Astatine-211-labelled PSMA-binding compounds

Abstract

The present invention provides compounds of Formula (I), pharmaceutical compositions comprising such compounds and methods of using such compounds for treating cancer.

Description

[0001] ASTATINE-211-LABELLED PSMA-BINDING COMPOUNDS

[0002] Related Application

[0003] This application claims the benefit of U.S. Provisional Application No. 63 / 574,815, filed on April 4, 2024. The entire teachings of the above application are incorporated herein by reference.

[0004] Background of the Invention

[0005] Targeted radiopharmaceuticals are in development for treating a variety of cancers, including prostate cancer. Such agents can be used to treat primary solid tumors, metastatic lesions and diffuse cancer cells or clusters of cancer cells. These targets differ in terms of size and distribution, as well as the optimum type of radiation for destroying cancer cells while minimizing damage to healthy tissue. There is thus a need for targeted therapies employing a variety of radioisotopes, including beta emitters and alpha emitters, for use against cancers in different tissues and forms.

[0006] Summary of the Invention

[0007] The present invention relates to compounds which bind to prostate-specific membrane antigen (PSMA) which are labelled with211At and are useful for treating cancers which express PSMA, such as prostate cancer.

[0008] In a first embodiment, the invention provides a compound of Formula (I), or a pharmaceutically acceptable salt or ester thereof, wherein n is 0 or 1; m is 0 or 1 :

[0009] L is a bivalent linker;

[0010] A is optionally substituted aryl or heteroaryl; and

[0011] At is astatine-211. In a second embodiment, the present invention provides pharmaceutical compositions comprising a compound of Formula (I), or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier or excipient.

[0012] In a third embodiment, the present invention provides methods of treating cancer, such as a cancer expressing PSMA, in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of a compound of Formula I or a pharmaceutically acceptable salt thereof.

[0013] In a fourth embodiment, the present invention provides methods of preparing compounds of Formula (I).

[0014] Brief Description of the Drawings

[0015] Figure 1 shows the ex-vivo biodistribution of211At-MIP-1095 at 30 mins, 2, 4 and 24 hours post IV injection in the LNCaP mouse model of prostate cancer. The graph to the left represents organs with low uptake and the graphs to the right represent organs with higher uptake. Bars represent mean ± SEM, n=2-4 / group.

[0016] Figure 2 shows the tumor to kidney ratios of177Lu-PSMA-617,177Lu-PSMA-I&T,123I-MIP-1095, and211At-MIP-1095 in the LNCaP mouse model of prostate cancer.

[0017] Figure 3 shows the ex-vivo biodistribution of211At-MIP-1095 at 30 mins, 2, 4 and 24 hours post IV injection in male Wistar rats. The graph to the left represents organs with low uptake and the graphs to the right represent organs with higher uptake. Bars represent mean ± SEM, n=3-4 / group.

[0018] Figure 4 shows the ex-vivo biodistribution of123I-MIP-1095 at 30 mins, 2, 4 and 24 hours post IV injection in male Wistar rats. The graph to the left represents organs with low uptake and the graphs to the right represent organs with higher uptake. Bars represent mean ± SEM, n=3-4 / group.

[0019] Figure 5 shows the human211At-MIP-1095 dosimetry data extrapolated from the ex- vivo biodistribution in male Wistar rats.

[0020] Figure 6 shows the human123I-MIP-1095 dosimetry data extrapolated from the ex- vivo biodistribution in male Wistar rats.

[0021] Detailed Description of the Invention

[0022] Astatine is the heaviest element of Group VIIA of the periodic table of the elements, which also includes fluorine, chlorine, bromine, and iodine. Astatine has characteristics of both a halogen and a metal. Like metals, stable cationic species of astatine, e.g., At+and AtO+, form complexes with anionic ligands and interact with organic species containing soft donor atoms. As a halogen, astatine exists as a stable At" in water and reacts as a nucleophile. Additionally, astatine serves as the strongest halogen-bond donor, which plays an important role in molecular recognition (Guerard, F. et al. Acc. Chem. Res. 2021, 54, 16, 3264-3275).

[0023] Astatine has 32 known isotopes, none of which is stable.211At was discovered in 1940 by irradiating bismuth with accelerated a particles (Corson, D.R. et al. Phys. Rev. 1940, 57, 459).211At has a half-life of 7.2 h and it decays to207Pb via a double-branched pathway, emitting high-energy a particles. The short path length (<100 pm) of a particles makes211At attractive for use in radiopharmaceuticals as it potentially allows for treating small clusters or isolated cancer cells with reduced irradiation of surrounding healthy issues (Guerard, F. et al. Nucl. Med. Mol. Imaging 2015, 59, 161-167).

[0024] The compounds of Formula (I) include a glutamic acid / lysine urea (GUL) moiety which has been shown to bind to PSMA on prostate cancer cells, and an aryl or heteroaryl group, denoted A, which is connected to the GUL group by bivalent linker L. The GUL targets the molecule to PSMA- expressing cancer cells which are killed by the alpha particles emitted by the At-215.

[0025] Group A of Formula (I) is preferably a 6 to 12-membered aryl group or a 5- to 10- membered heteroaryl group. The aryl group is preferably phenyl, naphthyl or biphenyl and more preferably phenyl. The heteroaryl group is preferably a monocyclic 5- or 6-membered heteroaryl or a 9- or 10-membered fused bicyclic heteroaryl. Preferred heteroaryl groups include pyridine, pyrimidine, pyrazine, pyrrole, imidazole, triazole, furan, oxazole, isoxazole, thiazole, quinoline, quinoxaline, indole, indazole, thiophene, benzimidazole, benzothiophene, and benzofuran. The aryl or heteroaryl optionally has one or more substituents in addition to the astatine-211. Preferably the aryl or heteroaryl groups has no substituents in addition to the astatine-211 or has one to four substituents preferably independently selected from halogen, hydroxyl and amino.

[0026] Group L of Formula (I) is a bivalent linker which connects the GUL moiety to aryl or heteroaryl group A. The bivalent linker can be any suitable group and is preferably a bivalent aliphatic group having a length of 1 to 12 atoms, preferably a length of 1 to 4 atoms. In certain embodiments, L consists solely of carbon atoms along its length. In other embodiments, L consists of carbon atoms and at least one heteroatom, such as a nitrogen, oxygen, or sulfur atom, along its length. L can be saturated or partially unsaturated. In certain embodiments, L comprises an olefinic bond. In certain embodiments, L comprises a carboncarbon triple bond. Suitable L groups include, but are not limited to, moieties of the formula - Xi-(CRiR2)n-Bi-, where Xi is absent, -C(0)-, -C(0)0-, or -C(O)NH-; each Ri and R2 is independently hydrogen, hydroxyl, amino or halogen; Bi is absent, -NHC(O)-, -OC(O)-, - NHC(O)NH-, -NH-C(O)-O-, -SO2-, or -NHSO2-; and n is 0 to 6; provided that n is at least 1 or at least one of Xi and Bi is not absent. In certain embodiments, each Ri and R2 is hydrogen.

[0027] In certain embodiments, L is a Ci-Ce-alkylene which is optionally terminated at one or both ends, when possible, by a group independently selected from -C(O)-, -C(O)NH-, - C(O)O-, -O-, -SO2-, and -NHSO2- and / or is interrupted by one or more, preferably 0 or 1, groups selected from -C(O)-, -C(O)NH-, -NH-, -NMe- and -O-. In certain embodiments, L is -CH2-, -C(O)NH-, -C(O)-, -SO2-, or -C(O)NH-CH2-.

[0028] In certain embodiments m and n are both 0. In certain embodiments m and n are both 1. In certain embodiments m is 1 and n is 0. In certain embodiments m is 0 and n is 1.

[0029] In certain embodiments, the compound of Formula (I) is represented by Formula (la), In certain embodiments, the compound of Formula (I) is represented by Formula (II),

[0030] Formula (III), Formula (IV), Formula (V) or Formula (VI):

[0031]

[0032] In certain embodiments of the compounds of Formulas (II) to (VI), n is 1 and m is 1.

[0033] In certain embodiments m is 1 and n is 0. In certain embodiments m is 0 and n is 1. In certain embodiments, the compound of Formula (I) is represented by Formula

[0034] (VII), Formula (VIII), Formula (IX), Formula (X) or Formula (XI):

[0035]

[0036] The compounds of the invention include, but are not limited to, compounds 1- below and pharmaceutically acceptable salts or esters thereof.

[0037] 

[0038]

[0039]

[0040] Definitions

[0041] Listed below are definitions of various terms used to describe this invention. These definitions apply to the terms as they are used throughout this specification and claims, unless otherwise limited in specific instances, either individually or as part of a larger group.

[0042] The term "aryl," as used herein, refers to a mono- or polycyclic carbocyclic ring system comprising at least one aromatic ring. Preferred aryl groups are CL-C 12-ary I groups, including, but not limited to, phenyl, naphthyl, tetrahydronaphthyl, indanyl, and indenyl. A polycyclic aryl is a polycyclic ring system that comprises at least one aromatic ring. Polycyclic aryls can comprise fused rings, covalently attached rings or a combination thereof. The term "heteroaryl," as used herein, refers to a mono- or polycyclic aromatic radical having one or more ring atom selected from S, O and N; and the remaining ring atoms are carbon, wherein any N or S contained within the ring may be optionally oxidized. In certain embodiments, a heteroaryl group is a 5- to 10-membered heteroaryl, such as a 5- or 6- membered monocyclic heteroaryl or an 8- to 10-membered bicyclic heteroaryl. Heteroaryl groups include, but are not limited to, pyridinyl, pyrazinyl, pyrimidinyl, pyrrolyl, pyrazolyl, imidazolyl, thiazolyl, oxazolyl, isooxazolyl, thiadiazolyl, oxadiazolyl, thiophenyl, furanyl, quinolinyl, isoquinolinyl, benzimidazolyl, benzoxazolyl, quinoxalinyl. A polycyclic heteroaryl can comprise fused rings, covalently attached rings or a combination thereof. A heteroaryl group can be C-attached or N-attached where possible.

[0043] In accordance with the invention, aryl and heteroaryl groups can be substituted or unsubstituted.

[0044] The term “alkyl”, as used herein, refers to saturated, straight- or branched-chain hydrocarbon radicals. "Ci-C4alkyl,” "Ci-C6alkyl,” “Ci-C8alkyl,” “C1-C12 alkyl," "C2-C4 alkyl,” and "C3-C6 alkyl,” refer to alkyl groups containing from 1 to 4, 1 to 6, 1 to 8, 1 to 12, 2 to 4, and 3 to 6 carbon atoms, respectively. Examples of Ci-Cs alkyl groups include, but are not limited to, methyl, ethyl, propyl, isopropyl, / / -butyl, ec-butyl, tert-butyl, n-pentyl, neopentyl, n-hexyl, n-heptyl and n-octyl radicals.

[0045] The term “alkenyl”, as used herein, refers to straight- or branched-chain hydrocarbon radicals having at least one carbon-carbon double bond. “C2-C8 alkenyl,” “C2-C12 alkenyl," “C2-C4 alkenyl,” “C3-C4 alkenyl,” and “C3-C6 alkenyl,” refer to alkenyl groups containing from 2 to 8, 2 to 12, 2 to 4, 3 to 4. or 3 to 6 carbon atoms, respectively. Alkenyl groups include, but are not limited to, ethenyl, propenyl, butenyl, 2-methyl-2-buten-2-yl, heptenyl, octenyl, and the like.

[0046] The term “alkynyl”, as used herein, refers to straight- or branched-chain hydrocarbon radicals having at least one carbon-carbon triple bond. “C2-C8 alkynyl,” “C2-C12 alkynyl," “C2-C4 alkynyl,” “C3-C4 alkynyl,” and “C3-C6 alkynyl,” refer to alkynyl groups containing from 2 to 8t, 2 to 12, 2 to 4, 3 to 4 or 3 to 6 carbon atoms respectively. Representative alkynyl groups include, but are not limited to, ethynyl, 2-propynyl, 2-butynyl, heptynyl, octynyl, and the like.

[0047] The term “cycloalkyl,” as used herein, refers to a monocyclic or polycyclic saturated carbocyclic ring, such as a bi- or tri-cyclic fused, bridged or spiro system. The ring carbon atoms are optionally oxo- substituted or optionally substituted with an exocyclic olefinic double bond. Preferred cycloalkyl groups include C3-C12 cycloalkyl, C3-C6 cycloalkyl, C3-C8 cycloalkyl and C4-C7 cycloalkyl. Examples of C3-C12 cycloalkyl include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cyclopentyl, cyclooctyl, 4-methylene- cyclohexyl, bicyclo[2.2.1]heptyl, bicyclo[3.1.0]hexyl, spiro[2.5]octyl, 3- methylenebicyclo[3.2.1]octyl, spiro[4.4]nonanyl, and the like.

[0048] The term “cycloalkenyl,” as used herein, refers to monocyclic or polycyclic carbocyclic ring, such as a bi- or tri-cyclic fused, bridged or spiro system having at least one carbon-carbon double bond. The ring carbon atoms are optionally oxo-substituted or optionally substituted with an exocyclic olefinic double bond. Preferred cycloalkenyl groups include C3-C12 cycloalkenyl, C4-Ci2-cycloalkenyl, C3-C8 cycloalkenyl, C4-C8 cycloalkenyl and C5-C7 cycloalkenyl groups. Examples of C3-C12 cycloalkenyl include, but are not limited to, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl, cyclooctenyl, bicyclo[2.2.1]hept-2-enyl, bicyclo[3.1.0]hex-2-enyl, spiro[2.5]oct-4-enyl, spiro[4.4]non-2- enyl, bicyclo[4.2.1]non-3-en-12-yl, and the like.

[0049] As used herein, the term “arylalkyl” means a functional group wherein an alkylene chain is attached to an aryl group, e.g., -(CH2)n-phenyl, where n is 1 to 12, preferably 1 to 6 and more preferably 1 or 2. The term “substituted arylalkyl” means an arylalkyl functional group in which the aryl group is substituted. Similarly, the term “heteroarylalkyl” means a functional group wherein an alkylene chain, is attached to a heteroaryl group, e.g., -(CH2)n- heteroaryl, where n is 1 to 12, preferably 1 to 6 and more preferably 1 or 2. The term “substituted heteroarylalkyl” means a heteroarylalkyl functional group in which the heteroaryl group is substituted.

[0050] As used herein, the term “alkoxy” is a radical in which an alkyl group having the designated number of carbon atoms is connected to the rest of the molecule via an oxygen atom. Alkoxy groups include Ci-Ci2-alkoxy, Ci-Cs-alkoxy, Ci-Ce-alkoxy, Ci-C4-alkoxy and Ci-C3-alkoxy groups. Examples of alkoxy groups include, but are not limited to, methoxy, ethoxy, n-propoxy, 2-propoxy (isopropoxy) and the higher homologs and isomers. Preferred alkoxy are Ci-Csalkoxy.

[0051] An “aliphatic” group is a non-aromatic moiety comprised of any combination of carbon atoms, hydrogen atoms, halogen atoms, oxygen, nitrogen, or other atoms, and optionally contains one or more units of unsaturation, e.g., double and / or triple bonds. Examples of aliphatic groups are functional groups, such as alkyl, alkenyl, alkynyl, O, OH, NH, NH2, C(O), S(O)2, C(O)O, C(O)NH, OC(O)O, OC(O)NH, OC(O)NH2, S(O)2NH, S(O)2NH2, NHC(O)NH2, NHC(O)C(O)NH, NHS(O)2NH, NHS(O)2NH2, C(0)NHS(0)2, C(0)NHS(0)2NH or C(O)NHS(O)2NH2, and the like, groups comprising one or more functional groups, non-aromatic hydrocarbons (optionally substituted), and groups wherein one or more carbons of a non-aromatic hydrocarbon (optionally substituted) is replaced by a functional group. Carbon atoms of an aliphatic group can be optionally oxo- substituted. An aliphatic group may be straight chained, branched, cyclic, or a combination thereof and preferably contains between about 1 and about 24 carbon atoms, more typically between about 1 and about 12 carbon atoms. In addition to aliphatic hydrocarbon groups, as used herein, aliphatic groups expressly include, for example, alkoxyalkyls, poly alkoxy alkyls, such as polyalkylene glycols, polyamines, and polyimines, for example. Aliphatic groups may be optionally substituted.

[0052] The terms “heterocyclic” and “heterocycloalkyl” can be used interchangeably and refer to a non-aromatic ring or a polycyclic ring system, such as a bi- or tri-cyclic fused, bridged or spiro system, where (i) each ring system contains at least one heteroatom independently selected from oxygen, sulfur and nitrogen, (ii) each ring system can be saturated or unsaturated (iii) the nitrogen and sulfur heteroatoms may optionally be oxidized, (iv) the nitrogen heteroatom may optionally be quaternized, (v) any of the above rings may be fused to an aromatic ring, and (vi) the remaining ring atoms are carbon atoms which may be optionally oxo- substituted or optionally substituted with exocyclic olefinic double bond. Representative heterocycloalkyl groups include, but are not limited to, 1,3-dioxolane, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, imidazolinyl, imidazolidinyl, piperidinyl, piperazinyl, oxazolidinyl, isoxazolidinyl, morpholinyl, thiazolidinyl, isothiazolidinyl, quinoxalinyl, pyridazinonyl, 2-azabicyclo[2.2.1]-heptyl, 8-azabicyclo[3.2.1]octyl, 5- azaspiro[2.5]octyl, 2-oxa-7-azaspiro[4.4]nonanyl, 7-oxooxepan-4-yl, and tetrahydrofuryl. Such heterocyclic groups may be further substituted. Heteroaryl or Heterocyclic groups can be C-attached or N-attached where possible.

[0053] It is understood that any alkyl, alkenyl, alkynyl, alicyclic, cycloalkyl, cycloalkenyl, aryl, heteroaryl, heterocyclic, aliphatic moiety or the like described herein can also be a divalent or multivalent group when used as a linkage to connect two or more groups or substituents, which can be at the same or different atom(s). One of skill in the art can readily determine the valence of any such group from the context in which it occurs.

[0054] The term “substituted” refers to substitution by independent replacement of one, two, or three or more of the hydrogen atoms with substituents including, but not limited to, -F, -Cl, -Br, -I, -OH, Ci-Ci2-alkyl; C2-Ci2-alkenyl, C2-Ci2-alkynyl, -Cs-Cn-cycloalkyl, protected hydroxy, -NO2, -N3, -CN, -NH2, protected amino, oxo, thioxo, -NH-Ci-Ci2-alkyl, -NH-C2-C8- alkenyl, -NH-C2-C8-alkynyl, -NH-C3-Ci2-cycloalkyl, -NH-aryl, -NH-heteroaryl, -NH- heterocycloalkyl, -dialkylamino, -diarylamino, -diheteroarylamino, -O-Ci-Ci2-alkyl, -O-C2- Cs-alkenyl, -O-C2-C8-alkynyl, -O-C3-Ci2-cycloalkyl, -O-aryl, -O-heteroaryl, -O- heterocycloalkyl, -C(O)-Ci-Ci2-alkyl, -C(O)-C2-C8-alkenyl, -C(O)-C2-C8-alkynyl, -C(O)-C3- Ci2-cycloalkyl, -C(O)-aryl, -C(O)-heteroaryl, -C(O)-heterocycloalkyl, -CONH2, -CONH-Ci- Ci2-alkyl, -CONH-C2-C8-alkenyl, -CONH-C2-C8-alkynyl, -CONH-Cs-Cn-cycloalkyl, - CONH-aryl, -CONH-heteroaryl, -CONH-heterocycloalkyl, -OCO2-Ci-Ci2-alkyl, -OCO2-C2- Cs-alkenyl, -OCO2-C2-C8-alkynyl, -OCCh-Cs-Cn-cycloalkyl, -OCCh-aryl, -OCCh-heteroaryl, -OCCh-heterocycloalkyl, -CO2-C1-C12 alkyl, -CO2-C2-C8 alkenyl, -CO2-C2-C8 alkynyl, CO2- Cs-Cn-cycloalkyl, -CO2- aryl, CCh-heteroaryl, CCh-heterocyloalkyl, -OCONH2, -OCONH- Ci-Ci2-alkyl, -OCONH-C2-C8-alkenyl, -OCONH-C2-C8-alkynyl, -OCONH-C3-C12- cycloalkyl, -OCONH-aryl, -OCONH-heteroaryl, -OCONH- heterocyclo-alkyl, -NHC(O)H, - NHC(O)-Ci-Ci2-alkyl, -NHC(O)-C2-C8-alkenyl, -NHC(O)-C2-C8-alkynyl, -NHC(O)-C3-CI2- cycloalkyl, -NHC(O)-aryl, -NHC(O)-heteroaryl, -NHC(O)-heterocyclo-alkyl, -NHCO2-C1- Ci2-alkyl, -NHCO2-C2-C8-alkenyl, -NHCO2- C2-C8-alkynyl, -NHCCh-Cs-Cn-cycloalkyl, - NHCCh-aryl, -NHCCh-heteroaryl, -NHCO2- heterocycloalkyl, -NHC(O)NH2, -NHC(O)NH- Ci-Ci2-alkyl, NHC(O)NH-C2-C8-alkenyl, -NHC(O)NH-C2-C8-alkynyl, -NHC(O)NH-C3-CI2- cycloalkyl, -NHC(O)NH-aryl, -NHC(O)NH-heteroaryl, -NHC(O)NH-heterocycloalkyl, NHC(S)NH2, -NHC(S)NH-Ci-Ci2-alkyl, -NHC(S)NH-C2-C8-alkenyl, -NHC(S)NH-C2-C8- alkynyl, -NHC(S)NH-C3-Ci2-cycloalkyl, -NHC(S)NH-aryl, -NHC(S)NH-heteroaryl, - NHC(S)NH-heterocycloalkyl, -NHC(NH)NH2, -NHC(NH)NH-Ci-Ci2-alkyl, -NHC(NH)NH- C2-C8-alkenyl, -NHC(NH)NH-C2-C8-alkynyl, -NHC(NH)NH-C3-Ci2-cycloalkyl, - NHC(NH)NH-aryl, -NHC(NH)NH-heteroaryl, -NHC(NH)NH-heterocycloalkyl, -NHC(NH)- Ci-Ci2-alkyl, -NHC(NH)-C2-C8-alkenyl, -NHC(NH)-C2-C8-alkynyl, -NHC(NH)-C3-CI2- cycloalkyl, -NHC(NH)-aryl, -NHC(NH)-heteroaryl, -NHC(NH)-heterocycloalkyl, - C(NH)NH-Ci-Ci2-alkyl, -C(NH)NH-C2-C8-alkenyl, -C(NH)NH-C2-C8-alkynyl, -C(NH)NH- Cs-Cn-cycloalkyl, -C(NH)NH-aryl, -C(NH)NH-heteroaryl, -C(NH)NH-heterocycloalkyl, - S(O)-Ci-Ci2-alkyl, -S(O)-C2-C8-alkenyl, - S(O)-C2-C8-alkynyl, -S(O)-C3-Ci2-cycloalkyl, - S(O)-aryl, -S(O)-heteroaryl, -S(O)-heterocycloalkyl, -SO2NH2, -SO2NH-Ci-Ci2-alkyl, - SO2NH-C2-C8-alkenyl, -SO2NH- C2-C8-alkynyl, -SO2NH-C3-Ci2-cycloalkyl, -SChNH-aryl, - SO2NH-heteroaryl, -SO2NH- heterocycloalkyl, -NHSCh-Ci-Cn-alkyl, -NHSO2-C2-C8- alkenyl, - NHSO2-C2-C8-alkynyl, -NHSCh-Cs-Cn-cycloalkyl, -NHSCh-aryl, -NHSO2- heteroaryl, -NHSCh-heterocycloalkyl, -CH2NH2, -CH2SO2CH3, -aryl, -arylalkyl, -heteroaryl, -heteroaryl alkyl, -heterocycloalkyl, -Cs-Cn-cycloalkyl, polyalkoxyalkyl, polyalkoxy, - methoxymethoxy, -methoxyethoxy, -SH, -S-Ci-Ci2-alkyl, -S-C2-C8-alkenyl, -S-C2-C8- alkynyl, -S-Cs-Cn-cycloalkyl, -S-aryl, -S -heteroaryl, -S-heterocycloalkyl, or methylthiomethyl. In certain embodiments, the substituents are independently selected from halo, preferably Cl and F; Ci-C4-alkyl, preferably methyl and ethyl; halo-Ci-C4-alkyl, such as fluoromethyl, difluoromethyl, and trifluoromethyl; C2-C4-alkenyl; halo-C2-C4-alkenyl; C3-C6- cycloalkyl, such as cyclopropyl; Ci-C4-alkoxy, such as methoxy and ethoxy; halo-Ci-C4- alkoxy, such as fluoromethoxy, difluoromethoxy, and trifluoromethoxy; -CN; -OH; NH2; Ci- C4-alkylamino; di(Ci-C4-alkyl)amino; and NO2. It is understood that an aryl, heteroaryl, alkyl, alkenyl, alkynyl, cycloalkyl, or heterocycloalkyl in a substituent can be further substituted. In certain embodiments, a substituent in a substituted moiety is additionally optionally substituted with one or more groups, each group being independently selected from Ci-C4-alkyl; -CF3, -OCH3, -OCF3, -F, -Cl, -Br, -I, -OH, -NO2, -CN, and -NH2. Preferably, a substituted alkyl group is substituted with one or more halogen atoms, more preferably one or more fluorine or chlorine atoms.

[0055] The term “halo” or halogen” alone or as part of another substituent, as used herein, refers to a fluorine, chlorine, bromine, or iodine atom.

[0056] The term “optionally substituted,” as used herein, means that the referenced group may be substituted or unsubstituted. In one embodiment, the referenced group is optionally substituted with zero substituents, i.e., the referenced group is unsubstituted. In another embodiment, the referenced group is optionally substituted with one or more additional group(s) individually and independently selected from groups described herein.

[0057] The term “subject,” as used herein, refers to an animal. Preferably, the animal is a mammal. More preferably, the mammal is a human. A subject also refers to, for example, a dog, cat, horse, cow, pig, guinea pig, fish, bird, and the like.

[0058] The compounds of this invention may be modified by appending appropriate functionalities to enhance selective biological properties. Such modifications are known in the art and may include those which increase biological penetration into a given biological system (e.g., blood, lymphatic system, central nervous system), increase oral availability, increase solubility to allow administration by injection, alter metabolism and alter rate of excretion.

[0059] 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, allergic response and the like, 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. describes pharmaceutically acceptable salts in detail in J. Pharmaceutical Sciences, 66: 2-19 (1977). The salts can be prepared in situ during the final isolation and purification of the compounds of the invention, or separately by reacting the free base function with a suitable organic acid. Examples of pharmaceutically acceptable salts include, but are not limited to, nontoxic acid addition salts are salts of an amino group formed with inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid and perchloric acid or with organic acids such as acetic acid, maleic acid, tartaric acid, citric acid, succinic acid or malonic acid or by using other methods used in the art such as ion exchange. Other pharmaceutically acceptable salts include, but are not limited to, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentane-propionate, digluconate, dodecyl sulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemi sulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3 -phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, -toluenesulfonate, undecanoate, valerate salts, and the like. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Further pharmaceutically acceptable salts include, when appropriate, nontoxic ammonium, quaternary ammonium, and amine cations formed using counterions such as halide, hydroxide, carboxylate, sulfate, phosphate, nitrate, alkyl having from 1 to 6 carbon atoms, sulfonate, and aryl sulfonate.

[0060] The term “pharmaceutically acceptable ester” refers to a compound of Formula (I) in which one, two or three of the carboxyl groups is esterified, such that in vivo cleavage of the one or more ester bonds produces an alcohol which is, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without undue toxicity, irritation, allergic response and the like, and is commensurate with a reasonable benefit / risk ratio. The one or more esters can be esterified with the same group or different groups. Preferably each esterified carboxyl group is independently esterified with a Ci-Cn-alkyl, a halogenated Ci-Cn-alkyl, a C2-Ci2-alkenyl, a halogenated C2-Ci2-alkenyl, a C2-Ci2-alkynyl, or a halogenated C2-Ci2-alkynyl. More preferably each esterified carboxyl group is esterified with a Ci-Ce-alkyl. Pharmaceutical Compositions

[0061] In another embodiment, the present invention provides a pharmaceutical composition comprising a compound of Formula (I) or a pharmaceutically acceptable salt thereof and a pharmaceutically acceptable carrier or excipient. The pharmaceutical composition can be, for example, formulated for administration orally, parenterally, by inhalation spray, topically, rectally, nasally, buccally, vaginally or via an implanted reservoir. The term "parenteral" as used herein includes subcutaneous, intravenous, intramuscular, intra-articular, intra-synovial, intrasternal, intrathecal, intrahepatic, intralesional and intracranial injection or infusion techniques. Preferably, the pharmaceutical composition of the invention is suitable for intravenous administration, such as a sterile injectable composition. Such an injectable pharmaceutical composition can be, for example, an aqueous solution, an aqueous suspension, or an oleaginous suspension. These compositions can be prepared 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.

[0062] In some embodiments, the sterile injectable composition comprises the compound of the invention at a concentration of 0.0001-0.1 mg / mL. In some embodiments, the sterile injectable composition comprises the compound of the invention at a concentration of 0.001- 0.01 mg / mL. In some embodiments, the sterile injectable composition has a radiochemical purity > 90% or > 95%. In some embodiments, the sterile injectable composition comprises a stabilizing agent, such as a radio-stabilizing agent. In some embodiments, the sterile injectable composition has a pH of 3-7. In some embodiments, the sterile injectable composition has a pH of 4-6. In some embodiments, the sterile injectable preparation has a pH of 4.5-5.5.

[0063] Methods of Treating Cancer

[0064] In another embodiment, the present invention provides a method for treating cancer in a subject in need thereof, comprising the step of administering to the subject a therapeutically effective amount of a compound of Formula (I) or a pharmaceutically acceptable salt thereof.

[0065] The cancer to be treated is preferably a cancer which expresses PSMA. Such cancers include prostate cancer, including castration sensitive and castration resistant primary or metastatic prostate cancer. In certain embodiments, the cancer is castration resistant metastatic prostate cancer. Methods of Preparing Compounds of the Invention

[0066] Conventional211At-labeling strategies rely on the assumption that astatine behaves similarly to iodine, thus At" and At+are considered as typical astatine species for the nucleophilic and electrophilic reactions, respectively (Guerard, F. et al. Cancer Biother.Radiopharm. 2013, 28, 1-20). With recent advances of understanding the physicochemical properties of this rare radioelement, development of211At-radiolabeling strategies favors the use of more stable At" species including the aromatic nucleophilic substitution with diaryliodonium salts / aryliodonium ylides (Maingueneau C, et al. Chemistry. 2022 Feb 19;28(ll):e202104169; Guerard, F. et al. Chem. - Eur J. 2016, 22, 12332-12339) or the Cu-catalyzed [211At]astatination of organoboranes (Reily, S.W., et al. Org. Lett. 2018, 20, 7, 1752-1755; Berdal, M. et al. Chem. Sci. 2021, 12, 1458-1468).

[0067] Radiolabeling of PSMA binding compounds with 1-123 and 1-131 has been illustrated in several patents, including US 9,878,980 B2 and US 8,465,725 B2, using a corresponding arylstannane, such as compound III, to produce [123I]MIP-1095, which is also referred to herein as [123I]I-MIP-1095 and123I-MIP-1095 (Scheme 1). The radioiodination occurs at room temperature over a short reaction time. This method can also be applied to radioiodination of other PSMA binding compounds as disclosed in US 9,878,980 B2 and US

[0068] 8,465,725 B2.

[0069] Scheme 1. Synthesis of [123I]MIP-1095 using an organotin precursor

[0070] Schemes 2-7 below illustrate the production of211At-MIP-1095 disclosed herein, which is also referred to herein as Compound 5 and [211At]At-MIP-1095. The general methods presented in these schemes can also be used to produce other compounds of Formula (I), including Compounds 1-4 and 6-12.211At-labeling to produce the compounds of the invention can be performed via [211At]astatination as shown in Scheme 2 (Guerard, F. et al. Cancer Biother.Radiopharm. 2013, 28, 1-20). The halogen exchange approach utilizes compound II as a labeling precursor. The halodemetallation method employs trimethyl tin(III) or the less toxic Ar- SnBus analogue as labeling precursor. It has been adopted for the211At-labeling of molecules targeting PSMA (Vaidyanathan G, et al. Nucl Med Biol. 2021;94-95:67-80; Mease, B.C., et al. J Nucl Med. 2022, 63(2):259-267; Kiess, A.P et al. J Nucl Med. 2016, 57(10): 1569-1575. Once the aromatic substitution is achieved with211At using these methods, a subsequent Boc- deprotection yields [211At]MIP-1095.

[0071] V [211At]MIP-1095

[0072] Scheme 2.211At-labeling to produce211At-MIP-1095

[0073] The critical step in the astatodemetalation of the organotin precursor is to remove the unreacted astatine, oxidizer, and toxic stannylated precursor / side products. Although this can be achieved by using HPLC purification, it would require a lengthy isolation and may lead to a significant radioactivity retention in the chromatographic system, decreasing the labeling yield and efficiency. Alternatively, the ionic liquid organotin precursors can be utilized to simplify the purification steps. The imidazolium hexafluorophosphate derived precursor VI, an ionic liquid supported precursor, results in a faster purification step for [211At]MIP-1095 by using only a silica cartridge instead of HPLC for purification (Org. Biomol. Chem. 2016, 14, 2121-2126) (Scheme 3). Atypical reaction condition for the211At labeling involves heating for a suitable time (e.g., 70 °C, 45 min). Compound VI can be prepared from compound II in a similar manner as compound III.

[0074] Scheme 3. Ionic liquid supported organotin reagent for production of211At-MIP-1095 .

[0075] Besides the solution phase peptide synthesis (SolPPS) of PSMA-ligands, the solid phase peptide synthesis (SPPS) of PSMA-ligands is also widely utilized for the ease of incorporating amino acids onto the glutamate-urea-lysine backbone as well as the convenience of the following purification steps (El Fakiri, M. et al. J Nucl Med. 2024, 65(4), 593-599). In the acidic standard SPPS conditions, the trimethyl silyl group is reported to have a higher chemical stability than the corresponding stannyl moiety, thus more suitable as a211At-labeling precursor. In this case, the trimethyl silyl precursor VII is prepared from compound II or other halogen substituted analogues (i.e., -Cl / -Br) via palladium-mediated chemistry. Subsequent211At-labeling and deprotection leads to211At-MIP-1095 as shown in Scheme 4. One disadvantage of this method is that higher temperature in neat trifluoroacetic acid is required for211At-labeling (e.g., 70 °C, 10 min) since the reactivity of the arylsilyl group is relatively low toward electrophilic aromatic substitution. In cases when direct trimethylsilylation toward molecule II is challenging, a two-step synthesis might be required. For instance, the (4-isocyanatophenyl)trimethylsilane can be prepared before coupling it to the glutamate-urea-lysine backbone.

[0076] Scheme 4.211At-labeling to produce211At-MIP-1095 using a trimethyl silyl precursor According to the Pourbaix diagram, the nucleophilic At" is more stable than the electrophilic astatine species. Therefore, utilizing At" allows improved reproducibility and efficiency for the labeling process. At" also has a higher reactivity than anticipated from the trend observed with lighter halogens, allowing the development of labeling approaches with a broader substrate scope at a significantly lower temperature (Guerard, F. et al. Acc. Chem. Res. 2021, 54, 16, 3264-3275). One such radiolabeling strategy is to use At" in the aromatic nucleophilic substitution with diaryliodonium salts (Guerard, F. et al. Chem. - Eur J. 2016, 22, 12332-12339). Application of this method toward the synthesis of [211At]MIP-1095 is depicted in Scheme 5. The diaryliodonium salt VIII can be prepared from the aryl iodide II under oxidative reaction conditions. The211At-radiolabeling side product can be easily removed by silica cartridge filtration or HPLC purification. Atypical211At-labeling occurs at, for instance, 60 °C for 30 min. The final211At-MIP-1095 can be furnished after Boc- deprotection using TFA. Since the diaryliodonium salt needs to be prepared in oxidative reaction conditions, the success of the synthesis and the chemical stability of the resulting VIII are critical for preparing211At-MIP-1095 .

[0077] Scheme 5.211At-labeling to produce211At-MIP-1095 using diaryliodonium salts

[0078] To enhance the reactivity of aryl iodide II, it can also be oxidized to the corresponding aryliodonium ylide IX. Subsequent nucleophilic211At-labeling has been proved to be significantly more efficient (Maingueneau C, et al. Chemistry. 2022 Feb 19;28(ll):e202104169). The211At-labeling could be achieved at room temperature in 30 min. This strategy is shown in Scheme 6. The caveat of this method when applied to211At-MIP- 1095 is similar to the above diaryliodonium strategy due to the oxidative reaction required for the precursor synthesis.

[0079] Scheme 6.211At-labeling to produce211At-MIP-1095 using aryliodonium ylides

[0080] The copper-catalyzed halodeboronation of organoboranes is another method for [211At]astatination (Reily, S.W., et al. Org. Lett. 2018, 20, 7, 1752-1755; Berdal, M. et al. Chem. Sci. 2021, 12, 1458-1468). In certain embodiments, this method comprises the steps of:

[0081] (a) Reacting a compound of Formula (XII), wherein LG is a leaving group, with a boronic ester or boronic acid, to produce a compound of Formula (XIII), where R3 and R4 are independently hydroxyl or Ci-Ce-alkylO-, or R3 and R4 are taken together with the boron atom to form an optionally methyl-substituted 1,3,2-dioxaborinane or 1,3,2-dioxaborolane ring; (b) reacting the compound of Formula (VII) with a211At salt in the presence of a copper catalyst followed by addition of an acid to produce a compound of Formula (la),

[0082] The leaving group is any suitable moiety, such as iodide, chloride, bromide or triflate. The boronic ester is preferably bis(pinacolato)diboron, bis[(pinacolato)boryl]methane, bis(neopentylglycolato)diboron, bis(catecholato)diboron, trimethylborate, triisopropylborate or tri ethylborate. In certain embodiments, the boronic ester is bis(pinacolato)diboron or trimethylborate. Step (a) is preferably conducted in the presence of a Pd(II) catalyst, such as PdC12(dppf), and in a polar solvent such as oxane optionally in the presence of KO Ac. The211At salt of step (b) is preferably an alkali metal salt of211At-, such as [211At]NaAt or [211At]Kat, preferably [211At]NaAt. The copper catalyst of step (b) is preferably a Cu(II) catalyst such as Cu(OTf)2(pyr)4. The acid of step (b) is preferably a strong acid, such as trifluoroacetic acid.

[0083] This method features a broader substrate scope, milder reaction conditions (e.g., room temperature) compared to the other syntheses and shorter reaction times without the need for toxic organotin reagents. Furthermore, the aryl boronic acid moiety has been incorporated onto a monoclonal antibody (mAb) to facilitate a one-step211At-radiolabeling of mAb. The preconjugated mAb also demonstrated a long-term storability (>12 month).

[0084] Application of a specific embodiment of this method to the synthesis of211At-MIP- 1095 is shown in Scheme 7. Synthesis of the aryl organoborane X can be achieved from compound II or its analogues with other leaving groups (e.g., Cl, Br, OTf) via Miyaura borylation reaction (Zhang, L. J. et al. Am. Chem. Soc., 2019, 141, 9124-9128; Vami, A. J. et al. J. Org. Chem., 2020, 85, 6770-6777; Leermann T., et al., Org. Let., 2011, 13, 4479-4481). The [211At]astatination occurs at room temperature in 30 min using a Cu catalyst.

[0085] Scheme 7.211At-labeling to produce211At-MIP-1095 using copper-catalyzed halodeboronation

[0086] EXAMPLES

[0087] Example 1 Synthesis of2UAt-MIP-1095

[0088] Synthesis 1

[0089] 211At was produced via the209Bi(a, 2n)211At nuclear reaction, which was purified from the bismuth target by a dry distillation in Atley Cl 00 system1'3and eluted with chloroform4'5. The solvated astatine was evaporated to dryness under a stream of nitrogen. The dry residue was taken by a catalytic amount of A-iodosuccinimide (NIS) and 1% acetic acid in methanol before the addition of the tert-butyl -protected aryl stannyl precursor MIP-1182. The astatination occurred at room temperature for 10 min before being quenched by sodium ascorbate and loaded onto a Sep-Pak light C18 column. The column was washed with water to remove the Sn-containing species, such as the precursor and deastatination byproduct MIP- 1492 if any, and the reagents used.211At-MIP-1095-Ester was eluted with acetonitrile. Subsequent deprotection of211At-MIP-1095-Ester was conducted with trifluoroacetic acid (TFA) at room temperature for 10 min. The reaction mixture was neutralized and pH adjusted by adding 1.5 M sodium hydroxide and loaded onto the Oasis HLB cartridge. The cartridge was sequentially washed with sterile water for injection (SWFI), 20% ethanol in PBS, diluent solution, and eluted with 75% ethanol in diluent solution to remove the deastatination side products, such as MIP-1111 if any, TFA and acetonitrile. The resulting211At-MIP-1095 containing solution was then concentrated onto Sep-Pak NH2 light columns and washed with diluent solution and eluted with 0.2 M sodium hydroxide to remove the ethanol. The final product solution was further adjusted by adding the intermediate drug product (IDP) solution to allow animal injections. The composition of diluent solution and IDP solution is shown in the table below.

[0090] Composition of diluent solution and IDP solution.

[0091] Component Diluent Solution IDP Solution

[0092] Sodium Ascorbate 8.45 g 4.67 g

[0093] Ascorbic Acid 1.5 g 1.2 g

[0094] Sodium Hydroxide (2N) 13.47 g 7.2 g

[0095] GentisicAcid 3.56 g 2.06 g

[0096] SWFI 160.2 g 86.9 g

[0097] Synthesis 2

[0098] In a 3 mL flat bottom vial, dried [211At]At was added A-iodosuccinimide (NIS, 40 pL, 10 pg / mL) in methanol containing 1% acetic acid. The reaction was allowed to incubate for 30 sec, 700 rpm at 25°C. MIP-1182 in acetonitrile (0.5 mL, 0.1 mg / mL) was added to the reaction vial and allowed to agitate for 10 min, 700 rpm at 25°C. The reaction was then quenched with sodium ascorbate (1 mL, 1 mg / mL), agitated for 30 sec at 700 rpm. The mixture was loaded onto a Sep-Pak light C18 cartridge (Waters), which was preconditioned with 1 mL ethanol and 5 mL MilliQ water. The cartridge was then washed with 5 mL SWFI water and dried with 20 mL air.211At-MIP-l 182-Ester was eluted with 1 mL acetonitrile into a centrifuge tube and deprotected with 3 mL trifluoroacetic acid (TFA) over 10 min, 700 rpm at 25°C. The reaction mixture was diluted and pH adjusted by adding 22.5 mL of 1.5 M sodium hydroxide. The resulting solution containing211At-MIP-1095 was loaded onto an OASIS HLB Plus cartridge which was preconditioned with 2 mL ethanol, 5 mL water and 5 mL 1% sodium ascorbate solution. The cartridge was sequentially washed with 5 mL SWFI water, 2 mL 20% ethanol in PBS (10 mM, pH 7.4), 4 mL diluent solution and eluted with 3.5 mL 75% EtOH in diluent solution. The 75% EtOH in diluent solution containing211At-MIP- 1095 was then loaded onto the two Sep-Pak NH2-light cartridges connected in series, which were preconditioned with 1 mL EtOH and 5 mL 1% sodium ascorbate solution individually. The cartridges were washed with 10 mL of diluent solution and211At-MIP-1095 was eluted with 5 mL of 0.2 M sodium hydroxide solution. The eluted product was diluted to the desired activity concentration with IDP solution. The overall synthesis time was about 2 hours. This method was used to prepare a pilot batch and batches for use in the mouse and rat studies described below. Information on these three batches is provided in the table below. Batch Starting211At-MIP- Radiochemica Specific Specific Radioactivity Injected Radiochemical activity 1095 RCY1I purity EOS2activity activity concentration Dose M Bq stability (%,

[0099] (MBq) (n.d.c., %) (%) (GBq / pmol) (MBq / pg) (MBq / mL) (ng) 25°C, 4h, 6h)

[0100] Pilot 128.7 27.5 96.7 24.0 46.8 12.0 - >96

[0101] Mouse 336.2 49.2 99.6 161.5 285.4 3.0 0.3 (1.1) study

[0102] Rat 1677 11.6 91.7 63.0 111.7 8.7 2.66 (24) study

[0103] ’RCY, radiochemical yield;2EOS, end of synthesis

[0104] The radio-HPLC method used for quality control of211At-MIP-1095 and123I-MIP-1095 is summarized in the table below.

[0105] Example 2 Synthesis of123I-MIP-1095

[0106] MIP-1182123l-MIP-1095-Ester123l-MIP-1095

[0107] In a 5 mL glass vial containing [123I]NaI was added sterile water for injection (SWFI) (50 pL), 50% H2SO4 in SWFI (50 pL), oxidant (100 pL) [which was prepared fresh via the incubation of CH3COOH (200 pL) and 30% H2O2 (335 pL) followed by dilution to a final volume of 5 mL with SWFI], acetonitrile (0.5 mL), and the trimethyl stannane precursor MIP- 1182 (100 pL of a 1 mg / mL solution in acetonitrile). The mixture was vortexed for 1 min and allowed to incubate for an additional 10 min at room temperature. The reaction was quenched with 200 pL 0.1 M sodium thiosulfate. The product was then diluted in 18 mL SWFI and loaded onto a Cl 8 Sep Pak Plus column. The column was washed with 60 mL SWFI to remove unreacted radioiodine and inorganic and organic salts. The123I-MIP-1095-Ester was eluted from the column with 4 mL ethanol. The resulting solution, containing the123I-MIP- 1095-Ester, was evaporated to dryness under a stream of nitrogen and the residue was dissolved in methylene chloride (0.5 mL) and TFA (2 mL) and allowed to incubate for 45 min at room temperature. After deprotection, the solution was evaporated to dryness under a stream of nitrogen. The product was dissolved in 50% acetonitrile / water and purified on a C18 Sep Pak Plus column using a gradient of SWFI containing 0.1% acetic acid and ethanol. The product was finally eluted with 4 mL ethanol. The solution was evaporated to dryness under a stream of nitrogen and the residue was dissolved in a formulation matrix of 2% gentisate and 5% ascorbate / ascorbic acid, pH=5 to meet the desired activity concentration for in vivo application.

[0108] Quality control of123I-MIP-1095 batches was performed as described in Example 1.

[0109] Example 3 Determination of Biodistribution of2UAt-MIP-1095 in a Mouse Prostate Cancer Model

[0110] The biodistribution of211At-MIP-1095 was evaluated in NMRJ nude mice bearing LNCaP subcutaneous tumors by ex vivo gamma well counting at 30 min, 2 hr, 4 hr and 24 hr post injection.

[0111] The study design is summarized below. Results:

[0112] As shown in Figure 1, tumor uptake was stable between 30 mins and 4 hours post [211At]At-MIP-1095 injection. The uptake was 34.5 ± 8.4 %ID / g, 28.0 ± 5.0 %ID / g and 32.5 ± 5.4 %ID / g for 30 mins, 2 hr and 4 hr, respectively. At 24 hours post injection, the tumor uptake dropped to 5.0 ± 1.6 %ID / g.

[0113] Non-tumor uptake was highest in the thyroid and kidney, with peak uptake at 4 hour post injection, where the uptake was 33.8 ± 11.7 %ID / g and 47.3 ± 12.3 %ID / g for thyroid and kidney, respectively. Uptake was significantly lower in blood, brain, femur, heart, liver, lungs, muscle, spleen, and stomach.

[0114] Figure 2 is a graph comparing the tumor to kidney uptake ratio for211At-MIP-1095 determined in this study and in previously reported studies of177Lu-PSMA-617,177Lu-PSMA I&T, and123I-MIP-1095.

[0115] Example 3 Dosimetry of211At-MIP-1095 and [123I]I-MIP-1095

[0116] A study was conducted to compare the dosimetry of211At-MIP-1095 and [123I]I- MIP-1095 following a single IV administration to naive male Wistar rats. A total of 32 rats were evenly stratified into Groups A and B. The distribution of each compound was evaluated at 30 min, 2 hr, 4 hr and 24 hr post dosing, with 4 rats per compound per time point.

[0117] Synthesis of MIP-1095

[0118] [211At]At-MIP-1095 was produced as described in Example 1 except that 17.5 mL formulation buffer was added to the eluate to produce the final formulation. The radioactivity at end of synthesis was 194.5 MBq, and the final formulation had a [211At]At-MIP-1095 concentration of 8.7 MBq / mL. The radiochemical purity of the final formulation, as determined using the HPLC method of Example 1, was 91.7%. [123I]I-MIP- 1095 was synthesized as described in Example 2._The radioactivity of the formulation at end of synthesis was 85.9 MBq and the radiochemical purity was 99.1%, as determined using the method of Example 1.

[0119] The data were treated as follows:

[0120] 1. The measured activity in a sample was back-calculated to the time of euthanasia (radioactivity decay corrected).

[0121] 2. The corrected activity was divided by sample weight and injected activity to yield Bq / g at time of euthanasia per 1 MBq administered dose. Note that this parameter is equal to the %ID / g divided by 100 times a decay correction factor for the times since injection.

[0122] 3. These values were extrapolated to human expected uptake per gram by multiplying by the animal body weight and dividing by the human MIRD89 phantom weight; 60 kg for females and 73 kg for males.

[0123] 4. Conservatively, instantaneous uptake was assumed for all organs. except Blood, i.e. A(t0) = A(tl)

[0124] 5. The area under the activity -time curve (AUC) was calculated to determine the total number of disintegrations per gram tissue. Linear interpolation was used for AUC calculation. Activity still present at the last timepoint was assumed to fully decay in the tissue (the total number of remaining disintegrations from the measured activity at the last timepoint (n=A / lambda) is added to the AUC).

[0125] 6. The calculated total number of decays per gram tissue was converted to residence time per gram (MBq h / MBq / g).

[0126] 7. Values were multiplied with the organ mass in the respective male or female MIRD89 phantom, to get the human residence times.

[0127] 8. The values for human residence times were used as input in OLINDA / EXM.

[0128] 9. For each timepoint (0.5H, 2H, 4H and 24H), for each organ, the average of extrapolated human uptake per gram and the average of “times since injection” were calculated to give one datapoint for that specific timepoint on the time-integrated-activity- curve.

[0129] 10. The total excretion of the body was estimated using a biexponential fit of the ex vivo biodistribution data, total %ID in the animals plotted as a function of time.

[0130] 11. It is assumed that the excretion of the injection activity is only via the urine. 12. The dose to the bladder was calculated based on a dynamic bladder model. The dynamic bladder model in OLINDA / EXM was employed, using a 3 h bladder voiding interval.

[0131] Results

[0132] The results of this study are shown in Figures 3-6 and are summarized below.

[0133] 1. The highest uptake for both compounds was observed in the thyroid. For [211At] At- MIP-1095, the peak uptake was observed 4 hours post injection, with an uptake of 42.5 ± 2.8 %ID / g. For [123I]I-MIP-1095, the peak uptake was observed 24 hours post injection, with an uptake of 135.9 ± 20.2 %ID / g.

[0134] 2. Uptake in the kidneys peaked 2 hours post injection for both [211At]At-MIP-1095 and [123I]I-MIP-1095, with an uptake of 6.1 ± 0.4 %ID / g and 9.2 ± 0.6 %ID / g, respectively. This decreased to 0.3 ± 0.0 %ID / g and 0.1 ± 0.0 %ID / g 24 hours post injection for [211At]At-MIP-1095 and [123I]I-MIP-1095, respectively.

[0135] 3. The uptake in the stomach was highest in the group dosed with [211At]At-MIP-1095, where a peak uptake of 3.2 ± 0.6 %ID / g was observed 4 hours post injection, compared to 1.0 ± 0.1 %ID / g for [123I]I-MIP-1095.

[0136] 4. Spleen uptake was highest in the group dosed with [211At]At-MIP-1095 and was stable in this group from 0.5 hr to 4 hr post injection. At 4 hr post injection, the uptake in the spleen was 1.6 ± 0.1 %ID / g and 0.1 ± 0.0 %ID / g for [211At]At-MIP-1095 and [123I]I- MIP-1095, respectively.

[0137] 5. Liver uptake was highest in the group dosed with [123I]I-MIP-1095. At 4H post injection, the liver uptake was 0.2 ± 0.0 %ID / g and 2.5 ± 0.1 %ID / g for [211At]At-MIP- 1095 and [123I]I-MIP-1095, respectively.

[0138] 6. All other organs showed an uptake below 1.5 %ID / g.

[0139] While this invention has been particularly shown and described with references to preferred embodiments thereof, it will be understood by those skilled in the art that various changes in form and details may be made therein without departing from the scope of the invention encompassed by the appended claims.

Claims

ClaimsWhat is claimed is:or a pharmaceutically acceptable salt or ester thereof, wherein L is a bivalent linker;A is optionally substituted aryl or optionally substituted heteroaryl and At is astatine-211.

2. The compound of claim 1 represented by Formula (la),or a pharmaceutically acceptable salt or ester thereof.

3. The compound of claim 1 or claim 2, wherein A is an optionally substituted 6 to 12- membered aryl group or a 5- to 10-membered heteroaryl group.

4. The compound of claim 3, wherein A is phenyl, naphthyl or biphenyl, each of which is substituted with 0 to 4 substituents independently selected from halogen, hydroxyl and amino.

5. The compound of claim 3, wherein A is pyridine, pyrimidine, pyrazine, pyrrole, imidazole, triazole, furan, oxazole, isoxazole, thiazole, quinoline, quinoxaline, indole, indazole, thiophene, benzimidazole, benzothiophene, or benzofuran, each of which is substituted with 0 to 3 substituents independently selected from halogen, hydroxyl and amino.

6. The compound of any one of claims 1 to 5, wherein L is a bivalent aliphatic group having a length of 1 to 12 atoms.

7. The compound of claim 6, wherein L is represented by -Xi-(CRiR2)n-Bi-, wherein Xi is absent, -C(O)-, -C(O)O-, or -C(O)NH-; each Ri and R2 is independently hydrogen, hydroxyl, amino or halogen; Bi is absent, -NHC(O)-, -OC(O)-, -NHC(O)NH-, -NH-C(O)-O-, -SO2-, or -NHSO2-; and n is 0 to 6; provided that n is at least 1 or at least one of Xi and Bi is not absent.

8. The compound of claim 7, wherein each Ri and R2 is hydrogen.

9. The compound of claim 7, wherein L is -CH2-, -C(O)NH-, -C(O)- or -SO2-.

10. The compound of claim 7 or 8, wherein L has a length of 1 to 4 atoms.

11. The compound of claim 1, which is represented by one of Formulas (II) to (VI),or a pharmaceutically acceptable salt or ester thereof.

12. The compound of claim 11, wherein (i) m is 1 and n is 0; or (ii) m is 0 and n is 1.

13. The compound of claim 1, which is represented by one of Formulas (VII) to (XI),or a pharmaceutically acceptable salt or ester thereof.

14. The compound of claim 13 selected from the compounds set forth below,or a pharmaceutically acceptable salt or ester thereof.

15. The compound of claim 14 selected from the compounds set forth below,or a pharmaceutically acceptable salt or ester thereof.

16. A pharmaceutical composition comprising the compound of any one of claims 1 to 15, or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier or excipient.

17. A method for treating cancer in a subject in need thereof, comprising administering to the subject a therapeutically effective amount of the compound of any one of claims 1-15 or a pharmaceutically acceptable salt or ester thereof.

18. The method of claim 17, wherein the cancer is prostate cancer.

19. The method of claim 18, wherein the prostate cancer is castration sensitive primary or metastatic prostate cancer.

20. The method of claim 18, wherein the prostate cancer is castration resistant primary or metastatic prostate cancer.

Images