Modulators of neurodegeneration

Abstract

The present disclosure provides, e.g., benzo[c][1,2,5]thiadiazolyl compounds and methods of using these compounds, e.g., for treating neurodegenerative disorders such as Parkinson's disease (PD), multiple system atrophy (MSA), and Lewy body dementia. The present disclosure also provides benzo[c][1,2,5]thiadiazolyl compounds radiolabeled with a radioisotope, such as 11C, 18F, or 123 / 125I, and method of using the radiolabeled compounds for positron emission tomography (PET) or single-photon emission computed tomography (SPECT) brain imaging agents for diagnosis and / or monitoring treatment of the neurodegenerative disorders.

Description

[0001] Modulators of Neurodegeneration

[0002] CLAIM OF PRIORITY

[0003] This application claims the benefit of U.S. Provisional Application Serial No. 63 / 527,516, filed on July 18, 2023. The entire contents of the foregoing are incorporated herein by reference.

[0004] TECHNICAL FIELD

[0005] This invention relates to chemical compounds, and in particular to benzo[c][l,2,5]thiadiazolyl compounds that are binders with high affinity to a- synuclein fibrils, as well as amyloid plaques and / or tau tangles in brain tissues (e.g., neurons, glial cells, as well as the extracellular space). These compounds are useful, e.g., for treating neurodegenerative disorders such as Parkinson’s disease (PD), multiple system atrophy (MSA), and Lewy body dementia. When labeled with a radioisotope, such asnC,18F, or123 / 125I, the compounds are also positron emission tomography (PET) or single-photon emission computed tomography (SPECT) brain imaging agents useful, e.g. , as diagnostic tools for diagnosis and / or monitoring treatment of the neurodegenerative disorders.

[0006] BACKGROUND

[0007] There are numerous deadly diseases affecting current human population. For example, neurodegenerative diseases affect a significant segment of population, especially the elderly. As one example, Parkinson’s disease (“PD”), a synucleinopathy that affects movement, affects more than 10 million people worldwide with an estimated total annual economic burden of more than $52 billion. As another example, Alzheimer’s disease (“AD”), a P-amyloidopathy that affects approximately 44 million people world-wide, is the sixth leading cause of death with an estimated socioeconomic burden of more than $200 billion. In yet another example, Pick’s disease, a rare tauopathy characterized by a range of progressive neurological symptoms, affects 1 in 250,000 individuals with an estimated annual cost of treatment per patient of about $100,000. In sum, neurodegenerative diseases impose a substantial burden on patients, their family members, the healthcare system, and the society overall. Because of aging population worldwide, neurodegenerative disorders pose an increasing threat to public health. SUMMARY

[0008] The present disclosure is based, at least in part, on a realization that benzo[c][l,2,5]thiadiazolyl compounds bind with high affinity to a-synuclein protein. What is more, the compounds are also relatively selective for a-synuclein fibrils as opposed to amyloid plaques or tau tangles located in the brain tissues of individuals affected with neurodegeneration. In one example, the benzo[c][l,2,5]thiadiazolyl compounds are about 30x to about 50x more selective to a-synuclein fibrils as compared to p-amyloid plaques. What is more, the benzo[c][l,2,5]thiadiazolyl compounds are capable to permeate the blood brain barrier, to selectively and substantially accumulate in brain tissues (as opposed to any other tissues within a subject) upon administration, and to rapidly clear from the subject’s plasma upon exerting the therapeutic effect. Advantageously, the specific affinity of benzo[c][l,2,5]thiadiazolyl compounds within the present claims to protein aggregates involved in pathology of neurodegenerative disorders allows using these compounds as brain imaging agents upon labeling the compounds with an appropriate radioisotope. When labeled withnC or18F, the compounds can be detected in the brain using PET, while when labeled with123I or125I, the compounds can be detected in the brain using SPECT. The radiolabeled compounds are a useful diagnostic tool allowing to diagnose neurodegenerative disorders, to support clinical development of potential therapeutics (e.g., to screen drug candidate compounds for potential therapeutics), and to monitor treatment of the neurodegenerative disorders by the existing drugs and therapies.

[0009] In one general aspect, the present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein X1, R1, R2, R3, R4, L1, ring A, X2, and ring B are as described herein.

[0010] In another general aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier. In yet another general aspect, the present disclosure provides a method of treating a neurodegenerative disease or disorder as described herein, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I), or a therapeutically acceptable salt thereof.

[0011] In yet another general aspect, the present disclosure provides a compound of Formula (II): or a pharmaceutically acceptable salt thereof, wherein X1, R1, R2, R3, R4, L1, ring A, X2, and ring B are as described herein for Formula (I), and the compound comprises at least one radioisotope selected fromnC,18F,1231,125I, and131I.

[0012] In yet another general aspect, the present disclosure provides a pharmaceutical composition comprising a compound of Formula (II), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

[0013] In yet another general aspect, the present disclosure provides a method of imaging a brain of a subject as described herein, using the radiolabeled compound of Formula (II), or a pharmaceutically acceptable salt thereof.

[0014] In yet another general aspect, the present disclosure provides a method of diagnosing a neurodegenerative disease in a subject as described herein, using the radiolabeled compound of Formula (II), or a pharmaceutically acceptable salt thereof.

[0015] In yet another general aspect, the present disclosure provides a method of monitoring treatment of a neurodegenerative disease in a subject as described herein, using the radiolabeled compound of Formula (II), or a pharmaceutically acceptable salt thereof.

[0016] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which the present application belongs. Methods and materials are described herein for use in the present application; other, suitable methods and materials known in the art can also be used. The materials, methods, and examples are illustrative only and not intended to be limiting. All publications, patent applications, patents, sequences, database entries, and other references mentioned herein are incorporated by reference in their entirety. In case of conflict, the present specification, including definitions, will control.

[0017] Other features and advantages of the present application will be apparent from the following detailed description and figures, and from the claims.

[0018] DESCRIPTION OF DRAWINGS

[0019] FIG. 1 A contains results of radioligand binding assay for3H-SIL26.

[0020] FIG. IB contains results of radioligand binding assay to P-amyloid protein for compound SY-01.

[0021] FIG. 1C contains results of radioligand binding assay to tau protein for compound SY-01.

[0022] FIG. ID contains results of radioligand binding assay to a-synuclein protein for compound SY-01.

[0023] FIG. 2 contains results of a cell binding study for SY-01.

[0024] FIG. 3 contains images showing autoradiography study on human postmortem tissues fornC-SY-01.

[0025] DETAILED DESCRIPTION

[0026] In neuropathology, neurodegeneration is often featured by accumulation in brain cells and intracellular spaces of insoluble protein aggregates, such as a- synuclein fibrils, amyloid-P plaques, and tau tangles, as well as by marked neuroinflammation. Together, these pathologies lead to a reduction of brain volume and brain cell number, degeneration of neurons, dysfunction of microglia, and the development of various neurodegenerative disorders such as Parkinson’s disease (PD), multiple system atrophy (MSA), pure autonomic failure (PAF), Alzheimer’s disease (AD), frontotemporal lobar degeneration (FTD), Huntington’s disease (HD), Pick’s disease, and dementia, including dementia specifically associated with any of the aforementioned disorders. Without being bound by any theory, in one general aspect, the present disclosure provides compounds that selectively bind to protein aggregates that are implicated in neuropathology and neurodegeneration. As such, the compounds contribute to amelioration of neuronal loss and are therefore advantageously useful in treating the underlying neurological disorder (e.g., PD, MSA, PAF, AD, HD, or Pick’s disease). Certain embodiments of the therapeutic compounds (e.g., compounds of Formula I) and exemplary embodiments of diseases treatable by these compounds (e.g., synucleinopathies) are descnbed herein. Also, currently, diagnosis of neurodegenerative conditions in clinic has been a persistent challenge due to the limitation of present neuropsychological tests and neuroimaging. Imaging pathological protein aggregates in brain via PET or SPECT provides a useful way to both diagnose the neurodegeneration process and to evaluate pharmacological performance of a drug treatment. Without being bound by any theory, in a general aspect, when a PET or a SPECT imageable radioisotope (such asnC,18F,123I, or125I) is included in the chemical structure of the compound, the compound is useful as a radiotracer (an imaging agent) for diagnosing or monitoring treatment of various neurodegenerative conditions. Certain embodiments of the radiotracer compounds (e.g., compounds of Formula II) and exemplary embodiments of imaging methods in which the radiotracer compounds of this disclosure are advantageously useful, are described herein.

[0027] Therapeutic compounds

[0028] In one general aspect, the present disclosure provides a compound of Formula (I): or a pharmaceutically acceptable salt thereof, wherein:

[0029] X1is selected from S and 0;

[0030] R1, R2, and R3are each independently selected from halo, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=0)0H, C(=0)0(Ci-3 alkyl), C(=0)NH2, C(=0)NH(CI-3 alkyl), C(=0)N(CI-3 alkyl)2, amino, C1-3 alkylamino, and di(Ci-3 alkyl)amino;

[0031] R4is selected from H, C1-3 alkyl, and C1-3 haloalkyl;

[0032] L1is absent; or L1is selected fromn C1-6 alkylene and C3-6 cycloalkylene, wherein said Ci-6 alkylene is optionally interrupted with 1 or 2 groups independently selected from C(=0), S(=0)2, 0, and NH; ring A is absent, or ring A is a moiety of formula (i): a indicates a point of attachment to X2; b indicates a point of attachment to L1; ring C is selected from C3-6 cycloalkyl and 4-7-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from selected halo, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1.3 alkoxy, C 1-3 haloalkoxy, C(=O)OH, C(=O)O(Ci-3alkyl), C(=O)NH2, C(=O)NH(Ci-3alkyl), C(=O)N(CI-3alky 1)2, amino, Ci-3alkylamino, and di(C 1-3 alkyl)amino;

[0033] R5and R6are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl;

[0034] X2is selected from C(=O) and S(=O)2; and ring B is selected from Ce-io aryl and 5-14 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1.3 alkoxy, C1-3 haloalkoxy, S(=O)2(Ci-3alkyl), S(=O)2OH, C(=O)OH, C(=O)O(CI-3alkyl), C(=O)NH2, C(=0)NH(CI-3 alkyl), C(=O)N(CI-3 alkyl)2, amino, C1-3 alkylamino, and di(C 1-3 alkyl)amino.

[0035] In some embodiments, L1is absent. In some embodiments, ring A is absent.

[0036] In some embodiments, the compound of Formula (I) has formula or a pharmaceutically acceptable salt thereof.

[0037] In some embodiments, L1is selected fromn C1-6 alkylene and C3-6 cycloalkylene, wherein said Ci-s alkylene is optionally interrupted with 1 or 2 groups independently selected from C(=O), S(=O)2, 0, and NH. In some embodiments, ring A is a moiety of formula (i). In some embodiments, ring C is substituted with halo, OH, CN, NO2, C1.3 alkyl, C1-3 haloalky 1, C1.3 alkoxy, or C1.3 haloalkoxy. In some embodiments, ring C is substituted with halo, OH, CN, NO2, C1-3 alkyl, and C1-3 haloalkyl.

[0038] In some embodiments, the moiety of formula (i) has any one of the following

[0039] In some embodiments, the compound of Formula (I) has formula: or a pharmaceutically acceptable salt thereof.

[0040] In some embodiments, the compound of Formula (I) has formula: or a pharmaceutically acceptable salt thereof.

[0041] In some embodiments, the compound of Formula (I) has formula: or a pharmaceutically acceptable salt thereof. In some embodiments, the compound of Formula (I) has formula: or a pharmaceutically acceptable salt thereof.

[0042] In some embodiments, R5is H and R6is selected from C1-3 alkyl and C1-3 haloalkyl. In some embodiments, R6is C1.3 alkyl.

[0043] In some embodiments, L1is C1-6 alkylene, optionally interrupted with 0 or NH. In some embodiments, L1is C1-6 alkylene (e.g, ethylene or propylene). In some embodiments, L1is C1-6 alkylene interrupted with 0. In some embodiments, L1' is C1-3 alkylene-O-Ci-3 alkylene.

[0044] In some embodiments, L1is C3-6 cycloalkylene (e.g., cyclopropylene, cyclobutylene, cyclopentylene, or cyclohexylene).

[0045] In some embodiments, the compound of Formula (I) has formula: or a pharmaceutically acceptable salt thereof.

[0046] In some embodiments, R4is H. In some embodiments, R4is C1-3 alkyl.

[0047] In some embodiments, R1, R2, and R3are each independently selected from halo, CN, C1-3 alkyl, C1.3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, and C(=0)NH2.

[0048] In some embodiments, X1is 0. In some embodiments, X1is S.

[0049] In some embodiments, X2is C(=0). In some embodiments, X2is S(=0)2.

[0050] In some embodiments, ring B is Ce-io aryl, optionally substituted with 1 or 2 substituents independently selected from halo, CN, NO2, C1.3 alkyl, C1.3 haloalkyl, Ci-3alkoxy, C1.3 haloalkoxy, S(=O)2(Ci-3alkyl), S(=O)2OH, C(=O)OH, C(=O)O(Ci-3alkyl), and C(=0)NH2.

[0051] In some embodiments, ring B is Cg-io aryl, optionally substituted with 1 or 2 substituents independently selected from halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, S(=O)2(Ci-3 alkyl), and C(=0)NH2. In some embodiments, ring B is Ce-io aryl, optionally substituted with halo, CN, Ci-3 alkyl, C1.3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, S(=O)2(Ci-3 alkyl), or C(=O)NH2.

[0052] In some embodiments, ring B is Ce-io aryl, optionally substituted with 2 substituents independently selected from halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1.3 alkoxy, C1-3 haloalkoxy, S(=O)2(Ci-3 alkyl), and C(=0)NH2.

[0053] In some embodiments, ring B is 5-14 membered heteroaryl, optionally substituted with 1 or 2 substituents independently selected from halo, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, S(=O)2(C 1-3 alkyl), S(=O)2OH, C(=O)OH, C(=O)O(Ci-3 alkyl), and C(=O)NH2.

[0054] In some embodiments, ring B is 5-14 membered heteroaryl, optionally substituted with 1 or 2 substituents independently selected from halo, CN, C1-3 alkyl, C1.3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, S(=O)2(Ci-3 alkyl), and C(=O)NH2.

[0055] In some embodiments, ring B is 5-14 membered heteroaryl, optionally substituted with halo, CN, C1.3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, S(=O)2(Ci-3alkyl), or C(=O)NH2.

[0056] In some embodiments, ring B is 5-14 membered heteroaryl, optionally substituted with 2 substituents independently selected from halo, CN, C 1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, S(=O)2(Ci-3 alkyl), and C(=O)NH2.

[0057] In some embodiments, the compound is selected from any one of the following compounds:

[0058] or a pharmaceutically acceptable salt thereof.

[0059] Radiotracer compounds

[0060] In some embodiments, the compound of Formula (I) as described above comprises at least one radioisotope selected fromnC,18F,1231,125I, and131I. Accordingly, in one general aspect, the present disclosure provides a compound of Formula (II): or a pharmaceutically acceptable salt thereof, wherein the groups X1, R1, R2, R3, R4, L1, ring A, X2, and ring B are as described herein for Formula (I), and at least one of X1, R1, R2, R3, R4, L1, ring A, X2, and ring B comprises a radioisotope selected fromnC,18F,1231,123I, and131I.

[0061] In some embodiments, the compound of Formula (II) comprisesnC. In some embodiments, the compound of Formula (II) comprises18F. In some embodiments, the compound of Formula (II) comprises123I. In some embodiments, the compound of Formula (II) comprises125I. In some embodiments, the compound of Formula (II) comprises131I. In some embodiments, the compound of Formula (II) comprises a group selected from18F,1231,1251,131I,nCN,nC(=O)NH2,nCH3-,nCH3O-,18FCH2CH2-,18FCH2CH2O-, and18FCH2CH2CH2O-.

[0062] In some embodiments, R4is selected fromnCH3- and18FCH2CH2-. In some embodiments, ring B is substituted with at least one18F. In some embodiments, the compound of Formula (II) is selected from any one of the following compounds: or a pharmaceutically acceptable salt thereof.

[0063] Pharmaceutically acceptable salts

[0064] In some embodiments, a salt of any one of the compounds of the present disclosure (e.g., compound of Formula l or Formula II) is formed between an acid and a basic group of the compound, such as an amino functional group, or a base and an acidic group of the compound, such as a carboxyl functional group. According to another embodiment, the compound is a pharmaceutically acceptable acid addition salt.

[0065] In some embodiments, acids commonly employed to form pharmaceutically acceptable salts of the compounds include inorganic acids such as hydrogen bisulfide, hydrochloric acid, hydrobromic acid, hydroiodic acid, sulfuric acid and phosphoric acid, as well as organic acids such as para-toluenesulfonic acid, salicylic acid, tartaric acid, bitartaric acid, ascorbic acid, maleic acid, besylic acid, fumaric acid, gluconic acid, glucuronic acid, formic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, lactic acid, oxalic acid, parabromophenylsulfonic acid, carbonic acid, succinic acid, citric acid, benzoic acid and acetic acid, as well as related inorganic and organic acids. Such pharmaceutically acceptable salts thus include sulfate, pyrosulfate, bisulfate, sulfite, bisulfite, phosphate, monohydrogenphosphate, dihydrogenphosphate, metaphosphate, pyrophosphate, chloride, bromide, iodide, acetate, propionate, decanoate, caprylate, acrylate, formate, isobutyrate, caprate, heptanoate, propiolate, oxalate, malonate, succinate, suberate, sebacate, fumarate, maleate, butyne- 1,4-dioate, hexyne-l,6-dioate, benzoate, chlorobenzoate, methylbenzoate, dimtrobenzoate, hy droxybenzoate, methoxy benzoate, phthalate, terephthalate, sulfonate, xylene sulfonate, phenylacetate, phenylpropionate, phenylbutyrate, citrate, lactate, 0-hydroxybutyrate, glycolate, maleate, tartrate, methanesulfonate, propanesulfonate, naphthal ene-1 -sulfonate, naphthal ene-2- sulfonate, mandelate and other salts. In one embodiment, pharmaceutically acceptable acid addition salts include those formed with mineral acids such as hydrochloric acid and hydrobromic acid, and especially those formed with organic acids such as maleic acid.

[0066] In some embodiments, bases commonly employed to form pharmaceutically acceptable salts of the compounds include hydroxides of alkali metals, including sodium, potassium, and lithium; hydroxides of alkaline earth metals such as calcium and magnesium; hydroxides of other metals, such as aluminum and zinc; ammonia, organic amines such as unsubstituted or hydroxyl-substituted mono-, di-, or tri- alkylamines, dicyclohexylamine; tnbutyl amine; pyridine; N-methyl, N-ethylamine; diethylamine; tnethylamine; mono-, bis-, or tris-(2-OH-(Ci-C6)-alkylamine), such as N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine; N-methyl-D- glucamine; morpholine; thiomorpholine; piperidine; pyrrolidine; and amino acids such as arginine, lysine, and the like.

[0067] Compositions, formulations, and routes of administration

[0068] The present application also provides pharmaceutical compositions comprising an effective amount of a compound of the present disclosure (e.g., Formula (I) or Formula (II)) disclosed herein, or a pharmaceutically acceptable salt thereof; and a pharmaceutically acceptable carrier. The pharmaceutical composition may also comprise any one of the additional therapeutic agents described herein. In certain embodiments, the application also provides pharmaceutical compositions and dosage forms comprising any one the additional therapeutic agents described herein. The carrier(s) are “acceptable” in the sense of being compatible with the other ingredients of the formulation and, in the case of a pharmaceutically acceptable carrier, not deleterious to the recipient thereof in an amount used in the medicament.

[0069] Pharmaceutically acceptable carriers, adjuvants and vehicles that may be used in the pharmaceutical compositions of the present application include, but are not limited to, ion exchangers, alumina, aluminum stearate, lecithin, serum proteins, such as human serum albumin, buffer substances such as phosphates, glycine, sorbic acid, potassium sorbate, partial glyceride mixtures of saturated vegetable fatty acids, water, salts or electrolytes, such as protamine sulfate, disodium hydrogen phosphate, potassium hydrogen phosphate, sodium chloride, zinc salts, colloidal silica, magnesium trisilicate, polyvinyl pyrrolidone, cellulose-based substances, polyethylene glycol, sodium carboxymethylcellulose, polyacrylates, waxes, polyethylene-poly oxypropylene-block polymers, polyethylene glycol, and wool fat.

[0070] The compositions or dosage forms may contain any one of the compounds and therapeutic agents described herein in the range of 0.005% to 100% with the balance made up from the suitable pharmaceutically acceptable excipients. The contemplated compositions may contain 0.001%- 100% of any one of the compounds and therapeutic agents provided herein, in one embodiment 0.1-95%, in another embodiment 75-85%, in a further embodiment 20-80%, wherein the balance may be made up of any pharmaceutically acceptable excipient described herein, or any combination of these excipients.

[0071] Routes of administration and dosage forms

[0072] The pharmaceutical compositions of the present application include those suitable for any acceptable route of administration. Acceptable routes of administration include, but are not limited to, buccal, cutaneous, endocervical, endosinusial, endotracheal, enteral, epidural, interstitial, intra-abdominal, intraarterial, intrabronchial, intrabursal, intracerebral, intracistemal, intracoronary, intradermal, intraductal, intraduodenal, intradural, intraepidermal, intraesophageal, intragastric, intragingival, intraileal, intralymphatic, intramedullary, intrameningeal, intramuscular, intranasal, intraovarian, intraperitoneal, intraprostatic, intrapulmonary, intrasinal, intraspinal, intrasynovial, intratesticular, intrathecal, intratubular, intratumoral, intrauterine, intravascular, intravenous, nasal, nasogastric, oral, parenteral, percutaneous, peridural, rectal, respiratory (inhalation), subcutaneous, sublingual, submucosal, topical, transdermal, transmucosal, transtracheal, ureteral, urethral and vaginal.

[0073] Compositions and formulations described herein may conveniently be presented in a unit dosage form, e.g., tablets, sustained release capsules, and in liposomes, and may be prepared by any methods well known in the art of pharmacy. See, for example, Remington: The Science and Practice of Pharmacy, Lippincott Williams & Wilkins, Baltimore, MD (20th ed. 2000). Such preparative methods include the step of bringing into association with the molecule to be administered ingredients such as the carrier that constitutes one or more accessory ingredients. In general, the compositions are prepared by uniformly and intimately bringing into association the active ingredients with liquid earners, liposomes or finely divided solid carriers, or both, and then, if necessary, shaping the product.

[0074] In some embodiments, any one of the compounds and therapeutic agents disclosed herein are administered orally. Compositions of the present application suitable for oral administration may be presented as discrete units such as capsules, sachets, granules or tablets each containing a predetermined amount (e.g., effective amount) of the active ingredient; a powder or granules; a solution or a suspension in an aqueous liquid or a non-aqueous liquid; an oil-in-water liquid emulsion; a water-in- oil liquid emulsion; packed in liposomes; or as a bolus, etc. Soft gelatin capsules can be useful for containing such suspensions, which may beneficially increase the rate of compound absorption. In the case of tablets for oral use, carriers that are commonly used include lactose, sucrose, glucose, mannitol, and silicic acid and starches. Other acceptable excipients may include: a) fillers or extenders such as starches, lactose, sucrose, glucose, mannitol, and silicic acid, b) binders such as, for example, carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidinone, sucrose, and acacia, c) humectants such as glycerol, d) disintegrating agents such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate, e) solution retarding agents such as paraffin, f) absorption accelerators such as quaternary ammonium compounds, g) wetting agents such as, for example, cetyl alcohol and glycerol monostearate, h) absorbents such as kaolin and bentonite clay, and i) lubricants such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof. For oral administration in a capsule form, useful diluents include lactose and dried com starch. When aqueous suspensions are administered orally, the active ingredient is combined with emulsifying and suspending agents. If desired, certain sweetening and / or flavoring and / or coloring agents may be added. Compositions suitable for oral administration include lozenges comprising the ingredients in a flavored basis, usually sucrose and acacia or tragacanth; and pastilles comprising the active ingredient in an inert basis such as gelatin and glycerin, or sucrose and acacia.

[0075] Compositions suitable for parenteral administration include aqueous and nonaqueous sterile injection solutions or infusion solutions which may contain antioxidants, buffers, bacteriostats and solutes which render the formulation isotonic with the blood of the intended recipient; and aqueous and non-aqueous sterile suspensions which may include suspending agents and thickening agents. The formulations may be presented in unit-dose or multi-dose containers, for example, sealed ampules and vials, and may be stored in a freeze dried (lyophilized) condition requiring only the addition of the sterile liquid carrier, for example water for injections, saline (e.g, 0.9% saline solution) or 5% dextrose solution, immediately prior to use. Extemporaneous injection solutions and suspensions may be prepared from sterile powders, granules and tablets. The injection solutions may be in the form, for example, of a sterile injectable aqueous or oleaginous suspension. This suspension may be formulated according to techniques known in the art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may also be a sterile injectable solution or suspension in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1,3 -butanediol. Among the acceptable vehicles and solvents that may be employed are mannitol, water, Ringer's solution and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono- or diglycerides. Fatty acids, such as oleic acid and its glyceride derivatives are useful in the preparation of injectables, as are natural pharmaceutically-acceptable oils, such as olive oil or castor oil, especially in their poly oxyethylated versions. These oil solutions or suspensions may also contain a long-chain alcohol diluent or dispersant.

[0076] The pharmaceutical compositions of the present application may be administered in the form of suppositories for rectal administration. These compositions can be prepared by mixing a compound of the present application with a suitable non-irritating excipient which is solid at room temperature but liquid at the rectal temperature and therefore will melt in the rectum to release the active components. Such materials include, but are not limited to, cocoa butter, beeswax, and polyethylene glycols.

[0077] The pharmaceutical compositions of the present application may be administered by nasal aerosol or inhalation. Such compositions are prepared according to techniques w'ell-known in the art of pharmaceutical formulation and may be prepared as solutions in saline, employing benzyl alcohol or other suitable preservatives, absorption promoters to enhance bioavailability, fluorocarbons, and / or other solubilizing or dispersing agents known in the art. See, for example, U.S. Patent No. 6,803,031. Additional formulations and methods for intranasal administration are found in Ilium, L., J Pharm Pharmacol, 56:3-17, 2004 and Ilium, L., Eur J Pharm Sci 11: 1-18, 2000.

[0078] The topical compositions of the present disclosure can be prepared and used in the form of an aerosol spray, cream, emulsion, solid, liquid, dispersion, foam, oil, gel, hydrogel, lotion, mousse, ointment, powder, patch, pomade, solution, pump spray, stick, towelette, soap, or other forms commonly employed in the art of topical administration and / or cosmetic and skin care formulation. The topical compositions can be in an emulsion form. Topical administration of the pharmaceutical compositions of the present application is especially useful when the desired treatment involves areas or organs readily accessible by topical application. In some embodiments, the topical composition comprises a combination of any one of the compounds and therapeutic agents disclosed herein, and one or more additional ingredients, carriers, excipients, or diluents including, but not limited to, absorbents, anti-irritants, anti-acne agents, preservatives, antioxidants, coloring agents / pigments, emollients (moisturizers), emulsifiers, film-forming / holding agents, fragrances, leave- on exfoliants, prescription drugs, preservatives, scrub agents, silicones, skin- identical / repairing agents, slip agents, sunscreen actives, surfactants / detergent cleansing agents, penetration enhancers, and thickeners.

[0079] Dosages and regimens

[0080] In the pharmaceutical compositions of the present application, a compound of the present disclosure (e.g., a compound of Formula (I) or Formula (II)) is present in an effective amount. For example, the compound of Formula (I) may be present in a therapeutically effective amount. In another example, the compound of Formula (II) may be present in an amount that is effective for imaging organ and / or tissues of a subject, such as for brain imaging as described herein. Effective doses may vary, depending on the diseases treated, the severity of the disease, the route of administration, the sex, age and general health condition of the subject, excipient usage, the possibility of co-usage with other compounds, e.g, therapeutic treatments, other imaging agents, metabolism inhibitors, etc., and the judgment of the treating physician.

[0081] In some embodiments, an effective amount of the compound (e.g, Formula (I) or Formula (II)) can range, for example, from about 0.001 mg / kg to about 500 mg / kg (e.g., from about 0.001 mg / kg to about 200 mg / kg; from about 0.01 mg / kg to about 200 mg / kg; from about 0.01 mg / kg to about 150 mg / kg; from about 0.01 mg / kg to about 100 mg / kg; from about 0.01 mg / kg to about 50 mg / kg; from about 0.01 mg / kg to about 10 mg / kg; from about 0.01 mg / kg to about 5 mg / kg; from about 0.01 mg / kg to about 1 mg / kg; from about 0.01 mg / kg to about 0.5 mg / kg; from about 0.01 mg / kg to about 0.1 mg / kg; from about 0. 1 mg / kg to about 200 mg / kg; from about 0. 1 mg / kg to about 150 mg / kg; from about 0. 1 mg / kg to about 100 mg / kg; from about 0. 1 mg / kg to about 50 mg / kg; from about 0. 1 mg / kg to about 10 mg / kg; from about 0. 1 mg / kg to about 5 mg / kg; from about 0. 1 mg / kg to about 2 mg / kg; from about 0. 1 mg / kg to about 1 mg / kg; or from about 0.1 mg / kg to about 0.5 mg / kg). In some embodiments, an effective amount of a compound of Formula (I) or Formula (II) is about 0.1 mg / kg, about 0.5 mg / kg, about 1 mg / kg, about 2 mg / kg, or about 5 mg / kg.

[0082] The foregoing dosages can be administered on a daily basis (e.g, as a single dose or as two or more divided doses, e.g, once daily, twice daily, thrice daily) or non-daily basis (e.g., every other day, every two days, every three days, once weekly, twice weekly, once every two weeks, once a month) as determined by a treating physician or a diagnostician (e.g. , a practitioner responsible for administering an imaging agent).

[0083] Kits

[0084] The present invention also includes kits useful, for example, in the treatment of disorders, diseases and conditions referred to herein, which include one or more containers containing a pharmaceutical composition comprising a therapeutically effective amount of a compound of Formula (I) of the present disclosure, or an amount effective for imaging a brain of a subject of a compound of Formula (II) of the present disclosure. Such kits can further include, if desired, one or more of various conventional pharmaceutical kit components, such as, for example, containers with one or more pharmaceutically acceptable carriers, additional containers, etc. Instructions, either as inserts or as labels, indicating quantities of the components to be administered, guidelines for administration, and / or guidelines for mixing the components, can also be included in the kit. The kit may optionally include an additional therapeutic agent as described herein.

[0085] Methods of treatment In some embodiments, the present disclosure provides a method of modulating a-synuclein, -amyloid, and / or tau protein in a cell, the method comprising contacting the cell with an effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. In some embodiments, the modulating comprises binding, inhibiting, or activating, or any combination of the foregoing. In some embodiments, the contacting occurs in vitro, in vivo, or ex vivo. In some embodiments, the cell is a brain cell (e.g. , a neuron or a glial cell). In some embodiments, the modulation is selective with respect to a-synuclein, as opposed to P-amyloid, and / or tau protein (e.g., the modulation is 10*, 20*, 50*, I00x, or 1000* more selective with respect to a-synuclein). In some embodiments, the present disclosure provides a method of modulating a-synuclein, P-amyloid, and / or tau protein in a subject, the method comprising administering to a subject a therapeutically effective amount of a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same.

[0086] In some embodiments, the compounds of Formula (I) and related salts and compositions of the present disclosure are useful in treating neurodegenerative disease or disorder that affects the motor system.

[0087] Numerous scientific publications provide credible evidence of association between multisystem neurodegeneration and progressive aggregation of insoluble fibrillary synuclein (e.g., a-synuclein or aSyn) in neurons and glia. See, for example, Galvin et al., Arch Neurol., 2001, 58, 2, 186-190 and Sekiya et al., Mol Neurodegeneration 16, 83, 2021, Wong Y et al, Nat. Med, 2017, 23 (2), 1-13; Lashuel H et al., Nat. Rev. Neurosci., 2013, 14, 1, 38-48, among others. As such, without being bound by any particular theory or speculation, as used herein, the term "synucleinopathy" refers to a group of neurodegenerative disorders where aggregation of insoluble synuclein e.g., aSyn) protein fibrils in various CNS and / or peripheral nervous system (PNS) cells is implicated in pathology. In some embodiments, the present disclosure provides a method of treating a synucleinopathy in a subject (e.g, a subject in need of treatment, such as a subject identified as diagnosed with the synucleinopathy), the method comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. Suitable examples of synucleinopathies include dementia with Lew}7bodies, Parkinson’s disease (PD), multiple system atrophy (MSA), pure autonomic failure (PAF) (Bradbury-Eggleston syndrome), PD with dementia, olivopontocerebellar atrophy (OPCA), striatonigral degeneration (SND), neuroaxonal dystrophy, Shy-Drager syndrome, Alzheimer’s disease, Hallervorden- Spatz syndrome, and lysosomal storage diseases (e.g., Gaucher’s disease), among other neurodegenerative disorders where synuclein is involved, at least in part, in the disease pathology.

[0088] Numerous scientific publications provide credible evidence of association between neurodegeneration and amyloid peptide (e.g., P-amyloid such as A04O peptide and / or Ap42 peptide) misfolding and concomitant accumulation of amyloid peptide plaques in the brain. See, for example, Spires-Jones et al., Acta Neuropathologica, 134, 187-205, 2017; Selkoe D et al, JEMBOMol. Med., 2016, 8, 6, 595-608; and Selkoe D et al, Science, 2002, 19; 297, 5580, 353-6, among many others. In one example, P-amyloid is used as a diagnostic biomarker of Alzheimer’s disease (See, e.g., Nakamura et al., Nature, 2018, 554, 7691, 249-254, and Bateman RJ et al., N. Engl. J. Med., 2012, 367, 9, 795-804, as well as its main target for therapeutics (See, e.g, Swanson C et al., Alzheimer ’s Res. Ther, 2021, 13, 1, 80. As such, without being bound by any particular theory or speculation, as used herein, the term “amyloidopathy” or “P-amyloidopathy” refers to a group of neurodegenerative disorders where aggregation of insoluble amyloid plaques (e.g., P-amyloid plaques) in the brain is implicated in pathology. In some embodiments, the present disclosure provides a method of treating an amyloidopathy in a subject (e.g. , a subject in need of treatment, such as a subject identified as diagnosed with the amyloidopathy), the method comprising administering to the subject a compound of Formula (I), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. Suitable examples of amyloidopathies include premature aging, cerebral amyloid angiopathy, Alzheimer’s disease (AD), familial AD (FAD), and dementia associated with AD or FAD, among other neurodegenerative disorders where formation of amyloid plaques is involved, at least in part, in the disease pathology.

[0089] Numerous scientific publications provide credible evidence of association between neurodegeneration and misfolding of the tau protein and subsequent formation of neurofibrillary or gliofibrillary tangles in the brain (e.g., neurons, glial cells, and extracellular space). See, for example, Zhang et al., Molecular Neurodegeneration, 17, 28, 2022 and Handb Clin Neurol, 2017, 145, 355-368; Guo J et al., Cell, 2013, 154, 1, 103-17; Giasson et al., Science, 2003, 300, 5619, 636-40; and Bassil F et al., Neuron, 2020, 105, 2, 260-275, among many others. As such, without being bound by any particular theory or speculation, as used herein, the term "tauopathy" refers to a group of neurodegenerative disorders where tau-positive inclusions in the brain are implicated in pathology. In some embodiments, the present disclosure provides a method of treating a tauopathy in a subject (e.g., a subject in need of treatment, such as a subject identified as diagnosed with the tauopathy), the method comprising administering to the subject a compound of this disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. Suitable examples of tauopathies include Pick's disease, progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, primary age-related tauopathy, neurofibrillary tangle dementia, chronic traumatic encephalopathy (CTE), aging-related tau astrogliopathy, Richardson syndrome, cerebellar ataxia, globular glial tauopathy, and arg rophilic grain disease, among other neurodegenerative disorders where misfolding of tau protein is involved, at least in part, in the disease pathology.

[0090] In some embodiments, the present disclosure provides a method of treating a neurodegenerative disorder where any combination of synuclein, amyloid, and / or tau peptide or protein is implicated in the disease pathology. See, e.g, Irwin D et al., Nat. Rev. Neurosci., 2013, 14, 9, 626-36; Lloyd G et al., Mol Neurodegener., 2021, 16, 1, 63; and Ruffian C et al., Neuropathol. Appl. Neurobiol., 2016, 42, 5, 436-50, among others.

[0091] Without being bound by any particular theory or speculation, it is believed that misfolding and / or aggregation of synuclein, amyloid, and / or tau peptides or proteins causes, induces, increases, and / or enhances neuroinflammation, which process further contributes to the progression of neurodegeneration and related symptomology. See, e.g., Gate D et al, Science, 2021, 374, 6569, 868-874; Sebastian Monasor L et al, Elife, 2020, 9, e54083, among others. Accordingly, in some embodiments, the present disclosure provides a method of treating a neurodegenerative disorder (e.g, where inflammation is implicated in the disease pathology) in a subject (e.g., a subject in need of treatment, such as a subject identified as diagnosed with the neurodegenerative disorder), the method comprising administering to the subject a compound of this disclosure, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same. In some embodiments, the neurodegenerative disorder is selected from motor neuron disease (MND), Prion disease, frontotemporal lobar degeneration (FTD), dementia associated with FTD, amyotrophic lateral sclerosis (ALS, aka Leu Gehrig’s disease), Huntington’s disease (HD), and dementia associated with HD, Creutzfeldt- Jakob disease, Machado-Joseph disease, Binswanger’s disease, dementia, multiple sclerosis (“MS”), hippocampal sclerosis, Gaucher’s disease, neuronal ceroid lipofuscinosis, lysosomal storage disorders, progressive supranuclear palsy, corticobasal degeneration, spinal cerebellar ataxias, disturbances of consciousness disorders, hearing and balance impairments, CNS hypoxia, cerebral senility, brain injuries (e.g., stroke, traumatic brain injury', ischemic event, hypoxic event, or neuronal death), vascular cognitive impairment (VCI), spinocerebellar ataxia (SCA), and spinal muscular atrophy (SMA). In some embodiments, the disorder treatable by a compound of this disclosure is selected from accessory nen e disorder, autonomic dysreflexia, peripheral neuropathy, mononeuropathy, polyneuropathy, radial neuropathy, ulnar neuropathy, Villaret’s syndrome, Charcot-Marie-Tooth disease, diabetic neuropathy, nerve paralysis, and Homer’s syndrome.

[0092] Combination treatments

[0093] The compounds of the present disclosure can be used on combination with at least one medication or therapy useful, e.g., in treating or alleviating symptoms of a neurodegenerative disorder such as PD. Suitable examples of such medications include levodopa (L-dopa), carbidopa, safinamide, dopamine agonists (e.g, ropinirole, pramipexole, rotigotine), amantadine, trihexyphenidyl, benztropine, selegiline, rasagiline, tolcapone, entacapone, istradefylline, donepezil, rivastigmine, galantamine, memantine, midodrine, fludrocortisone, physostigmine, droxidopa, botulinum toxin, or a pharmaceutically acceptable salt thereof. The compound can also be used in combination with deep brain stimulation (DBS) neurosurgery. The compound of the present disclosure may be administered to the patient simultaneously with the additional therapeutic agent (in the same dosage form or in different dosage forms) or consecutively (the additional therapeutic agent may be administered before or after administration of the compound of the present disclosure).

[0094] Methods of imaging

[0095] In one general aspect, the present application relates to compounds of Formula (II) useful in imaging techniques, diagnosing and monitoring treatment of various diseases and conditions described herein. Such compounds are labeled in so far as each compound includes at least one radioisotope (e.g. , C, F, or I radioisotope as described herein).

[0096] Imaging techniques such as PET and SPECT have become an important clinical diagnostic and research modality, and also a valuable technology in drug discovery and development. PET offers picomolar sensitivity and is a fully translational technique that requires specific probes radiolabeled with a usually shortlived positron-emitting radionuclide. Carbon-11 (radioactive half-life (ti / 2) = 20.4 min) and fluorine-18 (ti / 2 = 109.7 min) are the most commonly used radionuclides in PET imaging. PET has provided the capability of measuring biological processes at the molecular and metabolic levels in vivo by the detection of the photons formed as a result of the annihilation of the emitted positrons. SPECT is a nuclear imaging scan that needs a radioactive tracer. The tracer is what allows doctors to see how blood flows to tissues and organs. The radioisotopes typically used in SPECT are iodine- 123, technetium-99m, xenon-133, thallium-201, and fluorine-18. These radioactive forms of natural elements pass through the body and can be detected by the appropriate scanner.

[0097] As a noninvasive medical and molecular imaging technique and a powerful tool in neurological research, PET offers the possibility of visualizing and analyzing the target proteins and / or protein aggregates under physiological and pathophysiological conditions. PET has often been used to detect disease-related biochemical changes before the disease-associated anatomical changes can be found using standard medical imaging modalities.

[0098] In some embodiments, the present disclosure provides a method of identifying and / or quantifying to a-synuclein fibrils, amyloid plaques, and / or tau tangles in the brain of a subject. This may be attained, for example, by imaging the brain (e.g. due to binding affinity of compounds of Formula (II) to the aforementioned proteins and protein aggregates). Imaging the brain may include imaging midbrain, brain stem, thalamus, striatum, cerebellum, and / or cortex. A method of imaging the brain comprises (i) administering to the subject an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same; (ii) waiting a time sufficient to allow the compound to accumulate in the brain to be imaged (e.g., 1 min, 5 min, 10 mm, 15 min, 30 min, 1 hour, 2 hours, 3 hours, or 5 hours), and (iii) imaging the brain with an imaging technique. In one example,18F and / ornC within the compound of Formula (II) are positron emitting radioisotopes, the suitable imaging techniques include positron emission tomography (PET) and its modification. As such, the imaging technique may be selected from positron emission tomography (PET) imaging, positron emission tomography with computer tomography (PET / CT) imaging, and positron emission tomography with magnetic resonance (PET / MRI) imaging. In another example, 123 / 125 / 131Jwithin the compound of Formula (II) are gamma emitting radiotracers, the suitable imaging techniques include single-photon emission computed tomography (SPECT) and it’s various modifications.

[0099] In some embodiments, the present disclosure provides a method of diagnosing (or an early detection) a neurodegenerative disorder (e.g., neurodegenerative disorder in which a-synuclein fibrils, amyloid plaques, and / or tau tangles are implicated, such as any of the neurodegenerative disorders described herein) in a subject, the method comprising imaging a brain of a subject according to any of the imaging methods described herein. In some embodiments, the method of diagnosing a subject includes (i) administering to the subject an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same; (ii) waiting a time sufficient to allow the compound to accumulate in the brain to be imaged (e.g., 1 min, 5 min, 10 min, 15 min, 30 min, 45 min, 1 hour, 2 hours, 3 hours, 4 hours, or 5 hours), and (iii) imaging the brain with an imaging technique. In some embodiments, the method includes observing a signal in step iii) (e.g., observing a signal in an image obtained in step iii) atributable to the radioisotope in the compound of Formula (II) is indicative of the neurodegenerative disease in the subject. The method may also comprise comparing images obtained from subjects exhibiting the symptoms of the disease or condition with the images obtained from healthy subjects. In one example, overabundance of a-synuclein fibrils, amyloid plaques, and / or tau tangles in the brain of the subject may be indicative of a neurodegenerative disease such as Parkinson’s disease, Alzheimer’s disease, Pick’s disease, dementia, or a related condition.

[0100] In some embodiments, the radiotracers of Formula (II) within the present claims are useful to study the molecular mechanisms involved in neurodegenerative diseases. For example, the compounds can be used to study molecular mechanisms leading to a-synuclein fibrils, amyloid plaques, and / or tau tangles formation. For example, the compound of Formula (II) can be co-administered with a modulator of a molecular mechanism suspected to be involved in a-synuclein fibrils, amyloid plaques, and / or tau tangles formation, and the absence or presence of those protein aggregates may be detected using an imaging technique as discussed herein. In some embodiments, the present disclosure provides a method of supporting a clinical development of potential therapeutics, which either prevent or inhibit formation of a- synuclein fibrils, amyloid plaques, and / or tau tangles, or lead to dissolution / degradation of those protein aggregates. In vivo imaging of pathological protein aggregates can help answer many vital questions in the drug discovery and development process such as whether potential drugs reach their molecular targets, the relationship between therapeutic dose and the desired outcome, the correlation between therapeutic affect and plasma drug levels, and the duration of time the drug remains at its target, and similar information. In some embodiments, the present disclosure provides a method of screening for potential therapeutics, for example, by detecting competitive binding of a drug candidate and a compound of Formula (II) to a-synuclein fibrils, amyloid plaques, and / or tau tangles in the brain. In one example, a compound of Formula (II) can be administered first and a first brain image can be obtained with a signal attributable to radioisotope in compound of Formula (II), followed by administering a test compound and obtaining a second brain image. The absence of a signal attributable to radioisotope in compound of Formula (II) in the second brain image may be indicative of test compound’s greater affinity to a- synuclein fibrils, amyloid plaques, and / or tau tangles in the brain and its potential therapeutic potency to treat associated neurodegenerative disorders.

[0101] In some embodiments, the present disclosure provides a method of monitoring treatment of neurodegenerative disease (e.g., neurodegenerative disease in pathology of which a-synuclein fibrils, amyloid plaques, and / or tau tangles are implicated, such as any of the diseases described herein) in a subject, the method comprising (i) administering to the subject an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same, (ii) waiting a time sufficient to allow the compound of Formula (II) to accumulate in a brain of the subject (e.g, 5 min, 15 min, 30 min, 45 min, 1 hour, 2 hours, 3 hours, 4 hours, or 5 hours); (iii) imaging the brain of the subject with an imaging technique; (iv) administering to the subject a therapeutic agent in an effective amount to treat the neurodegenerative disorder. In one example, aducanumab, lecanemab, donepezil, rivastigmine, galantamine, memantine, suvorexant, or an experimental drug substance for treating AD, or DLB, respectively, may be administered to a subject undergoing treatment of AD, or undergoing treatment of DLB, respectively. In another example, levodopa (L-dopa), carbidopa, safinamide, dopamine agonists (e.g., ropinirole, pramipexole, rotigotine), amantadine, trihexyphenidyl, benztropine, selegiline, rasagiline, tolcapone, entacapone, an a- synuclein or LRRK2 (dardarin) antisense oligonucleotide (e.g., ASO by Biogen or ION859 and ION464 by lonis), or an experimental drug substance for treating PD, or DLB, respectively, may be administered to a subject undergoing treatment of PD, or DLB, respectively. In another example, levodopa (L-dopa), carbidopa, safinamide, dopamine agonists (e.g., ropinirole, pramipexole, rotigotine), amantadine, trihexyphenidyl, benztropine, selegiline, rasagiline, tolcapone, entacapone, fludrocortisone, midodrine, physostigmine, droxidopa, or an experimental drug substance for treating MSA may be administered to a subject undergoing treatment of MSA. In some embodiments, the method further includes step (v) after (iv), administering to the subject an effective amount of a compound of Formula (II), or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition comprising same; (vi) waiting a time sufficient to allow the compound of Formula (II) to accumulate in the brain of the subject (e.g., 5 min, 15 min, 30 min, 45 min, 1 hour, 2 hours, 3 hours, 4 hours, or 5 hours); (vii) imaging the brain of the subject with an imaging technique; and (viii) comparing the image of step (iii) and the image of step (vii). In one example, observing a reduced signal attributable to the radioisotope in the compound of Formula (II) in step viii) is indicative of progression of treatment of the neurodegenerative disease. Suitable examples of diseases the treatment of which can be monitored according to the methods of the present disclosure include any of the diseases described herein. Some particular examples include dementia with Lewy bodies, Parkinson’s disease (PD), multiple system atrophy (MSA), and pure autonomic failure (PAF). Other suitable examples include Alzheimer’s disease (AD), familial AD (FAD), frontotemporal lobar degeneration (FTD), Huntington’s disease (HD), dementia associated with PD, AD, FAD, or HD, Pick’s disease, amy otrophic lateral sclerosis (ALS), progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, dementia, chronic traumatic encephalopathy (CTE), aging- related tau astrogliopathy, Richardson syndrome, cerebellar ataxia, globular glial tauopathy, argyrophilic grain disease, motor neuron disease (MND), and Prion disease. Definitions

[0102] As used herein, the term "about" means "approximately" (e.g., plus or minus approximately 10% of the indicated value).

[0103] At various places in the present specification, substituents of compounds of the invention are disclosed in groups or in ranges. It is specifically intended that the invention include each and every individual subcombination of the members of such groups and ranges. For example, the term “Ci-6 alkyl” is specifically intended to individually disclose methyl, ethyl, C3 alkyl, C4 alkyl, C5 alkyl, and CT, alkyl.

[0104] At various places in the present specification various aryl, heteroaiyl, cycloalkyl, and heterocycloalkyl rings are described. Unless otherwise specified, these rings can be attached to the rest of the molecule at any ring member as permitted by valency. For example, the term “a pyridine ring” or “pyridinyl” may refer to a pyridin-2-yl, py ri din-3 -yl, or pyridin-4-yl ring.

[0105] It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0106] The term “aromatic” refers to a carbocycle or heterocycle having one or more polyunsaturated rings having aromatic character (i.e., having (4n + 2) delocalized 71 (pi) electrons where n is an integer).

[0107] The term “n-membered” where n is an integer typically describes the number of ring-forming atoms in a moiety where the number of ring-forming atoms is n. For example, piperidinyl is an example of a 6-membered heterocycloalkyl ring, pyrazolyl is an example of a 5-membered heteroaryl ring, pyridyl is an example of a 6- membered heteroaryl ring, and 1,2,3,4-tetrahydro-naphthalene is an example of a 10- membered cycloalkyl group.

[0108] As used herein, the phrase “optionally substituted” means unsubstituted or substituted. The substituents are independently selected, and substitution may be at any chemically accessible position. As used herein, the term “substituted” means that a hydrogen atom is removed and replaced by a substituent. A single divalent substituent, e.g., oxo, can replace two hydrogen atoms. It is to be understood that substitution at a given atom is limited by valency. It is further appreciated that certain features of the invention, which are, for clarity, described in the context of separate embodiments, can also be provided in combination in a single embodiment. Conversely, various features of the invention which are, for brevity, described in the context of a single embodiment, can also be provided separately or in any suitable subcombination.

[0109] Throughout the definitions, the term “Cn-m” indicates a range which includes the endpoints, wherein n and m are integers and indicate the number of carbons. Examples include C1-4, Ci-6, and the like.

[0110] As used herein, the term “Cn-m alkyl”, employed alone or in combination with other terms, refers to a saturated hydrocarbon group that may be straight-chain or branched, having n to m carbons. Examples of alkyl moieties include, but are not limited to, chemical groups such as methyl, ethyl, w-propyl, isopropyl, w-butyl, tertbutyl, isobutyl, sec-butyl; higher homologs such as 2-methyl-l -butyl, n-pentyl, 3- pentyl, / ?-hexyl. 1,2,2-trimethylpropyl, and the like. In some embodiments, the alkyl group contains from 1 to 6 carbon atoms, from 1 to 4 carbon atoms, from 1 to 3 carbon atoms, or 1 to 2 carbon atoms.

[0111] As used herein, the term “Cn-malkylene”, employed alone or in combination with other terms, refers to a divalent alkyl linking group having n to m carbons. Examples of alkylene groups include, but are not limited to, ethan- 1,1 -diyl, ethan-1,2- diyl, propan- 1,1, -diyl, propan-1, 3-diyl, propan- 1,2-diyl, butan-l,4-diyl, butan-1,3- diyl, butan- 1,2-diyl, 2-methyl-propan-l, 3-diyl, and the like. In some embodiments, the alkylene moiety contains 2 to 6, 2 to 4, 2 to 3, 1 to 6, 1 to 4, or 1 to 2 carbon atoms.

[0112] As used herein, the term “Cn-mhaloalkyl”, employed alone or in combination with other terms, refers to an alkyl group having from one halogen atom to 2s+ 1 halogen atoms which may be the same or different, where “s” is the number of carbon atoms in the alkyl group, wherein the alkyl group has n to m carbon atoms. In some embodiments, the haloalkyl group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0113] As used herein, the term "aryl," employed alone or in combination with other terms, refers to an aromatic hydrocarbon group, which may be monocyclic or polycyclic (e.g., having 2, 3 or 4 fused rings). The term "Cn-maryl" refers to an aryl group having from n to m ring carbon atoms. Aryl groups include, e.g., phenyl, naphthyl, anthracenyl, phenanthrenyl, indanyl, indenyl, and the like. In some embodiments, aryl groups have from 6 to 10 carbon atoms. In some embodiments, the aryl group is phenyl or naphtyl.

[0114] As used herein, “cy chalky!” refers to non-aromatic cyclic hydrocarbons including cyclized alkyl and / or alkenyl groups. Cycloalkyl groups can include mono- or polycyclic (e.g., having 2, 3 or 4 fused rings) groups and spirocycles. Ringforming carbon atoms of a cycloalkyl group can be optionally substituted by 1 or 2 independently selected oxo or sulfide groups (e.g., C(O) or C(S)). Also included in the definition of cycloalkyl are moieties that have one or more aromatic rings fused (i.e., having a bond in common with) to the cycloalkyl ring, for example, benzo or thienyl derivatives of cyclopentane, cyclohexane, and the like. A cycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. Cycloalkyl groups can have 3, 4, 5, 6, 7, 8, 9, or 10 ring-forming carbons (C3-10). In some embodiments, the cycloalkyl is a C3-10 monocyclic or bicyclic cyclocalkyl. In some embodiments, the cycloalkyl is a C3-7 monocyclic cyclocalkyl. Example cycloalkyl groups include cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopentenyl, cyclohexenyl, cyclohexadienyl, cycloheptatrienyl, norbomyl, norpinyl, norcamyl, adamantyl, and the like. In some embodiments, cycloalkyl is cyclopropyl, cyclobutyl, cyclopentyl, or cyclohexyl.

[0115] As used herein, “heteroaryl” refers to a monocyclic or polycyclic aromatic heterocycle having at least one heteroatom ring member selected from sulfur, oxygen, and nitrogen. In some embodiments, the heteroaryl ring has 1, 2, 3, or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, any nng-forming N in a heteroaryl moiety can be an N-oxide. In some embodiments, the heteroaryl is a 5-10 membered monocyclic or bicyclic heteroaryl having 1, 2, 3 or 4 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl is a 5-6 monocyclic heteroaryl having 1 or 2 heteroatom ring members independently selected from nitrogen, sulfur and oxygen. In some embodiments, the heteroaryl is a fivemembered or six-membereted heteroaryl ring. A five-membered heteroaryl ring is a heteroaryl with a ring having five ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, 0, and S. Exemplary five-membered ring heteroaryls are thienyl, furyl, pyrrolyl, imidazolyl, thiazolyl, oxazolyl, pyrazolyl, isothiazolyl, isoxazolyl, 1,2,3-triazolyl, tetrazolyl, 1,2,3-thiadiazolyl, 1,2,3- oxadiazolyl, 1,2,4-triazolyl, 1,2,4-thiadiazolyl, 1,2,4-oxadiazolyl, 1,3,4-triazolyl, 1,3,4-thiadiazolyl, and 1,3,4-oxadiazolyl. A six-membered heteroaryl ring is a heteroaryl with a ring having six ring atoms wherein one or more (e.g., 1, 2, or 3) ring atoms are independently selected from N, 0, and S. Exemplary six-membered ring heteroaryls are pyridyl, pyrazinyl, pyrimidinyl, triazinyl and pyridazinyl.

[0116] As used herein, “heterocycloalkyl” refers to non-aromatic monocyclic or polycyclic heterocycles having one or more ring-forming heteroatoms selected from 0, N, or S. Included in heterocycloalkyd are monocyclic 4-, 5-, 6-, 7-, 8-, 9- or 10- membered heterocycloalkyl groups. Heterocycloalkyl groups can also include spirocycles. Example heterocycloalkyl groups include pyrrolidin-2-one, 1,3- isoxazolidin-2-one, pyranyl, tetrahydropuran, oxetanyl, azetidinyl, morpholino, thiomorpholino, piperazinyl, tetrahydrofuranyl, tetrahydrothienyl, piperidinyl, pyrrolidinyl, isoxazolidinyl, isothiazolidinyl, pyrazolidinyl, oxazolidinyl, thiazolidinyl, imidazolidinyl, azepanyl, benzazapene, and the like. Ring-forming carbon atoms and heteroatoms of a heterocycloalkyl group can be optionally substituted by 1 or 2 independently selected oxo or sulfido groups (e.g., C(0), S(0), C(S), or S(0)2, etc.). The heterocycloalkyl group can be attached through a ringforming carbon atom or a ring-forming heteroatom. In some embodiments, the heterocycloalkyl group contains 0 to 3 double bonds. In some embodiments, the heterocycloalkyl group contains 0 to 2 double bonds. Also included in the definition of heterocycloalkyl are moieties that have one or more aromatic rings fused (z.e., having a bond in common with) to the cycloalkyl nng, for example, benzo or thienyl derivatives of piperidine, morpholine, azepine, etc. A heterocycloalkyl group containing a fused aromatic ring can be attached through any ring-forming atom including a ring-forming atom of the fused aromatic ring. In some embodiments, the heterocycloalkyl is a monocyclic 4-6 membered heterocycloalkyl having 1 or 2 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members. In some embodiments, the heterocycloalkyl is a monocyclic or bicyclic 4-10 membered heterocycloalkyl having 1, 2, 3, or 4 heteroatoms independently selected from nitrogen, oxygen, or sulfur and having one or more oxidized ring members.

[0117] At certain places, the definitions or embodiments refer to specific rings (e.g., an azetidine ring, a pyridine nng, etc.). Unless otherwise indicated, these rings can be attached to any ring member provided that the valency of the atom is not exceeded. For example, an azetidine ring may be attached at any position of the ring, whereas a pyridin-3-yl ring is attached at the 3-position.

[0118] As used herein, the term “Cn-malkoxy”, employed alone or in combination with other terms, refers to a group of formula -O-alkyl, wherein the alkyl group has n to m carbons. Example alkoxy groups include, but are not limited to, methoxy, ethoxy, propoxy (e.g., n-propoxy and isopropoxy), butoxy (e.g., n-butoxy and tertbutoxy), and the like. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0119] As used herein, “Cn-m haloalkoxy” refers to a group of formula -O-haloalkyl having n to m carbon atoms. An example haloalkoxy group is OCF3. In some embodiments, the haloalkoxy group is fluorinated only. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0120] As used herein, “halo” refers to F, Cl, Br, or I. In some embodiments, a halo is F, Cl, or Br.

[0121] As used herein, the term “amino” refers to a group of formula -NH2.

[0122] As used herein, the term “Cn-malkylamino” refers to a group of formula -NH(alkyl), wherein the alkyl group has n to m carbon atoms. In some embodiments, the alkyl group has 1 to 6, 1 to 4, or 1 to 3 carbon atoms. Examples of alkylamino groups include, but are not limited to, N-methylamino, N-ethylamino, N- propylamino (e.g., N-( / ?-propyl)amino and N-isopropylamino), N-butylamino (e.g., N- (w-butyl)amino and N-(tert-butyl)amino), and the like.

[0123] As used herein, the term “di(Cn-m-alkyl)amino” refers to a group of formula - N(alkyl)2, wherein the two alkyl groups each has, independently, n to m carbon atoms. In some embodiments, each alkyl group independently has 1 to 6, 1 to 4, or 1 to 3 carbon atoms.

[0124] The term “compound” as used herein is meant to include all stereoisomers, geometric isomers, tautomers, and isotopes of the structures depicted. Compounds herein identified by name or structure as one particular tautomeric form are intended to include other tautomeric forms unless otherwise specified. Any atom identified in the compounds herein that is not specifically designated as radioisotope is present at is natural isotopic abundance.

[0125] The compounds descnbed herein can be asymmetric e.g., having one or more stereocenters). All stereoisomers, such as enantiomers and diastereomers, are intended unless otherwise indicated. Compounds of the present invention that contain asymmetrically substituted carbon atoms can be isolated in optically active or racemic forms. Methods on how to prepare optically active forms from optically inactive starting materials are known in the art, such as by resolution of racemic mixtures or by stereoselective synthesis. Many geometric isomers of olefins, C=N double bonds, N=N double bonds, and the like can also be present in the compounds described herein, and all such stable isomers are contemplated in the present invention. Cis and trans geometric isomers of the compounds of the present invention are described and may be isolated as a mixture of isomers or as separated isomeric forms. In some embodiments, the compound has the (R) -con figuration. In some embodiments, the compound has the (S) -con figuration.

[0126] Compounds provided herein also include tautomeric forms. Tautomeric forms result from the swapping of a single bond with an adjacent double bond together with the concomitant migration of a proton. Tautomeric forms include prototropic tautomers which are isomeric protonation states having the same empirical formula and total charge. Example prototropic tautomers include ketone - enol pairs, amide - imidic acid pairs, lactam - lactim pairs, enamine - imine pairs, and annular forms where a proton can occupy two or more positions of a heterocyclic system, for example, 1H- and 3H-imidazole, 1H-, 2H- and 4H- 1,2,4-triazole, 1H- and 2H- isoindole, and 1H- and 2H-pyrazole. Tautomeric forms can be in equilibrium or sterically locked into one form by appropriate substitution.

[0127] As used herein, the term “individual”, “patient”, or “subject” used interchangeably, refers to any animal, including mammals, preferably mice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep, horses, or primates, and most preferably humans.

[0128] As used herein, the phrase “effective amount” or “therapeutically effective amount” refers to the amount of active compound or pharmaceutical agent that elicits the biological or medicinal response in a tissue, system, animal, individual or human that is being sought by a researcher, veterinarian, medical doctor or other clinician.

[0129] As used herein the term “treating” or “treatment” refers to 1) inhibiting the disease; for example, inhibiting a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (i.e. , arresting further development of the pathology and / or symptomatology), or 2) ameliorating the disease; for example, ameliorating a disease, condition or disorder in an individual who is experiencing or displaying the pathology or symptomatology of the disease, condition or disorder (z.e., reversing the pathology and / or symptomatology).

[0130] As used herein, the term “preventing” or “prevention” of a disease, condition or disorder refers to decreasing the risk of occurrence of the disease, condition or disorder in a subject or group of subjects (e.g., a subject or group of subjects predisposed to or susceptible to the disease, condition or disorder). In some embodiments, preventing a disease, condition or disorder refers to decreasing the possibility of acquiring the disease, condition or disorder and / or its associated symptoms. In some embodiments, preventing a disease, condition or disorder refers to completely or almost completely stopping the disease, condition or disorder from occurring.

[0131] As used herein, the term “radioisotope” refers to an atom having an atomic mass or mass number different from the atomic mass or mass number typically found in nature (i.e., naturally occurring).

[0132] As used herein, the term “isotopic enrichment factor” refers to the ratio between the isotopic abundance and the natural abundance of a specified isotope.

[0133] “18F” refers to the radioisotope of fluorine having 9 protons and 9 neutrons. “F” refers to the stable isotope of fluorine having 9 protons and 10 neutrons (i.e., the “19F isotope”). A compound of the present disclosure has an isotopic enrichment factor for each designated18F atom of at least 3500 (52.5%18F incorporation at each designated18F atom), at least 4000 (60%18F incorporation), at least 4500 (67.5%18F incorporation), at least 5000 (75%18F), at least 5500 (82.5%18F incorporation), at least 6000 (90%18F incorporation), at least 6333.3 (95%18F incorporation), at least 6466.7 (97%18F incorporation), at least 6600 (99%18F incorporation), or at least 6633.3 (99.5%18F incorporation).

[0134] “nC” refers to the radioisotope of carbon having 6 protons and 5 neutrons. “C” refers to the stable isotope of carbon having 6 protons and 6 neutrons (i.e., the “12C isotope”). A compound of the present disclosure has an isotopic enrichment factor for each designatednC atom of at least 3500 (52.5%nC incorporation at each designatednC atom), at least 4000 (60%nC incorporation), at least 4500 (67.5%nC incorporation), at least 5000 (75%nC), at least 5500 (82.5%nC incorporation), at least 6000 (90%nC incorporation), at least 6333.3 (95%nC incorporation), at least 6466.7 (97%nC incorporation), at least 6600 (99%nC incorporation), or at least 6633.3 (99.5%nC incorporation). “123I” refers to the radioisotope of iodine having 53 protons and 70 neutrons. “125I” refers to the radioisotope of iodine having 53 protons and 72 neutrons. “131I” refers to the radioisotope of iodine having 53 protons and 78 neutrons. “I” refers to any abundant, stable isotope or a combination of stable, non-radioactive isotopes of iodine (e.g., the “127I isotope”). A compound of the present disclosure has an isotopic enrichment factor for each designated123 / 125 / 131i atom of at least 3500 (52.5% incorporation at each designated123 / 125 / 131i atom), at least 4000 (60% incorporation), at least 4500 (67.5% incorporation), at least 5000 (75% incorporation), at least 5500 (82.5% incorporation), at least 6000 (90% incorporation), at least 6333.3 (95% incorporation), at least 6466.7 (97% incorporation), at least 6600 (99% incorporation), or at least 6633.3 (99.5% incorporation).

[0135] EXAMPLES

[0136] Materials and methods

[0137] All commercially available reagents were used without further purification unless otherwise stated. Analytical thin layer chromatography (TLC) was performed using Silica Gel GF254 plates (Merck Millipore co, .ltd, 0.2 mm thick). Compounds were purified using CombiFlash Rf 150 (Teledyne ISCO co, .ltd). and13C spectra were recorded on Bruker 500 MHz. Chemical shifts in1H NMR spectra were reported in parts per million (ppm) on the 5 scale from an internal standard of CDCh (7.26 ppm). Data were reported as follows: chemical shift (5 ppm), multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = Broad), coupling constant in hertz (Hz), and integration. Chemical shifts of13C NMR spectra were reported in ppm from the central peak of CDCh (77.0 ppm) on the 8 scale. MS data was recorded on Agilent Technologies 6310 quadrupole mass spectrometer.

[0138] PET / CT / MR imaging was performed in anesthetized (isoflurane) animals to minimize discomfort. Highly trained animal technicians monitored animal safety throughout all procedures, and veterinary staff were responsible for daily care. All mice were socially housed in cages appropriate for the physical and behavioral health of the individual animal and were given unlimited access to food and water, with additional nutritional supplements provided as prescribed by the attending veterinary staff. Example 1 - synthesis of compound N-(benzo[c][l,2,5]thiadiazol-5- ylmethyl)-N-(methyl-llC)-3-(methylsulfonyl)benzenesulfonamide ([11C]SY-01)

[0139] [nC]CO2 was obtained via the14N (p, a)nC reaction on nitrogen with 2.5% oxygen, with 11 MeV protons (Siemens Eclipse cyclotron), and trapped on molecular sieves in a TRACERlab FX-Mel synthesizer (General Electric). [nC]CH4 was obtained by the reduction of [nC]CO2 in the presence of Ni / hydrogen at 350 °C, which re-circulated through an oven containing E to produce [nC]CH3l via a radical reaction.

[0140] The prepared [nC]CH3l was trapped in anhydrous DMF (300 pL) containing SY-01 precursor (1.0 mg) and K2CO3 (1.0 mg). The reaction vessel was heated at 80 °C and kept there for 3 min. The radioactive mixture containing CJSY-Ol was quenched by addition of an HPLC mobile phase (0.7 mL) and then applied to a reverse phase semipreparative HPLC (Phenomenex Gemini -NX 5u C18 110A, 250 x 10 mm, 5.0 mL / min, a gradient of 10-90 % CH3CN in H2O of 0.1% ammonium formate). A radioactive fraction having a retention time of 8 mm was collected in a flask, and diluted in water (30 mL). The final product was reformulated by loading onto a solid-phase exchange (SPE) C-18 cartridge (Waters WAT020515 Sep-Pak Plus Short Cl 8), rinsing with water (4 x 5 mL), eluting with EtOH (0.3 mL), and diluting with saline (2.7 mL). The chemical and radiochemical purity of the final product was tested by analytical HPLC (VARI AN Puruit XRs 5 C18, 150 x 4.6 mm), eluting with a gradient of 10-90 % CH3CN in H2O of 0.1 % TFA, at a flow rate of 2 mL / min.

[0141] The following compounds may be prepared using methods and procedures similar to those used to prepare [nC]SY-01:

[0142]

[0143] For cmpd SY-01 (binding affinity tested by Radioligand free Binding Test using Biolayer Interferometry (BLI)):

[0144] Alpha synuclein aggregates: Kj: 50 nM. Abeta amyloid aggregates: Ka: 29.41 pM.

[0145] Tau aggregates: Kj: 213 nM.

[0146] SY-01 was evaluated in a-synuclein binding assay and compared to a- synuclein fibril binding radioligand SIL23: Additional experimental details are provided in Figures 1A-3.

Claims

OTHER EMBODIMENTSIt is to be understood that while the present application has been described in conjunction with the detailed description thereof, the foregoing description is intended to illustrate and not limit the scope of the present application, which is defined by the scope of the appended claims. Other aspects, advantages, and modifications are within the scope of the following claims.WHAT IS CLAIMED IS:

1. A compound of F ormula (I) :or a pharmaceutically acceptable salt thereof, wherein:X1is selected from S and 0;R1, R2, and R3are each independently selected from halo, OH, CN, NO2, C1.3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=0)0(Ci-3 alkyl), C(=0)NH2, C(=0)NH(CI-3 alkyl), C(=0)N(CI-3 alkyl)2, amino, C1-3 alkylamino, and di(Ci-3 alkyl)amino;R4is selected from H, C1-3 alkyl, and C1-3 haloalkyl;L1is absent; or L1is selected fromn Ci-6 alkylene and C3-6 cycloalkylene, wherein said Ci-6 alkylene is optionally interrupted with 1 or 2 groups independently selected from C(=0), S(=0)2, 0, and NH; ring A is absent, or ring A is a moiety of formula (i):a indicates a point of attachment to X2; b indicates a point of attachment to L1; ring C is selected from C3-6 cycloalkyl and 4-7-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from selected halo, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1.3 alkoxy, C 1-3 haloalkoxy, C(=0)0H, C(=O)O(Ci-3alkyl), C(=0)NH2, C(=O)NH(CI-3alkyl), C(=0)N(CI-3 alky 1)2, amino, C1-3 alkylamino, and di (C 1-3 alkyl)amino;R5and R6are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl;X2is selected from C(=0) and S(=0)2; and ring B is selected from Ce-io aryl and 5-14 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selectedfrom halo, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, S(=O)2(Ci-3alkyl), S(=O)2OH, C(=O)OH, C(=O)O(CI-3alkyl), C(=O)NH2, C(=0)NH(CI-3 alkyl), C(=0)N(CI-3 alkyl)2, amino, C1-3 alkylamino, and di(C 1-3 alkyl)amino.

2. The compound of claim 1, wherein the compound of Formula (I) has formula:or a pharmaceutically acceptable salt thereof.

3. The compound of claim 1, wherein the compound of Formula (I) has formula:or a pharmaceutically acceptable salt thereof, wherein:L1is selected fromn Ci-6 alkylene and C3-6 cycloalkylene, wherein said Ci- 6 alkylene is optionally interrupted with 1 or 2 groups independently selected from C(=O), S(=O)2, 0, and NH.

4. The compound of claim 3, wherein the compound of Formula (I) has formula:or a pharmaceutically acceptable salt thereof.

5. The compound of claim 3, wherein the compound of Formula (I) has formula:or a pharmaceutically acceptable salt thereof.

6. The compound of claim 3, wherein the compound of Formula (I) has formula:or a pharmaceutically acceptable salt thereof.

7. The compound of any one of claims 3-6, wherein L1is Ci-6 alkylene, optionally interrupted with 0 or NH.

8. The compound of any one of claims 3-6, wherein L1is Ci-6 alkylene.

9. The compound of any one of claims 3-6, wherein L1is Ci-6 alkylene interrupted with 0.

10. The compound of any one of claims 3-6, wherein L1is C1-3 alkylene-O-Ci-3 alkylene.

11. The compound of any one of claims 3-6, wherein L1is C3-6 cycloalkylene.

12. The compound of any one of claims 1-11, wherein R4is H or C1-3 alkyl.

13. The compound of any one of claims 1-12, wherein R1, R2, and R3are each independently selected from halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, and C(=0)NH2.The compound of claim 1, wherein the compound is selected from any one of the following compounds:or a pharmaceutically acceptable salt thereof.

15. A pharmaceutical composition comprising a compound of claim 1, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

16. A method of treating a neurodegenerative disease or disorder selected from dementia with Lewy bodies, Parkinson’s disease (PD), multiple system atrophy (MSA), pure autonomic failure (PAF), Alzheimer’s disease (AD), familial AD (FAD), frontotemporal lobar degeneration (FTD), Huntington’s disease (HD), dementia associated with PD, AD, FAD, or HD, Pick’s disease, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, dementia, chronic traumatic encephalopathy (CTE), aging-related tau astrogliopathy, Richardson syndrome, cerebellar ataxia, globular glial tauopathy, argyrophilic grain disease, motor neuron disease (MND), and Prion disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1, or a therapeutically acceptable salt thereof.

17. A compound of F ormula (II):or a pharmaceutically acceptable salt thereof, wherein:the compound comprises at least one radioisotope selected fromnC,18F,123I,125I, and13I;X1is selected from S and 0;R1. R2, and R3are each independently selected from halo, OH, CN, NO2, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=O)O(Ci- 3 alkyl), C(=O)NH2, C(=O)NH(CI-3alkyl), C(=O)N(CI-3alkyl)2, amino, C1-3 alkylamino, and di(Ci-3 alkyl)amino;R4is selected from H, C1-3 alkyl, and C 1-3 haloalkyl;L1is absent; or L1is selected fromn C1-6 alkylene and C3-6 cycloalkylene, wherein said Ci-s alkylene is optionally interrupted with 1 or 2 groups independently selected from C(=0), S(=0)2, 0, and NH; ring A is absent, or ring A is a moiety of formula (i):a indicates a point of attachment to X2; b indicates a point of attachment to L1; ring C is selected from C3-6 cycloalkyl and 4-7-membered heterocycloalkyl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from selected halo, OH, CN, N02, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, C(=O)OH, C(=0)0(Ci-3 alkyl), C(=0)NH2, C(=0)NH(CI-3 alkyl), C(=0)N(CI-3 alkyl)2, amino, C1-3 alkylamino, and di(Ci-3 alkyl)amino;R5and R6are each independently selected from H, C1-3 alkyl, and C1-3 haloalkyl;X2is selected from C(=0) and S(=0)2; and ring B is selected from Ce-io aryl and 5-14 membered heteroaryl, each of which is optionally substituted with 1, 2, or 3 substituents independently selected from halo, OH, CN, N02, C1.3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, S(=O)2(Ci-3alkyl), S(=O)2OH, C(=O)OH, C(=O)O(Ci-3alkyl), C(=0)NH2, C(=O)NH(CI-3alkyl), C(=O)N(CI-3alkyl)2, ammo, C1.3 alkylamino, and di(Ci-3 alkyl)amino.

18. The compound of claim 17, wherein the compound of Formula (II) comprises at least one radioisotope selected fromnC,18F,1231,125I, and131I.

19. The compound of claim 17, wherein the compound of Formula (II) is selected from18F,1231,1251,131I,nCN,nC(=O)NH2,nCH3-,nCH3O-,18FCH2CH2-, 18FCH2CH2O-, and18FCH2CH2CH2O-.

20. The compound of any one of claims 17-19, wherein the compound of Formula(II) has formula:or a pharmaceutically acceptable salt thereof.

21. The compound of any one of claims 17-19, wherein the compound of Formula(II) has formula:or a pharmaceutically acceptable salt thereof, wherein:L1is selected fromn Ci-6 alkylene and C3-s cycloalkylene, wherein said Ci- 6 alkylene is optionally interrupted with 1 or 2 groups independently selected from C(=O), S(=O)2, 0, and NH.

22. The compound of claim 21, wherein the compound of Formula (II) has formula:or a pharmaceutically acceptable salt thereof.The compound of claim 21, wherein the compound of Formula (II) has formula:or a pharmaceutically acceptable salt thereof.

24. The compound of claim 21, wherein the compound of Formula (II) has formula:or a pharmaceutically acceptable salt thereof.

25. The compound of any one of claims 21-24, wherein L1is Ci-s alkylene, optionally interrupted with 0 or NH.

26. The compound of any one of claims 21-24, wherein L1is Ci-6 alkylene.

27. The compound of any one of claims 21-24, wherein L1is Ci-s alkylene interrupted with 0.

28. The compound of any one of claims 21-24, wherein L1is C1-3 alkylene-O-Ci-3 alkylene.

29. The compound of any one of claims 21-24, wherein L1is C3-6 cycloalkylene.

30. The compound of any one of claims 17-29, wherein R4is H or C1.3 alkyl.

31. The compound of claim 30, wherein R4comprisesnCH3- or18FCH2CH2-.

32. The compound of any one of claims 17-29, wherein R1, R2, and R3are each independently selected from halo, CN, C1-3 alkyl, C1-3 haloalkyl, C1-3 alkoxy, C1-3 haloalkoxy, and C(=O)NH2.

33. The compound of claim 17, wherein the compound of Formula (II) is selected from any one of the following compounds:or a pharmaceutically acceptable salt thereof.

34. A pharmaceutical composition comprising a compound of claim 17, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.

35. A method of imaging a brain of a subject, the method comprising:i) administering to the subject an effective amount of a compound of claim 17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 34; ii) waiting a time sufficient to allow the compound to accumulate in the brain to be imaged; and iii) imaging the brain with an imaging technique.

36. The method of claim 35, wherein the compound binds to a-synuclein fibrils, amyloid plaques, or tau tangles in the brain.

37. A method of diagnosing a neurodegenerative disease in a subject, the method comprising imaging a brain of a subject according to a method of claim 35, wherein observing a signal in step iii) attributable to the radioisotope in the compound of claim 17 is indicative of the neurodegenerative disease in the subject.

38. A method of monitoring treatment of a neurodegenerative disease in a subject, the method comprising: i) administenng to the subject an effective amount of a compound of claim 17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 34; ii) waiting a time sufficient to allow the compound to accumulate in a brain of the subject; iii) imaging the brain of the subject with an imaging technique; iv) administenng to the subject a therapeutic agent in an effective amount to treat the neurodegenerative disease; v) after iv), administering to the subject an effective amount of a compound of claim 17, or a pharmaceutically acceptable salt thereof, or a pharmaceutical composition of claim 34; vi) waiting a time sufficient to allow the compound to accumulate in the brain of the subject; vii) imaging the brain of the subject with an imaging technique; and viii) comparing the image of step iii) and the image of step vii), wherein observing a reduced signal attributable to the radioisotope in the compound of claim 17 in step viii) is indicative of progression of treatment of the neurodegenerative disease.

39. The method of any one of claims 35-38, wherein the imaging technique is selected from positron emission tomography (PET) imaging, positron emission tomography with computer tomography (PET / CT) imaging, positron emission tomography with magnetic resonance (PET / MRI) imaging, and single-photon emission computerized tomography (SPECT) imaging.

40. The method of claim 37 or 38, wherein the neurodegenerative disease is selected from dementia with Lewy bodies, Parkinson’s disease (PD), multiple system atrophy (MSA), pure autonomic failure (PAF), Alzheimer’s disease (AD), familial AD (FAD), frontotemporal lobar degeneration (FTD), Huntington’s disease (HD), dementia associated with PD, AD, FAD, or HD, Pick’s disease, amyotrophic lateral sclerosis (ALS), progressive supranuclear palsy, corticobasal degeneration, argyrophilic grain disease, dementia, chronic traumatic encephalopathy (CTE), aging-related tau astrogliopathy, Richardson syndrome, cerebellar ataxia, globular glial tauopathy, argyrophilic grain disease, motor neuron disease (MND), and Prion disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a compound of claim 1, or a therapeutically acceptable salt thereof.

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