compound of Formula I-A for use in methods for treating a VMAT2-mediated disorder in a subject in need of such treatment, comprising administering to the subject a therapeutically effective amount of a compound of Formula I-A. Also provided is the use of certain compounds disclosed herein in the manufacture of a medicament for the treatment of a disorder ameliorated by the inhibition of VMATAZ2.

[0047] The term "VMAT2-mediated disorder" refers to a disorder that is characterized by abnormal VMAT2 activity. A VMAT2-mediated disorder may be completely or partially mediated by modulating VMAT2. In particular, a VMAT2-mediated disorder is one in which inhibition of VMAT2 results in some effect on the underlying disorder.

[0048] VMAT2-mediated disorders, include chronic hyperkinetic movement disorders, and / or any disorder which can lessened, alleviated, or prevented by administering a VMAT2 inhibitor. The term "chronic hyperkinetic movement disorders" refers to disorders characterized by non-purposeful, repetitive, disordered motor acts, variously termed "compulsive", "rhythmical", or "stereotyped." In humans, chronic hyperkinetic movement disorders can be psychogenic (e.g., tics), idiopathic (as in, e.g., Tourette's syndrome and Parkinson's disease, genetic (as in, e.g., the chorea characteristic of Huntington's Disease), infectious (as in, e.g., Sydenham's Chorea), or, as in tardive dyskinesia, drug-induced. Unless otherwise stated, "chronic hyperkinetic movement disorders" refers to and includes all psychogenic, idiopathic, genetic, and drug-induced movement disorders.

[0049] In certain embodiments, the chronic hyperkinetic movement disorder is Huntington's disease. In certain embodiments, the chronic hyperkinetic movement disorder is Parkinson's disease.Deuterated amyloid imaging agents for Alzheimer Disease

[0050] In Alzheimer disease (AD) β-amyloid peptide (Aβ) aggregates are deposited in extracellular plaques typically composed of straight fibrils. These structures are also found in normal aging and are sometimes referred to as senile plaques. Aβ plaque deposition (i.e. Amyloid hypothesis) is considered the key pathophysiological event leading to AD (Gauthier, Alzheimer Dement 2016, 12:60-4; Harrison, Br. J. Psychiatry 2016, 208:1-3). Research into Aβ plaque-specific imaging agents is one of the most fascinating developments in the field of brain imaging over the past fifteen years, and has been extensively reviewed. The most well characterized PET imaging agent for Aβ plaques in the brain is 11< C-6-OH-BTA-1, ( 11< C-PIB) (Mathis, Semin. Nucl. Med. 2012, 42:423-32), and has been used as a tracer for imaging Aβ plaques in the brain of suspected AD patients. Many different core structures have been prepared and tested. Among the hundreds of potential ligands that show good binding to Aβ plaques, four 18< F labeled tracers, suitable for commercial distribution, have been successfully tested in humans (Kung, ACS Med Chem Lett 2012, 3:265-7; Villemagne, Semin. Nucl. Med. 2017, 47:75-88), and the FDA has approved three (AMYVID, NEURACEQ, and VIZAMYL) for human Aβ imaging (Scheme 2). Another Aβ plaque imaging agent, structurally similar to flutemetamol (VIZAMYL), NAV4694, has also shown excellent in vitro binding and promising in vivo kinetics in human studies (Rowe, J. Nucl. Med. 2013, 54:880-6).

[0051] 11< C-PIB was the first agent tested in humans, which led to the development of 18< F-Vizamyl and NAV4694. Additionally, modifying 11< C-SB-13 led to the discovery of stilbene and the styrylpyridine series of agents. Three units of polyethylene glycol chains were attached to the core. The polyethylene glycol chains are useful for adjusting the lipophilicity and providing a suitable position for fluorine substitution. All of these PET imaging agents contain an N-methyl group attached to a phenyl ring. The electron donating N-methyl anilinyl group plays an important role in binding the target sites in the Aβ plaques. Without wishing to be bound by theory, it is believed that substituting the N-methyl group with a deuterated N-methyl group can reduce the N-demethylation reaction in vivo.

[0052] Previous reports on in vivo metabolism of 18< F-AV-45 (AMYVID) showed a rapid change in the plasma after intravenous (i.v.) injection. In vivo metabolism of 18< F-AV-45 in mice showed that, at 30 min after an intravenous injection, only 30% of the parent 18< F-AV-45 remained in the plasma. The biologic T 1 / 2 of 18< F-AV-45 in mouse plasma was estimated to be less than 30 min. Metabolite profiling and identification of the metabolites were done by HPLC with radioactive detection and liquid chromatography / mass spectroscopy analysis. One of the plasma metabolites was N-demethylated 18< F-AV-160, which constituted about 48% of the metabolites at 30 min after injection (Scheme 3). The brain uptake of 18< F-AV-160 at 2 min after injection was 4.5 %ID / g of tissue, and decreased to 1.8 %ID / g at 60 min. The initial uptake of the parent 18< F-AV-45 was 1.5-fold higher than this metabolite. No significant binding to Aβ plaques was observed with the metabolites using AD brain-section autoradiography and the in vitro AD brain homogenate binding assay. The inhibition constant of AV-160 (K i = 54 ± 5 nM) indicates at least a 20-fold reduction of binding affinity to Aβ plaques in AD brain tissue homogenates, as compared with that of the nonradioactive version of 18< F-AV-45 (K i = 2.87 ± 0.17 nM) (Choi, J. Nucl. Med. 2009, 50:1887-94).

[0053] In humans, the in vivo metabolism was found to be similar to that in mice (Wong, J. Nucl. Med. 2010, 51:913-20). After an injection of 18< F-AV-45, the total radioactivity in plasma and the fraction of plasma radioactivity accounted for by 18< F-AV-45 were rapidly reduced. Plasma radioactivity was decreased by approximately 80% within 10 min and by approximately 90% within 20 min of the injection. In addition to the parent compound, 18< F-AV-45, three metabolite peaks were observed in human plasma. One of the major peaks was matched to cold reference as desmethyl- 18< F-AV-45 (N-desmethyl 18< F-AV-45, i.e., 18< F-AV-160). In comparison, 18< F-AV-1 (NUERACEQ) also displayed a rapid in vivo metabolism; one of the major metabolites in human plasma was the N-desmethyl 18< F-AV-1 (see Scheme 3). It is believed that the N-demethylation leads to reduced binding affinities towards Aβ plaques in the brain, and contributes to increased non-specific binding. Therefore, a novel strategy to reduce the in vivo production of 18< F-AV-160 by slowing the N-demethylation process by substituting a deuterated N-methyl group on AV-45, should improve imaging by increased uptake of 18< F-AV-45 to Aβ plaques in the brain and a decrease of non-specific binding (Scheme 4). Deuterated FPBM as serotonin transporter (SERT) imaging agents

[0054] Serotonin neurons in the central nervous system play an important role in normal brain function. Serotonin transporters (SERT) localized on serotonin neurons serve as the main re-uptake mechanism for terminating the action of serotonin by transporting serotonin, the neurotransmitter, from the synapse back into the presynaptic neuron. These transporters are important for controlling serotonin concentration in the synapse and its binding to the postsynaptic serotonin receptors. Selective serotonin reuptake inhibitors (SSRIs), such as Fluoxetine, Sertraline, Paroxetine, Escitalopram, specifically target SERT and prevent serotonin reuptake to the neurons. Consequently, SSRIs are useful in the treatment of depression as well as many other psychiatric conditions by controlling the concentration of serotonin in the synapse (Bousman, BMC Psychiatry 2017, 17:60). They are generally considered as the first-line therapy for depression, and they are one of the most commonly prescribed classes of drugs in the world. Positron emission tomography (PET) imaging with a suitably 18< F labeled SERT inhibitor is useful as a method for probing pathophysiological and therapeutic mechanisms in various psychological diseases (Spies, Lancet Psychiatry 2015, 2:743-55). A number of SERT ligands for in vivo imaging have been developed (see structures below). 11< C-McN5652 was the first SERT PET imaging tracer used in humans. Development of 18< F-FMe-(+)-McN5652, an S- 18< F-fluoromethyl analogue of (+)-McN5652, showed favorable features for SERT imaging with PET in humans (Hesse, J. Nucl. Med. Mol. Imaging 2012, 39:1001-11). PET imaging is also suitable for in vivo quantification of SERT.

[0055] Ligands with a core structure of bisphenylthiol also showed promising results as in vivo SERT imaging agents. The most commonly used SERT PET imaging agent is 11< C-DASB (Wilson, J. Med. Chem. 2000, 43:3103-10; Wilson, Nucl. Med. Biol. 2002, 29:509-15). It showed excellent selectivity, high reproducibility, and simple kinetic modeling for quantification (Kupers, Neuroimage 2011, 54:1336-43; Ginovart, Synapse 2004, 52:89-99). However, 11< C-DASB is a 11< C-labeled radiotracer that is limited by a short physical half-life (20 min), which is unsuitable for widespread clinical application. 18< F has a longer half-life (110 min) and can be produced in several curies of activity by a cyclotron. This makes it feasible to radiolabel at a radiopharmacy and distribute the ligand regionally. Thus, an 18< F-labeled SERT imaging agent may be valuable for commercial delivery via radiopharmacies. Significant efforts have been made to develop such 18< F-labeled radiotracers for SERT imaging. One promising 18< F-labeled ligand is 18< F-4-FADAM (Huang, Eur. J. Nucl. Med. Mol. Imaging 2013, 40:115-24; Shiue, J. Nucl. Med. 2003, 44:1890-7).

[0056] Results from the first human study of 18< F-4-FADAM showed that it was safe and effective for mapping SERT regional binding sites (Huang, Eur. J. Nucl. Med. Mol. Imaging 2013, 40:115-24). The regional specific uptake in the human brain correlated well with the known distribution of SERT. The optimal imaging time (about 120 min) was slightly long, but acceptable for routine clinical use. An alternative bisphenylthiol derivative, 18< F-FPBM, with a different substitution on the phenyl ring has been shown to possess high selective binding (K i = 0.38 nM), high brain uptake (0.99% dose / g at 2 min post iv injection), and an excellent in vivo target-to-non-target ratio (7.7 at 120 min post injection) (Wang, Nucl. Med. Biol. 2008, 35:447-58; Wang, J. Nucl. Med. 2009, 50:1509-17; Wang, Nucl. Med. Biol. 2010, 37:479-86). Previously, the labeling of this diarylsulfide was performed by a nucleophilic fluorination with K 18< F-F / K 2.2.2 via TsO-precursor (Scheme 5) (Qiao, Nucl. Med. Biol. 2016, 43:470-7; Zhu, Nucl. Med. Biol. 2013, 40:974-9). The desired product, 18< F-FPBM, was further purified by either high-performance liquid chromatography (HPLC) or solid phase extraction (SPE). During the labeling procedure it was observed that an elimination reaction led to the production of a vinyl side product.

[0057] Similar to that observed for 18< F-FP-DTBZ ( 18< F-AV-133), the elimination reaction may occur by breaking the C-H bond first. Without wishing to be bound by theory, it is believed that substituting the hydrogen atoms on the propyl group with deuterium can reduce the eliminating reaction, thus improving the labeling reaction. In addition, N,N-dimethyl groups can be replaced by two deuterated methyl groups, which will resist the in vivo de-methylation reaction. ExamplesExample 1Synthesis of Compound Ia

[0058] Synthesis of compound Ia-2: (2R,3R,11R)-3-Isobutyl-10-methoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinoline-2,9-diol

[0059] A mixture of 9-benzyl protected DTBZ (Ia-1, 380 mg, 0.96 mmol) and 10% dry Pd / C (15 mg) was stirred in THF (10 mL) and EtOH (5 mL) under H 2 at room temperature for 6 h. The reaction mixture was filtered and washed with EtOH (10 mL) and THF (10 mL). The solvent was removed under vacuum to give Ia-2 (255 mg, 87%) as a yellow solid. 1< HNMR (400 MHz, CDCl 3 ) δ 6.68 (s, 1H), 6.67 (s, 1H), 3.87 (s, 3H), 3.44-3.38 (m, 1H), 3.16-2.97 (m, 4H), 2.66-2.56 (m, 2H), 2.49-2.42 (m, 1H), 1.99 (t, J=2.01 Hz, 1H), 1.79-1.68 (m, 2H), 1.57-1.45 (m, 3H), 1.12-1.05 (m, 1H), 0.97-0.93 (m, 6H). HRMS calcd. for C 18 H 27 NO 3 [M+H] +< 306.2069. found 306.2100. Synthesis of compound Ia-4: [1,1,2,2,3,3-D 6 ]-Propane-1,3-diylbis(4-methylbenzenesulfonate)

[0060] To a solution of compound Ia-3 (270 mg, 3.29 mmol) (99 atom %D) in THF (10 mL) was added NaOH (527 mg, 13.17 mmol) in H 2 O (5 mL) at 0 °C. The reaction mixture was stirred at room temperature for 1 h. TsCl (1.88 g, 9.88 mmol) in THF (10 mL) was then added dropwise. The reaction was stirred at room temperature for 24 h. H 2 O (20mL) was added and the mixture was extracted with ethyl acetate (3 × 30 mL). The organic layers were combined and dried over anhydrous MgSO 4 , filtered and the filtrate was evaporated in vacuum, purified by flash chromatography (silica gel) (Ethyl Acetate (EA) / Hexane, 0% to 60%, vol / vol) to give [1,1,2,2,3,3-D 6 ]-propane-1,3-diylbis(4-methylbenzenesulfonate), Ia-4, (970 mg, 76%) as a white solid. 1< HNMR (400 MHz, CDCl 3 ) δ 7.78-7.76 (m, 4H), 7.38-7.36 (m, 4H), 2.483 (s, 6H), HRMS calcd. for C 17 H 14 D 6 O 6 S 2 [M+H] +< 391.1156. found 391.1140. Synthesis of compound Ia-5: 3-(((2R,3R,11R)-2-Hydroxy-3-isobutyl-10-methoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-9-yl)oxy)propyl-[1,1,2,2,3,3-D 6 ])-4-methylbenzenesulfonate.

[0061] A mixture of Ia-2 (44 mg, 0.14 mmol) and K 2 CO 3 (119 mg, 0.86 mmol) was stirred in DMF (4 mL) at room temperature for 1 h. Compound Ia-4 (68 mg, 0.17 mmol) was then added and the reaction mixture was stirred for 24 h at room temperature. Water (5 mL) was added, and the mixture was extracted with ethyl acetate (5 × 15 mL). The organic layers were combined and dried over anhydrous MgSO 4 , filtered and the filtrate was evaporated in vacuum, purified by flash chromatography (silica gel) (MeOH / DCM, 0% to 10%, vol / vol) to give Ia-5 (33.7 mg, 45%) as a light yellow solid. 1< HNMR (400 MHz, CDCl 3 ) δ 7.80-7.78 (m, 2H), 7.30-7.29 (m, 2H), 6.68 (s, 1H), 6.54 (s, 1H), 3.78 (s, 3H), 3.43-3.39 (m, 1H), 3.15-2.97 (m, 4H), 2.65-2.57 (m, 2H), 2.50-2.44 (m, 1H), 2.43 (s, 3H), 2.00 (t, J=2.01 Hz, 1H), 1.78-1.68 (m, 2H), 1.64-1.47 (m, 3H), 1.12-1.05 (m, 1H), 0.98-0.94 (m, 6H). HRMS calcd. for C 28 H 33 D 6 NO 6 S [M+H] +< 524.2953. found 524.2963. Synthesis of compound Ia: (2R,3R,11R)-9-(3-Fluoropropoxy-[1,1,2,2,3,3-D 6 ])-3-isobutyl-10-methoxy-2,3,4,6,7,11b-hexahydro-1H-pyrido[2,1-a]isoquinolin-2-ol.

[0062] A mixture of compound Ia-5 (30 mg, 0.06 mmol) and 1M TBAF in THF (0.17 mL, 0.17 mmol) was stirred in anhydrous THF (5 mL) at 60 °C for 5 h. H 2 O (5 mL) was added, and the mixture was extracted with ethyl acetate (5 × 10 mL). The organic layers were combined and dried over anhydrous MgSO 4 , filtered and the filtrate was evaporated in vacuum, purified by flash chromatography (silica gel) (MeOH / DCM, 0% to 10%, vol / vol) to give Ia (11.2 mg, 26%) as a light yellow solid. 1< HNMR (400 MHz, CDCl 3 ) δ 6.71 (s, 1H), 6.64 (s, 1H), 3.84 (s, 3H), 3.44-3.38 (m, 1H), 3.16-2.98 (m, 4H), 2.66-2.57 (m, 2H), 2.51-2.44 (m, 1H), 2.00 (t, J=2.01 Hz, 1H), 1.79-1.68 (m, 2H), 1.56-1.47 (m, 3H), 1.12-1.05 (m, 1H), 0.97-0.94 (m, 6H). HRMS calcd. for C 21 H 26 D 6 FNO 3 [M+H] +< 372.2821. found 372.2824.

[0063] Preparation of 18< F-Ia ( 18< F-AV-133-D6) by radiolabeling was accomplished by the following steps. 18< F fluoride was loaded on an activated QMA light cartridge and eluted with 0.7 mL K 222 / K 2 CO 3 solution (40 mg K 2 CO 3 , 220 mg K 222 , 3.6 mL water, 18.4 mL ACN) into conical vial. The solution was dried under a flow of argon at 80 °C and azeotropically dried twice with 1 mL acetonitrile. 1 mg Ia-5 was dissolved in 0.5 ml DMSO (anhydrous) and added to dried [ 18< F]F -< / K 222 / K 2 CO 3 complex. The reaction mixture was heated for 15 min at 115 °C. The resulting reaction mixture was cooled to room temperature and added to 8 mL water. The mixture was loaded onto an Oasis HLB (3cc) cartridge. Eluted and washed twice with 3 mL water. The desired 18< F-Ia was eluted with 1 ml acetonitrile (yield: 62%, RCP ~98% HPLC (Supelco Ascentis 150 × 4.6 mm, ACN / 10 mM ammonium format buffer (AFB) 45 / 55, 1 mL / min). To this solution was added about 1 mL of 10 mM AFB and injected onto prep HPLC (Phenomenex Gemini 250 ×10 mm, ACN / 10 mM AFB 45 / 55, 3 mL / min). The eluent of the desired 18< F-Ia was collected (660 µCi mCi, retention time 14 - 15 min). The solution was mixed with 18 mL water and added onto an Oasis HLB 3cc. The activity was eluted with 1 mL 100% ethanol (590 µCi). Solution was concentrated to about 200 µL volume diluted with 1.8 mL buffer. HPLC profile on HPLC (HPLC: Supelco Ascentis 150 × 4.6 mm, ACN / 10 mM AFB 45 / 55, 1 mL / min) showed single peak at 6 minutes for 18< F-Ia ( 18< F-AV-133-D6), RCY 48% (dc): RCP: 99%; SA ~ 182 Ci / mmol (measured at 280 nm). The retention time corresponded to cold Ia. Example 2In vitro binding assay for Ki determination AV-133 vs AV-133-D6 (Ia)

[0064] Tissue homogenates of striatum (dissected from rat brain) were prepared in 50 mM of HEPES, pH 7.5, and 0.3 M of sucrose. Compounds were examined for their ability to compete for the binding of 18< F-AV-133 or 18< F-AV-133-D6 ( 18< F-Ia ) (0.15-0.2 nM) at concentrations ranging from 10 -7< to 10 -12< M. The binding assays were performed in glass tubes (12 x 75 mm) in a final volume of 0.25 mL. The nonspecific binding was defined with 10 µM (±)-tetrabenazine (TBZ). After incubation for 90 min at room temperature, the bound ligand was separated from the free ligand by filtration through glass fiber filters. The filters were washed three times with 4 mL of ice-cold PBS buffer, pH 7.4 and the radioactivity on the filters was counted with a gamma counter (WIZARD 2< , Perkin-Elmer). Data were analyzed using the nonlinear least-square curve fitting program LIGAND to determine IC 50 and Ki was calculated by Cheng-Prusoff equation using 0.11 nM as Kd of AV-133 and AV-133-D6 (Ia). Table 1a.Comparison of in vitro binding affinity (Ki, nM) to vesicular monoamine transporter 2 (VMAT2) for (±)TBZ, AV-133, and AV-133-D6 (Ia) Hot ligandKi of cold competing drug (nM, Avg ± SD, n=3)(±)TBZAV-133Ia (AV-133-D6) 18< F-AV-133-D61.65 ± 0.070.26 ± 0.030.33 ± 0.06 18< F-AV-1331.49 ± 0.240.33 ± 0.020.32 ± 0.07

[0065] The (±)TBZ showed a lower binding affinity comparable to reported in the literature. Results of binding studies for AV-133 and AV-133-D6 (Ia) showed that hydrogen to deuterium substitution provided the same binding affinity to the VMAT2 binding sites. The results showed that 18< F-AV-133-D6 (Ia) is an excellent PET imaging agent for VMAT2 binding sites. Similar to the recently approved deuterated tetrabenazine SD-809, the "cold" AV-133-D6 (Ia) which shows a higher binding affinity to the target sites (VMAT2), may be a useful therapeutic agent for movement disorders.Example 3Comparison of FP-DTBZ biodistribution data in rats: 18< F-FP-(+)DTBZ vs 18< F-FP-DTBZ-D6 ( 18< F-Ia)

[0066]

[0067] Three rats per group were used for each biodistribution study. While under isoflurane anesthesia, 0.2 mL of a saline solution containing 20 µCi of radioactive tracer was injected into the femoral vein. The rats were sacrificed at the time indicated by cardiac excision while under isoflurane anesthesia. Organs of interest were removed and weighed, and the radioactivity was counted. The percent dose per organ was calculated by comparing the tissue counts to counts of 1% of the initial dose (100 times diluted aliquots of the injected material) measured at the same time. Regional brain distribution in rats was measured after an iv injection of the radioactive tracer. Samples from different brain regions (cortex, striatum, hippocampus, cerebellum and hypothalamus) were dissected, weighed and counted. The percentage dose / g of each sample was calculated by comparing sample counts with the counts of the diluted initial dose described above. The ratio was calculated by dividing the percentage dose / g of each region by that of the cerebellum. The cerebellum was used as the reference region for calculating the ratio of target to non-target binding, because only a trace amount of VMAT2 binding site is present in the cerebellum. Table 1b. Biodistribution in normal male CD rats after an IV injection of 18< F-FP-(+)DTBZ (average of 3 rats ± SD )% dose / g2 min60 min120 minBlood0.24 ±0.030.12 ±0.000.07 ±0.01Heart0.96 ±0.080.22 ±0.030.16 ±0.01Muscle0.11 ±0.020.10 ±0.010.07 ±0.00Lung1.03 ±0.030.41 ±0.030.31 ±0.02Kidney2.66 ±0.150.63 ±0.050.45 ±0.02Spleen1.19 ±0.100.50 ±0.040.37 ±0.05Pancreas2.29 ±0.364.48 ±0.273.56 ±0.42Liver2.28 ±0.042.59 ±0.212.12 ±0.20Skin0.19 ±0.030.24 ±0.030.17 ±0.01Brain0.83 ±0.060.35 ±0.030.26 ±0.03Bone0.45 ±0.031.13 ±0.071.86 ±0.24 Regional Brain Distribution (% dose / gram ± SD) for 18< F-FP-(+)DTBZ

[0068] 2 min60 min120 minCerebellum0.68 ±0.060.19 ±0.020.13 ±0.01Striatum1.12 ±0.041.04 ±0.050.87 ±0.12Hippocampus0.80 ±0.070.30 ±0.010.24 ±0.03Cortex0.82 ±0.070.21 ±0.010.15 ±0.02Remainder0.83 ±0.060.31 ±0.020.21 ±0.02Hypothalamus1.06 ±0.100.73 ±0.110.54 ±0.11 Ratio vs. Cerebellum for 18< F-FP-(+)DTBZ

[0069] 2 min60 min120 minCerebellum1.00 ±0.001.00 ±0.001.00 ±0.00Striatum1.66 ±0.155.66 ±0.726.54 ±0.59Hippocampus1.19 ±0.031.64 ±0.191.79 ±0.12Cortex1.21 ±0.041.13 ±0.091.11 ±0.09Remainder1.23 ±0.031.68 ±0.071.59 ±0.09Hypothalamus1.57 ±0.043.91 ±0.374.04 ±0.66 Table 1c. Biodistribution in normal male CD IGS rats after an IV injection of 18< F-FP-(+)DTBZ-D6 ( 18< F-Ia ) (average of 3 rats ± SD ) % dose / g2 min60 min120 minBlood0.23 ±0.030.11 ±0.010.10 ±0.00Heart0.69 ±0.120.26 ±0.010.21 ±0.01Muscle0.17 ±0.020.11 ±0.000.09 ±0.01Lung0.87 ±0.050.49 ±0.000.41 ±0.01Kidney1.89 ±0.070.66 ±0.040.59 ±0.02Spleen1.04 ±0.100.66 ±0.030.51 ±0.03Pancreas2.62 ±0.155.01 ±0.694.49 ±0.17Liver2.79 ±0.123.19 ±0.463.10 ±0.49Skin0.24 ±0.020.25 ±0.010.21 ±0.01Brain0.64 ±0.070.44 ±0.020.34 ±0.02Bone0.33 ±0.040.47 ±0.020.65 ±0.03 Regional Brain Distribution (% dose / gram ± SD) for 18< F-FP-(+)DTBZ-D6 ( 18< F-Ia )

[0070] 2 min60 min120 minCerebellum0.48 ±0.040.23 ±0.010.18 ±0.01Striatum1.00 ±0.221.40 ±0.061.00 ±0.08Hippocampus0.60 ±0.070.39 ±0.010.31 ±0.04Cortex0.65 ±0.070.26 ±0.010.20 ±0.00Remainder0.64 ±0.070.37 ±0.020.28 ±0.02Hypothalamus0.82 ±0.100.91 ±0.030.65 ±0.11 Ratio vs. Cerebellum for 18< F-FP- (+)DTBZ-D6 ( 18< F-Ia)

[0071] 2 min60 min120 minCerebellum1.00 ±0.001.00 ±0.001.00 ±0.00Striatum2.08 ±0.306.05 ±0.435.49 ±0.43Hippocampus1.26 ±0.041.68 ±0.121.74 ±0.32Cortex1.36 ±0.051.13 ±0.021.10 ±0.09Remainder1.33 ±0.031.59 ±0.041.52 ±0.03Hypothalamus1.71 ±0.103.93 ±0.153.56 ±0.49

[0072] This comparison biodistribution study in rats between 18< F-FP-(+)DTBZ and 18< F-FP-DTBZ-D6 ( 18< F-Ia) demonstrated that there was good similarity. However, the most noticeable difference is the bone uptake. The deuterated 18< F-FP-DTBZ-D6 ( 18< F-Ia) showed a clearly distinctive lowering of the bone uptake, the bone uptake at 60 and 120 min were 1.33 and 1.86 %dose / g for 18< F-FP- (+)DTBZ, while the deuterated 18< F-FP-DTBZ-D6 ( 18< F-Ia) showed bone uptake of 0.47 and 0.65 %dose / g, respectively. The improvement shown in lowering the bone uptake is likely associated with the higher bond energy of C-D as compared to C-H; as a consequence it reduces the level of free 18< F fluoride in the blood circulation.

[0073] One other major observation is the improved brain uptake at 120 min after iv injection. The total brain uptake were 0.26 vs 0.34 %dose / g for 18< F-FP-(+)DTBZ and 18< F-FP-DTBZ-D6 ( 18< F-Ia), respectively. This amounts to a 40% increase in total brain uptake. The two agents showed comparable regional brain uptake ratios; at 60 min post i.v. injection the striatum / cerebellum ratios were 5.66 vs 6.05 for 18< F-FP-(+)DTBZ and 18< F-FP-DTBZ-D6 ( 18< F-Ia), respectively.

[0074] The hydrogen to deuterium substitution presents a clear beneficial effect on improving the in vivo pharmacokinetics of the imaging agents targeting VMAT2 in the brain; as such, the novel new chemical entity with deuterium substitution provides a better specific target binding and regional brain signal for PET imaging of VMAT2 in the brain.

[0075] The hydrogen to deuterium substitution of 18< F-FP-DTBZ to 18< F-FP-DTBZ-D6 clearly reduced the rate of in vivo metabolism and improved the in vivo pharmacokinetics.

[0076] The novel new chemical entity with deuterium substitution provides a better specific target binding and regional brain signal for PET imaging of VMAT2 in the brain.References:

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Claims

1. A compound of Formula I-A: or a pharmaceutically acceptable salt thereof, wherein: R1 is C1-4 alkyl and is optionally substituted with one or more deuterium atoms; and X is 18F or F; Y is -(CD2)3-.

2. The compound of claim 1, having Formula I-B: or a pharmaceutically acceptable salt thereof.

3. The compound of any one of claims 1 to 2, or a pharmaceutically acceptable salt thereof, wherein R1 is methyl and is optionally substituted with one or more deuterium atoms, preferably having Formula I-C: or a pharmaceutically acceptable salt thereof, more preferably having the following structure: or a pharmaceutically acceptable salt thereof, or having the following structure: or a pharmaceutically acceptable salt thereof; or having the following structure: or a pharmaceutically acceptable salt thereof, or having the following structure: or a pharmaceutically acceptable salt thereof.

4. A compound having the following structure: or a pharmaceutically acceptable salt thereof.

5. The compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, wherein the deuterium enrichment for each designated deuterium atom is at least 50%, preferably at least 80%, more preferably at least 90%, and most preferably at least 95%.

6. A pharmaceutical composition comprising a compound of any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

7. A method for imaging a subject, comprising administering the compound or a pharmaceutically acceptable salt thereof of any one of the claims 1 to 3, wherein X is 18F, to said subject; and obtaining an image of said subject or a portion of said subject, preferably comprising administering an effective amount of the compound or a pharmaceutically acceptable salt thereof to a subject; and detecting the pattern of radioactivity of the compound in said subject.