Preparation of radiohalogenated compounds for nuclear medicine by reductive elimination from bismuth(v) halides

Abstract

The present invention relates to a process for preparation of a compound of Formula (I): where ring A, ring B, Hal, R1, and R2 are as described herein.

Description

PREPARATION OF RADIOHALOGENATED COMPOUNDS FOR NUCLEAR MEDICINE BY REDUCTIVE ELIMINATION FROM BISMUTH(V) HALIDES

[0001] This application claims the priority benefit of U.S. Provisional Patent Application Serial No.63 / 652,853 , filed May 29, 2024, which is hereby incorporated by reference in its entirety. FIELD

[0002] The present disclosure relates to the preparation of radiohalogenated compounds for nuclear medicine by reductive elimination from bismuth(V) halides. BACKGROUND

[0003] The burgeoning demand for novel radiopharmaceuticals for molecular imaging and precision treatment strategies requires the expansion of the toolbox of targeting molecules and robust radiosynthesis methods for synthesizing these compounds. Small molecules labeled with radioactive isotopes of halogens (e.g.,18F,76Br,77Br,124I,131I,211At) are widely used for diagnostic imaging, molecular radiotherapy, biological research, and drug discovery because of their chemical properties and nuclear decay characteristics (Adam, M.J., “Radiohalogenated Carbohydrates for Use in PET and SPECT,” J. Label. Compd. Radiopharm.45:167-180 (2002); Glaser et al., “Applications of Positron-Emitting Halogens in PET Oncology (Review),” Int. J. Oncol.22:253-267 (2003); Adam and Wilbur, “Radiohalogens for Imaging and Therapy,” Chem. Soc. Rev.34:153-163 (2005); Jadvar, H., “Molecular Imaging of Prostate Cancer with 18F- Fluorodeoxyglucose PET,” Nat. Rev. Urol.6(6):317–323 (2009); Zhu et al., “PET / SPECT Imaging Agents for Neurodegenerative Diseases,” Chem. Soc. Rev.43(19):6686–6691 (2014); Pimlott and Sutherland, “Molecular Tracers for the PET and SPECT Imaging of Disease,” Chem. Soc. Rev.40(1):149-162 (2011); Chen et al., “18F-FDOPA PET Imaging of Brain Tumors: Comparison Study with 18F-FDG PET and Evaluation of Diagnostic Accuracy,” Journal of Nuclear Medicine 47(6):904–911 (2006); Rowland et al., “Radiobromine for Imaging and Therapy,” In Handbook of Radiopharmaceuticals John Wiley & Sons, Ltd, pp 441–465 (2002); Mumtaz et al., “Radioiodine I-131 For The Therapy Of Graves’ Disease,” Malays. J. Med .Sci. 16(1):25–33 (2009); Silberstein, E. B., “Radioiodine: The Classic Theranostic Agent,” Seminars in Nuclear Medicine 42(3):164–170 (2012); Fakiri et al., “New Series of PSMA-Targeting Inhibitors for Astatine-211 Targeted Radionuclide Therapy of Prostate Cancer,” Journal of Nuclear Medicine 63(2):2878–2878 (2022); Chakravarty et al., “Astatine-211 for PSMA- Targeted α-Radiation Therapy of Micrometastatic Prostate Cancer: A Sustainable Approach 313156387v3Towards Precision Oncology,” Eur. J. Nucl. Med. Mol. Imaging 50(7):1844–1847 (2023)). Late- stage incorporation of the radiohalide into the highly functionalized drug molecules is challenging because the radionuclide is present in substantially sub-stoichiometric amounts (~1000-fold molar deficit), may have undesired cross-reactivity against other functional groups, or may react too slowly under the required reaction conditions to obtain the radiopharmaceutical with sufficient quantities and molar activities for its intended application.

[0004] Conventional approaches to radiohalogenation of aryl rings, such as isotopic exchange (Mangner et al., “Solid-Phase Exchange Radioiodination of Aryl Iodides. Facilitation by Ammonium Sulfate,” J. Org. Chem.47(8):1484−1488 (1982)), nucleophilic aromatic substitution (Giglio et al., “Synthesis and Initial Evaluation of Radioactive 5-I-α-Methyl- Tryptophan: A Trp Based Agent Targeting IDO-1,” Med. Chem. Commun.10:814-816 (2019); Hamacher and Coenen, “No-Carrier-Added Nucleophilic18F-labelling in an Electrochemical Cell Exemplified by the Routine Production of [18F]altanserin,” Appl. Radiat. Isot.64:989−94 (2006)), electrophilic aromatic substitution (Adam et al., “Synthesis of L-6-[123I]Iodo-m-tyrosine a Potential Spect Brain Imaging Agent,” Journal of Labelled Compounds and Radiopharmaceuticals 28:1065–1072 (1990); Moerlein, S. M., “No-Carrier-Added Radiobromination and Radioiodination of Aromatic Rings Using in-situ Generated Peracetic Acid,” J. Chem. Soc., Perkin Trans.1:779-786 (1988); Srivastava et al., “Potential Cerebral Perfusion Agents: Synthesis and Evaluation of a Radioiodinated Vinylalkylbarbituric Acid Analog,” J. Med. Chem.26:742–746 (1983); Kabalka et al., “Synthesis of Radioiodinated Aryl Iodides Via Boronate Precursors,” Nucl. Med. Biol.29:841–843 (2002)), halo-destannylation (Chitneni et al., “Synthesis and Evaluation of Radiolabeled AGI-5198 Analogues as Candidate Radiotracers for Imaging Mutant IDH1 Expression in Tumors,” Bioorg. Med. Chem. Lett. 28:694–699 (2018)), and halo-desilylation (Nakagawa et al., “Synthesis of [123I]- iodometomidate From a Polymer-supported Precursor With a Large Excluded Volume,” RSC Adv.6:12215–12218 (2016)), are limited by harsh reaction conditions, low yields, or contamination with toxic organostannyl compounds (Petrov et al., “Synthesis of Radioiodinated Compounds. Classical Approaches and Achievements of Recent Years,” Int. J. Mol. Sci. 23(22):13789 (2022)). Therefore, newer methods, such as click-type reactions (Bauer et al., “Click Chemistry and Radiochemistry: An Update,” Bioconjugate Chem.34(11):1925–1950 (2023)), Sandmeyer radiohalogenation of diazonium salts (Meyer et al., “Reaction of Aromatic Diazonium Salts With Carrier-free Radioiodine and Astatine. Evidence for Complex Formation,” J. Am. Chem. Soc.101(11):3121–3123 (1979)), diaryliodonium salt-mediated radiohalogenations (Pike, V. W., “Hypervalent Aryliodine Compounds as Precursors for Radiofluorination,” J. 313156387v3Labelled Comp. Radiopharm.61(3):196–227 (2018); Neumann et al., “Efficient Automated Syntheses of High Specific Activity 6-[18F]fluorodopamine Using a Diaryliodonium Salt Precursor,” J. Labelled Comp. Radiopharm.59(1):30-4 (2016); Guérard et al., “Bifunctional Aryliodonium Salts for Highly Efficient Radioiodination and Astatination of Antibodies,” Bioorg. Med. Chem.25(21):5975–5980 (2017)), and transition metal-mediated radiohalogenation of aryl boron compounds (Dubost et al., “Palladium-Mediated Site-Selective C-H Radioiodination,” Org. Lett.20(19):6302–6305 (2018); Cant et al., “Nickel-Mediated Radioiodination of Aryl and Heteroaryl Bromides: Rapid Synthesis of Tracers for SPECT Imaging,” Angew. Chem. Int. Ed. Engl.52(30):7829-32 (2013); Wilson et al., “Radiosynthesis of SPECT Tracers via a Copper Mediated 123I Iodination of (Hetero)Aryl Boron Reagents,” Chem. Commun.52(90):13277–13280 (2016); Mixdorf et al., “Copper-Mediated Radiobromination of (Hetero)Aryl Boronic Pinacol Esters,” J. Org. Chem.88(4):2089–2094 (2023); Makaravage et al., “Copper-Mediated Radiofluorination of Arylstannanes with [18F]KF,” Organic Letters 18(20):5440-5443 (2016)), have been developed to accomplish these reactions under milder conditions using non-toxic reagents. Notwithstanding these improvements, these methods often require challenging precursor syntheses, generate untraceable inorganic and organometallic salts as reaction byproducts and reagents, and suffer from poor yields and reproducibility (Dubost et al., “Recent Advances in Synthetic Methods for Radioiodination,” J. Org. Chem.85(13):8300– 8310 (2020); Seevers and Counsell, “Radioiodination Techniques for Small Organic Molecules,” Chem. Rev.82(6):575–590 (1982)). Copper-mediated radiohalogenation of aryl rings has become one of the most widely used methods in radiochemistry. However, it is often substrate- dependent and relies heavily on the presence of suitable ligands (McErlain et al., “Ligand- Enabled Copper-Mediated Radioiodination of Arenes,” Org. Lett.26(7):1528-1532 (2024); Reilly et al., “Cu-Catalyzed [211At]Astatination and [125I]Iodination of Boronic Esters at Room Temperature,” Org. Lett.20(7):1752-1755 (2018)). Additionally, the method lacks reproducibility on a large scale (Zhou et al., “A Practical Protocol for Large-scale Copper- mediated Radioiodination of Organoboronic Precursors: Radiosynthesis of [123 I]KX-1 for Auger Radiotherapy,” J. Labelled Comp. Radiopharm.66(13):435-439 (2023)), making it unsuitable for routine radiosynthesis without extensive optimization. As a result, laborious screening is required to optimize the reaction conditions to yield enough radiopharmaceuticals required for preclinical and clinical studies (Kondo et al., “Copper-Mediated Radioiodination Reaction Through Aryl Boronic Acid or Ester Precursor and its Application to Direct Radiolabeling of a Cyclic Peptide,” J. Radioanal. Nucl. Chem.64(8):336−345 (2021); Dong et al., “Synthesis Principle and Practice with Radioactive Iodines and Astatine: Advances Made So 313156387v3Far,” J. Org. Chem.89(17):11837-11863 (2024); Sharninghausen et al., “NHC-Copper Mediated Ligand-Directed Radiofluorination of Aryl Halides,” J. Am. Chem. Soc.142(16):7362–7367 (2020)).

[0005] The present disclosure is directed to overcoming these and other deficiencies in the art. SUMMARY

[0006] One aspect of the present disclosure relates to a process for preparation of a compound of Formula (I):whereis a point of attachment of ring A to ring B or, if ring B is absent, to R1or R2group; is a single or a double bond; ring B is optional and, if present, is aryl or heteroaryl; Hal is halogen or radioisotope of halogen; X is independently selected at each occurrence from C, N, O, or S; R1is optional and, if present, is selected from the group consisting of H, halogen, CN, C1-6alkyl, -OC1-6alkyl, CF3, -C(O)H, -C(O)C1-6alkyl, -C(O)OC1-6alkyl, 313156387v3R2is optional and, if present, is selected from the group consisting of H, halogen, CN, C1-6alkyl, -OC1-6alkyl, CF3, -C(O)H, -C(O)C1-6alkyl, -C(O)OC1-6alkyl,R3is optional and, if present, is selected from the group consisting of H, halogen, CN, C1-6alkyl, -OC1-6alkyl, CF3, -C(O)H, -C(O)C1-6alkyl, -C(O)OC1-6alkyl, 313156387v3R4is optional and, if present, is selected from the group consisting of H, halogen, CN, C1-6alkyl, -OC1-6alkyl, CF3, -C(O)H, -C(O)C1-6alkyl, -C(O)OC1-6alkyl,R5is optional and, if present, is selected from the group consisting of H, halogen, CN, C1-6alkyl, -OC1-6alkyl, CF3, -C(O)H, -C(O)C1-6alkyl, -C(O)OC1-6alkyl, 313156387v3n is independently selected at each occurrence from 1, 2, 3, 4, or 5. This process comprises: providing a compound of Formula (IIa) or (IIb):where R is halogen; R´ is optional and, if present, is independently H, OCH3, or CF3; and X1is OTf or BF4; providing a compound of Formula (III): R6-Hal (III), where R6is Na, K, Cs, NH4, or (C1-6alkyl)4N; and reacting the compound of Formula (IIa) or (IIb) with the compound of Formula (III) under conditions effective to produce the compound of Formula (I).

[0007] Another aspect of the present disclosure relates to a process for preparation of a compound of Formula (I): 313156387v3whereis a point of attachment of ring A to ring B; is a single or a double bond; ring B is optional and, if present, is selected from the group consisting of C5aryl, C6aryl, C4heteroaryl, C5heteroaryl, and C6heteroaryl; Hal is halogen or radioisotope of halogen; X is independently selected at each occurrence from C or N; R1is optional and, if present, is selected from the group consisting of H, halogen, CN, C1-6alkyl, -OC1-6alkyl, CF3, -C(O)H, -C(O)C1-6alkyl, -C(O)OC1-6alkyl,R2is optional and, if present, is selected from the group consisting of H, halogen, CN, C1-6alkyl, -OC1-6alkyl, CF3, -C(O)H, -C(O)C1-6alkyl, -C(O)OC1-6alkyl,313156387v3R3is optional and, if present, is selected from the group consisting of H, halogen, CN, C1-6alkyl, -OC1-6alkyl, CF3, -C(O)H, -C(O)C1-6alkyl, -C(O)OC1-6alkyl,R4is optional and, if present, is selected from the group consisting of H, halogen, CN, C1-6alkyl, -OC1-6alkyl, CF3, -C(O)H, -C(O)C1-6alkyl, -C(O)OC1-6alkyl,R5is optional and, if present, is selected from the group consisting of H, halogen, CN, C1-6alkyl, -OC1-6alkyl, CF3, -C(O)H, -C(O)C1-6alkyl, -C(O)OC1-6alkyl,This process comprises: providing a compound of Formula (IIa) or (IIb):where R is halogen; and X1is OTf or BF4; 313156387v3providing a compound of Formula (III): R6-Hal (III), where R6is Na, K, or (CH3CH2CH2CH2)4N; and reacting the compound of Formula (IIa) or (IIb) with the compound of Formula (III) under conditions effective to produce the compound of Formula (I).

[0008] (Radio)haloaromatic moieties are prevalent in drug molecules and radiopharmaceuticals, but, despite decades-long interest in these compounds, there are few methods available for the rapid, efficient, and reproducible (radio)halogenation of electron- deficient or sterically hindered aromatic rings when the halide is in significant stoichiometric deficiency. Disclosed herein is a convenient method of regioselective bismuth-mediated radiohalogenation of arylboronates that tolerates a wide range of functional groups and is effective with electron-rich, deficient, neutral, and sterically crowded aryl and heteroaryl rings (FIG.1C).77Br-,124I-, and211At-labeled derivatives of radiopharmaceuticals were prepared, including the prostate-specific membrane antigen (PSMA) inhibitor MIP-1095, with excellent radiochemical conversion (80-99%), radiochemical yield (42-78%), and radiochemical purity (>99%) at molar activities exceeding 250 GBq / µmol (FIG.2). These experiments highlight the suitability of this method for the synthesis of (radio)haloaromatic drugs and radiopharmaceuticals for clinical applications. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] FIGs.1A-1D show Bi(V)-mediated aryl halogenation reactions. FIG.1A shows regioselective transfer of ortho-methyl substituted aryl rings to iodide by an open aryl ligand system (previous work) (Debnath et al., “Regioselective Reductive Elimination from Bismuth(V) Compounds for Aryl Transfer to Nucleophile,” Advanced Synthesis & Catalysis 366(5):1128- 1136 (2024), which is hereby incorporated by reference in its entirety). FIG.1B shows bismuth- mediated fluorination of arenes reported by Cornella and coworkers (Zhou et al., “A Practical Protocol for Large-scale Copper-mediated Radioiodination of Organoboronic Precursors: Radiosynthesis of [123 I]KX-1 for Auger Radiotherapy,” J. Labelled Comp. Radiopharm. 66(13):435-439 (2023); Kondo et al., “Copper-mediated Radioiodination Reaction Through Aryl Boronic Acid or Ester Precursor and its Application to Direct Radiolabeling of a Cyclic Peptide,” J. Radioanal. Nucl. Chem.64(8):336−345 (2021), which are hereby incorporated by reference in their entirety). FIG.1C shows regioselective aryl transfer to radionuclides (77Br,124 / 125I, and211At) using a bridged aryl ligand system (present disclosure). FIG.1D shows an initial reaction 313156387v3resulting in the formation of [125I]iodobenzene in 74-84% radiochemical conversion as assessed by radio-HPLC (n=2).

[0010] FIG.2 shows an overview of a convenient method of regioselective bismuth- mediated radiohalogenation of arylboronates, which can be used to prepare77Br-,124I-, and211At-labeled derivatives of radiopharmaceuticals, including the prostate-specific membrane antigen (PSMA) inhibitor MIP-1095, with excellent radiochemical conversion (80-99%), radiochemical yield (42-78%), and radiochemical purity (>99%) at molar activities exceeding 250 GBq / µmol.

[0011] FIG.3 shows identification of reagents to promote synthesis of bismacycle(V) at room temperature and optimization of the transmetalation step. Reactions with compounds 5a-5e were carried out at room temperature using one equivalent of bismacycle 4 in acetonitrile. The addition of either 1 equivalent of KF or 1 equivalent of K2CO3was investigated.

[0012] FIG.4 shows a representative chromatogram of compound (6a).

[0013] FIG.5 shows a representative chromatogram of compound (17b).

[0014] FIG.6 shows a representative chromatogram of compound (18b).

[0015] FIG.7 shows a representative chromatogram of the Boc and urea protected [125I]MIBG intermediate.

[0016] FIG.8 shows a representative (radio)chromatogram of Boc protected [125I]MIP- 1095.

[0017] FIG.9 shows a representative chromatogram of crude [124I]MIP-1095.

[0018] FIG.10 shows a representative chromatogram of [124I]MIP-1095.

[0019] FIG.11 shows a flow diagram showing the key radiosynthetic steps following addition of Na[124I]I to the reaction mixture.

[0020] FIG.12 shows a representative chromatogram of compound (22).

[0021] FIG.13 shows a representative chromatogram of compound (23).

[0022] FIG.14 shows a representative chromatogram of compound (8a).

[0023] FIG.15 shows a representative chromatogram of compound (8b).

[0024] FIG.16 shows a representative chromatogram of compound (8c).

[0025] FIG.17 shows a representative chromatogram of compound (8d).

[0026] FIG.18 shows a representative chromatogram of compound (8e).

[0027] FIG.19 shows a representative chromatogram of compound (8f).

[0028] FIG.20 shows a representative chromatogram of compound (8g).

[0029] FIG.21 shows a representative chromatogram of compound (9a).

[0030] FIG.22 shows a representative chromatogram of compound (9b). 313156387v3

[0031] FIG.23 shows a representative chromatogram of compound (9c).

[0032] FIG.24 shows a representative chromatogram of compound (9d).

[0033] FIG.25 shows a representative chromatogram of compound (9e).

[0034] FIG.26 shows a representative chromatogram of compound (9f).

[0035] FIG.27 shows a representative chromatogram of compound (9g).

[0036] FIG.28 shows a representative chromatogram of compound (9h).

[0037] FIG.29 shows a representative chromatogram of compound (6c).

[0038] FIG.30 shows a representative chromatogram of compound (6d).

[0039] FIG.31 shows a representative chromatogram of compound (10).

[0040] FIG.32 shows a representative chromatogram of compound (11).

[0041] FIG.33 shows a representative chromatogram of compound (12).

[0042] FIG.34 shows a representative chromatogram of compound (8h).

[0043] FIG.35 shows a representative chromatogram of compound (6b).

[0044] FIG.36 shows a representative chromatogram of compound (13).

[0045] FIG.37 shows a representative chromatogram of compound (14).

[0046] FIG.38 shows a representative chromatogram of compound (15).

[0047] FIG.39 shows a representative chromatogram of compound (17a).

[0048] FIG.40 shows a representative chromatogram of compound (17b).

[0049] FIG.41 shows a representative chromatogram of compound (17c).

[0050] FIG.42 shows a representative chromatogram of compound (17d).

[0051] FIG.43 shows a representative chromatogram of compound (17e).

[0052] FIG.44 shows a representative chromatogram of compound (17g).

[0053] FIG.45 shows a representative chromatogram of compound (17h).

[0054] FIG.46 shows a representative chromatogram of compound (18a).

[0055] FIG.47 shows a representative chromatogram of compound (18b).

[0056] FIG.48 shows a representative chromatogram of compound (18c).

[0057] FIG.49 shows a representative chromatogram of compound (18d).

[0058] FIG.50 shows a representative chromatogram of the Boc and urea protected [125I]MIBG intermediate.

[0059] FIG.51 shows a representative chromatogram of compound (22).

[0060] FIG.52 shows a representative chromatogram of compound (23).

[0061] FIGs.53A-53B show conditions for developing a one-pot radiosynthesis of iodoarenes via reductive elimination. FIG.53A shows a two-step, one-pot synthesis incorporating oxidation and reductive elimination (RE). The duration of the oxidation reaction 313156387v3and the reductive elimination reaction was 10 min and 2 hours, respectively. The radiochemical conversion (RCC) was assessed by radio-HPLC and expressed as the percentage of total [125I]iodide incorporated into the aryl ring (n=1). FIG.53B shows a three-step, one-pot synthesis incorporating transmetalation, oxidation, and reductive elimination. All reactions were performed at room temperature using 0.8 equivalents of the oxidizing agent. The transmetalation reaction was undertaken for 2 hours using boronic acid 5a, 4 hours using pinacol borane 5b, and 1 hour using trifluoroborate 5c. Oxidation times were 10 min for F-TEDA and Cl2FPyOTf. The RE time was 2 hours. Stoichiometric amounts (1 eq.) of KF or K2CO3were added as indicated. RCC was determined by radio-HPLC (n=1).

[0062] FIGs.54A-54C show a rationale for regioselectivity of aryl group transfer. FIG. 54A shows a postulated mechanism for the Bi-mediated radiohalogenation of aryl trifluoroborate. FIG.54B shows an optimized ground state structure of Bi(V) compound (7a) with the iodide ligand in equatorial (left) or axial (right) positions. FIG.54C shows an optimized ground state structure of Bi(V) compound (7b) with the iodide ligand in equatorial (left) or axial (right) positions. Ground state structure optimization was performed using the B3LYP / LanL2DZ basis set.

[0063] FIGs.55A-55D show a one-pot radiohalogenation of aryl rings. Reactions consisted of a transmetalation step lasting 1 hour, an oxidation step lasting 1 hour, and a reductive elimination step lasting 1-4 hours. Radiochemical conversion (RCC) was determined by radio-HPLC and is reported for each compound. Compounds were isolated by HPLC in ≥ 99% radiochemical purity. FIG.55A shows substrate scope of bismuth-mediated [125I]iodination of potassium aryltrifluoroborates and aryl boronic acids. FIG.55B shows [77Br]bromination of aryl boron compounds. The reductive elimination step took place at 80 ⁰C. FIG.55C shows [211At]astatination of aryl boron compounds. The reductive elimination step was fixed at 2 hours due to the short half-life of astatine-211. FIG.55D shows [18F]Fluorination of unsubstituted arenes from the transmetalated bismacycle Bi(III) precursor was not observed.

[0064] FIG.56A-56C show an application of the one-pot bismuth-mediated radiohalogenation to prepare radiopharmaceuticals. FIG.56A shows radiosynthesis of meta- [125I]iodobenzylguanidine. FIG.56B shows radiosynthesis of [124 / 125I]MIP-1095 and its t-butyl protected [77Br]bromo- and [211At]astatine analogs. FIG.56C shows compounds were purified by HPLC, and [124I]MIP-1095 was used to perform in vivo microPET / CT imaging of LNCaP tumors in a xenograft mouse model. The mice were intravenously administered 4.44 MBq [124I]MIP-1095 and imaged 1 hour post injection. 313156387v3DETAILED DESCRIPTION

[0065] One aspect of the present disclosure relates to a process for preparation of a compound of Formula (I):whereis a point of attachment of ring A to ring B or, if ring B is absent, to R1or R2group; is a single or a double bond; ring B is optional and, if present, is aryl or heteroaryl; Hal is halogen or radioisotope of halogen; X is independently selected at each occurrence from C, N, O, or S; R1is optional and, if present, is selected from the group consisting of H, halogen, CN, C1-6alkyl, -OC1-6alkyl, CF3, -C(O)H, -C(O)C1-6alkyl, -C(O)OC1-6alkyl,R2is optional and, if present, is selected from the group consisting of H, halogen, CN, C1-6alkyl, -OC1-6alkyl, CF3, -C(O)H, -C(O)C1-6alkyl, -C(O)OC1-6alkyl, 313156387v3R3is optional and, if present, is selected from the group consisting of H, halogen, CN, C1-6alkyl, -OC1-6alkyl, CF3, -C(O)H, -C(O)C1-6alkyl, -C(O)OC1-6alkyl,R4is optional and, if present, is selected from the group consisting of H, halogen, CN, C1-6alkyl, -OC1-6alkyl, CF3, -C(O)H, -C(O)C1-6alkyl, -C(O)OC1-6alkyl, 313156387v3R5is optional and, if present, is selected from the group consisting of H, halogen, CN, C1-6alkyl, -OC1-6alkyl, CF3, -C(O)H, -C(O)C1-6alkyl, -C(O)OC1-6alkyl,n is independently selected at each occurrence from 1, 2, 3, 4, or 5. This process comprises: providing a compound of Formula (IIa) or (IIb):where R is halogen; 313156387v3R´ is optional and, if present, is independently H, OCH3, or CF3; and X1is OTf or BF4; providing a compound of Formula (III): R6-Hal (III), where R6is Na, K, Cs, NH4, or (C1-6alkyl)4N; and reacting the compound of Formula (IIa) or (IIb) with the compound of Formula (III) under conditions effective to produce the compound of Formula (I).

[0066] Another aspect of the present disclosure relates to a process for preparation of a compound of Formula (I):whereis a point of attachment of ring A to ring B; is a single or a double bond; ring B is optional and, if present, is selected from the group consisting of C5aryl, C6aryl, C4heteroaryl, C5heteroaryl, and C6heteroaryl; Hal is halogen or radioisotope of halogen; X is independently selected at each occurrence from C or N; 313156387v3R1is optional and, if present, is selected from the group consisting of H, halogen, CN, C1-6alkyl, -OC1-6alkyl, CF3, -C(O)H, -C(O)C1-6alkyl, -C(O)OC1-6alkyl,R2is optional and, if present, is selected from the group consisting of H, halogen, CN, C1-6alkyl, -OC1-6alkyl, CF3, -C(O)H, -C(O)C1-6alkyl, -C(O)OC1-6alkyl,R3is optional and, if present, is selected from the group consisting of H, halogen, CN, C1-6alkyl, -OC1-6alkyl, CF3, -C(O)H, -C(O)C1-6alkyl, -C(O)OC1-6alkyl,R4is optional and, if present, is selected from the group consisting of H, halogen, CN, C1-6alkyl, -OC1-6alkyl, CF3, -C(O)H, -C(O)C1-6alkyl, -C(O)OC1-6alkyl,313156387v3R5is optional and, if present, is selected from the group consisting of H, halogen, CN, C1-This process comprises: providing a compound of Formula (IIa) or (IIb):where R is halogen; and X1is OTf or BF4; providing a compound of Formula (III): R6-Hal (III), where R6is Na, K, or (CH3CH2CH2CH2)4N; and reacting the compound of Formula (IIa) or (IIb) with the compound of Formula (III) under conditions effective to produce the compound of Formula (I).

[0067] As used above, and throughout the description herein, the following terms, unless otherwise indicated, shall be understood to have the following meanings. If not defined otherwise herein, all technical and scientific terms used herein have the same meaning as is commonly understood by one of ordinary skill in the art to which this technology belongs. In the event that there is a plurality of definitions for a term herein, those in this section prevail unless stated otherwise.

[0068] In this specification and the appended claims, the singular forms “a,” “an,” and “the” include plural references unless the context clearly dictates otherwise. 313156387v3

[0069] The terms “comprising,” “comprises,” and “comprised of” as used herein are synonymous with “including,” “includes,” or “containing,” “contains,” and are inclusive or open-ended and do not exclude additional, non-recited members, elements, or method steps.

[0070] The terms “comprising,” “comprises,” and “comprised of” also encompass the term “consisting of.” The transitional term “comprising,” which is synonymous with “including,” “containing,” or “characterized by,” is inclusive or open-ended and does not exclude additional, un-recited elements or method steps. By contrast, the transitional phrase “consisting of” excludes any element, step, or ingredient not specified in the claim. The transitional phrase “consisting essentially of” limits the scope of a claim to the specified materials or steps “and those that do not materially affect the basic and novel characteristic(s)” of the claimed subject matter. In some embodiments or claims where the term comprising is used as the transition phrase, such embodiments can also be envisioned with replacement of the term “comprising” with the terms “consisting of” or “consisting essentially of.”

[0071] Terms of degree such as “substantially,” “about,” and “approximately” and the symbol as used herein mean a reasonable amount of deviation of the modified term such that the end result is not significantly changed. These terms of degree should be construed as including a deviation of at least ±0.1% (and up to ±1%, ±5%, or ±10%) of the modified term if this deviation would not negate the meaning of the word it modifies. Unless otherwise clear from context, all numerical values provided herein are modified by the term about. All numerical values provided herein that are modified by terms of degree set forth in this paragraph (e.g.,are also explicitly disclosed without the term of degree. For example, “about 1%” is also explicitly disclosed as “1%”.

[0072] The term “and / or” as used herein means that the listed items are present, or used, individually or in combination. In effect, this term means that “at least one of” or “one or more” of the listed items is used or present.

[0073] The recitation of numerical ranges by endpoints includes all numbers and fractions subsumed within the respective ranges, as well as the recited endpoints. Any listed range can be easily recognized as sufficiently describing and enabling the same range being broken down into at least equal halves, thirds, quarters, fifths, tenths, etc. As a non-limiting example, each range discussed herein can be readily broken down into a lower third, middle third and upper third, etc. As will also be understood by one skilled in the art all language such as “up to,” “at least,” and the like include the number recited and refer to ranges which can be subsequently broken down into subranges as discussed above. Finally, as will be understood by one skilled in the art, a range includes each individual member. 313156387v3

[0074] The term “alkyl” means an aliphatic hydrocarbon group which may be straight or branched having about 1 to about 23 carbon atoms in the chain. For example, straight or branched carbon chain could have 1 to 6 carbon atoms. Branched means that one or more lower alkyl groups such as methyl, ethyl or propyl are attached to a linear alkyl chain. Exemplary alkyl groups include methyl, ethyl, n-propyl, i-propyl, n-butyl, t-butyl, n-pentyl, and 3-pentyl.

[0075] The term “aryl” means an aromatic monocyclic or multicyclic ring system of 6 to about 14 carbon atoms, preferably of 6 to about 10 carbon atoms. Representative aryl groups include phenyl and naphthyl. The term “arylene” refers to a group obtained by removal of a hydrogen atom from an aryl group. Non-limiting examples of arylene include phenylene and naphthylene.

[0076] The term “heteroaryl” means an aromatic monocyclic or multicyclic ring system of about 5 to about 14 ring atoms, preferably about 5 to about 10 ring atoms, in which one or more of the atoms in the ring system is / are element(s) other than carbon, for example, nitrogen, oxygen, or sulfur. In the case of multicyclic ring system, only one of the rings needs to be aromatic for the ring system to be defined as “Heteroaryl”. Preferred heteroaryls contain about 5 to 6 ring atoms. The prefix aza, oxa, thia, or thio before heteroaryl means that at least a nitrogen, oxygen, or sulfur atom, respectively, is present as a ring atom. A nitrogen atom of a heteroaryl is optionally oxidized to the corresponding N-oxide. Representative heteroaryls include pyridyl, 2- oxo-pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, triazinyl, furanyl, pyrrolyl, thiophenyl, pyrazolyl, imidazolyl, oxazolyl, isoxazolyl, thiazolyl, isothiazolyl, triazolyl, oxadiazolyl, thiadiazolyl, tetrazolyl, indolyl, isoindolyl, benzofuranyl, benzothiophenyl, indolinyl, 2- oxoindolinyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, indazolyl, benzimidazolyl, benzooxazolyl, benzothiazolyl, benzoisoxazolyl, benzoisothiazolyl, benzotriazolyl, benzo[1,3]dioxolyl, quinolinyl, isoquinolinyl, quinazolinyl, cinnolinyl, pthalazinyl, quinoxalinyl, 2,3-dihydro-benzo[1,4]dioxinyl, benzo[1,2,3]triazinyl, benzo[1,2,4]triazinyl, 4H-chromenyl, indolizinyl, quinolizinyl, 6aH-thieno[2,3-d]imidazolyl, 1H-pyrrolo[2,3-b]pyridinyl, imidazo[1,2- a]pyridinyl, pyrazolo[1,5-a]pyridinyl, [1,2,4]triazolo[4,3-a]pyridinyl, [1,2,4]triazolo[1,5- a]pyridinyl, thieno[2,3-b]furanyl, thieno[2,3-b]pyridinyl, thieno[3,2-b]pyridinyl, furo[2,3- b]pyridinyl, furo[3,2-b]pyridinyl, thieno[3,2-d]pyrimidinyl, furo[3,2-d]pyrimidinyl, thieno[2,3- b]pyrazinyl, imidazo[1,2-a]pyrazinyl, 5,6,7,8-tetrahydroimidazo[1,2-a]pyrazinyl, 6,7-dihydro- 4H-pyrazolo[5,1-c][1,4]oxazinyl, 2-oxo-2,3-dihydrobenzo[d]oxazolyl, 3,3-dimethyl-2- oxoindolinyl, 2-oxo-2,3-dihydro-1H-pyrrolo[2,3-b]pyridinyl, benzo[c][1,2,5]oxadiazolyl, benzo[c][1,2,5]thiadiazolyl, 3,4-dihydro-2H-benzo[b][1,4]oxazinyl, 5,6,7,8-tetrahydro- [1,2,4]triazolo[4,3-a]pyrazinyl, [1,2,4]triazolo[4,3-a]pyrazinyl, 3-oxo-[1,2,4]triazolo[4,3- 313156387v3a]pyridin-2(3H)-yl, and the like. The term “heteroarylene” refers to a group obtained by removal of a hydrogen atom from a heteroaryl group. Exemplary heteroarylene groups include, but are not limited to, groups derived from the heteroaryl groups described above.

[0077] The term “substituted” or “substitution” of an atom means that one or more hydrogen on the designated atom is replaced with a selection from the indicated group, provided that the designated atom's normal valency is not exceeded.

[0078] “Unsubstituted” atoms bear all of the hydrogen atoms dictated by their valency. When a substituent is keto (i.e., =O), then two hydrogens on the atom are replaced. Combinations of substituents and / or variables are permissible only if such combinations result in stable compounds; by “stable compound” or “stable structure” is meant a compound that is sufficiently robust to survive isolation to a useful degree of purity from a reaction mixture, and formulation into an efficacious therapeutic agent.

[0079] The term “optionally substituted” is used to indicate that a group may have a substituent at each substitutable atom of the group (including more than one substituent on a single atom), provided that the designated atom's normal valency is not exceeded and the identity of each substituent is independent of the others. Up to three H atoms in each residue are replaced with alkyl, halogen, haloalkyl, hydroxy, loweralkoxy, carboxy, carboalkoxy (also referred to as alkoxycarbonyl), carboxamido (also referred to as alkylaminocarbonyl), cyano, carbonyl, nitro, amino, alkylamino, dialkylamino, mercapto, alkylthio, sulfoxide, sulfone, acylamino, amidino, phenyl, benzyl, heteroaryl, phenoxy, benzyloxy, or heteroaryloxy.

[0080] Compounds described herein may contain one or more asymmetric centers and may thus give rise to enantiomers, diastereomers, and other stereoisomeric forms. Each chiral center may be defined, in terms of absolute stereochemistry, as (R)- or (S)-. This technology is meant to include all such possible isomers, as well as mixtures thereof, including racemic and optically pure forms. Optically active (R)- and (S)-, (-)- and (+)-, or (D)- and (L)- isomers may be prepared using chiral synthons or chiral reagents, or resolved using conventional techniques. When the compounds described herein contain olefinic double bonds or other centers of geometric asymmetry, and unless specified otherwise, it is intended that the compounds include both E and Z geometric isomers. Likewise, all tautomeric forms are also intended to be included.

[0081] The term “halogen” or “Hal” means fluoro (F), chloro (Cl), bromo (Br), iodo (I), or astato (At).

[0082] The term “becquerel” or “Bq” is a unit of radioactivity. One becquerel (Bq) is equal to one radioactive decay per second. The term “MBq” refers to mega becquerel.

[0083] In some embodiments, Hal is a radioisotope of halogen (radiohalogen). 313156387v3

[0084] In some embodiments Hal is, without limitation I, Br, Cl, F,18F,123I,76Br,77Br,124I,125I,131I,34mCl, and211At.

[0085] In some embodiments, A is definedis independently selected at each occurrence from C, N, NH, O, or S, but it is to be understood that when X is O, S, or NH, such X is not substituted with R3, R4, or R5or attached to ring B, and X can only be O or S in the five-membered ring.

[0086] In some embodiments ring A can be, without limitation, selected the group

[0087] In some embodiments ring A can be, without limitation, selected from the group consisting313156387v3

[0089] In some embodiments, R1, R2, R3, R4, or R5is

[0090] In some embodiments, R is F. 313156387v3

[0091] In some embodiments, the compound of Formula (I) is

[0092] In some embodiments, the compound of Formula (I) is

[0093] In some embodiments, the compound of Formula (I) has Formula (I´): 313156387v3Hal R5X X 4 X X R X R2R3(I´).

[0094] In some embodiments, the compound of Formula (III) can be, without limitation, tetrabutylammonium iodide, tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetraethylammonium iodide, tetraethylammonium fluoride, tetraethylammonium chloride, tetraethylammonium bromide, NaF, NaBr, NaI, Na[18F], Na[123I], Na[76Br], Na[77Br], Na[124I], Na[125I], Na[131I], Na[34mCl] and Na[211At].

[0095] In some embodiments, reacting the compound of Formula (IIa) or (IIb) with the compound of Formula (III) is carried out at room temperature. In some embodiments, reacting the compound of Formula (IIa) or (IIb) with the compound of Formula (III) is carried out at a temperature of from about 0°C to about 120°C. For example, in some embodiments, the reacting is carried out at a temperature of from about 0°C to about 20°C, about 0°C to about 40°C, about 0°C to about 60°C, about 0°C to about 80°C, about 0°C to about 100°C, about 20°C to about 30°C, about 20°C to about 40°C, about 20°C to about 60°C, about 20°C to about 80°C, about 20°C to about 100°C, about 20°C to about 120°C, about 40°C to about 60°C, about 40°C to about 80°C, about 40°C to about 100°C, about 40°C to about 120°C, about 60°C to about 80°C, about 60°C to about 100°C, about 60°C to about 120°C, about 70°C to about 80°C, about 70°C to about 90°C, about 70°C to about 100°C, about 70°C to about 120°C, about 80°C to about 100°C, about 80°C to about 120°C, or about 100°C to about 120°C .

[0096] In some embodiments, reacting the intermediate compound of Formula (IIa) or (IIb) with the compound of Formula (III) is carried out in a polar, aprotic solvent. Suitable polar, aprotic solvents that can be used include, without limitation, acetonitrile, dioxane, tetrahydrofuran, dimethylformamide, dimethylsulfoxide, or combinations thereof.

[0097] In some embodiments, reacting the compound of Formula (IIa) or (IIb) with the compound of Formula (III) is carried out for from about 30 min to about 24 hours. For example, in some embodiments, the reacting is carried out for from about 30 min to about 1 hour, about 30 min to about 5 hours, about 30 min to about 10 hours, about 30 min to about 15 hours, about 30 min to about 20 hours, about 1 hour to about 5 hours, about 1 hour to about 10 hours, about 1 hour to about 15 hours, about 1 hour to about 20 hours, about 1 hour to about 24 hours, about 5 hours to about 10 hours, about 5 hours to about 15 hours, about 5 hours to about 20 hours, about 5 hours to about 24 hours, about 10 hours to about 15 hours, about 10 hours to about 20 hours, 313156387v3about 10 hours to about 24 hours, about 15 hours to about 20 hours, about 15 hours to about 24 hours, or about 20 hours to about 24 hours.

[0098] In some embodiments, providing a compound of Formula (IIa) or (IIb) comprises: providing a compound of Formula (A):providing an oxidizing agent; and reacting the compound of Formula (A) with the oxidizing agent under conditions effective to produce the compound of Formula (IIa) or (IIb).

[0099] In some embodiments, providing a compound of Formula (A) comprises: providing a compound of Formula (IV):where LG is a leaving group; providing a compound of Formula (V):where Y is Cl, F, or OTf ; and reacting the compound of Formula (IV) with the compound of Formula (V) under conditions effective to produce the compound of Formula (A).

[0100] In some embodiments, providing a compound of Formula (IIa) or (IIb) comprises: providing a compound of Formula (IV): 313156387v3where LG is a leaving group; providing a compound of Formula (V):reacting the compound of Formula (IV) with the compound of Formula (V) under conditions effective to produce the compound of Formula (IIa) or (IIb).

[0101]

[0102] In some embodiments, reacting the compound of Formula (IV) with the compound of Formula (V) is carried out in the presence of an oxidizing agent. Suitable oxidizing agents include, without limitation, 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (SelectfluorTM), 2,6-dichloro-1-fluoropyridinium triflate, and 2,6-dichloro- 1-fluoropyridinium tetrafluoroborate.

[0103] In some embodiments, reacting the compound of Formula (IV) with the compound of Formula (V) is carried out in acetonitrile or CD3CN.

[0104] In some embodiments, reacting the compound of Formula (IV) with the compound of Formula (V) is carried out at a temperature of from about 20°C to about 40°C. For example, in some embodiments, reacting the compound of Formula (IV) with the compound of Formula (V) is carried out at a temperature of from about 20°C to about 25°C, about 20°C to about 30°C, about 20°C to about 35°C, about 25°C to about 30°C, about 25°C to about 35°C, about 25°C to about 40°C, about 30°C to about 35°C, or about 35°C to about 40°C.

[0105] In some embodiments, reacting the compound of Formula (IV) with the compound of Formula (V) is carried out for from about 5 min to about 48 hours. In some embodiments, reacting the compound of Formula (IV) with the compound of Formula (V) is carried out for from about 15 min to about 2 hours. For example, in some embodiments, reacting the compound of Formula (IV) with the compound of Formula (V) is carried out for from about 5 min to about 1 hour, about 5 min to about 5 hours, about 5 min to about 10 hours, about 5 min 313156387v3to about 15 hours, about 5 min to about 20 hours, about 5 min to about 25 hours, about 5 min to about 30 hours, about 5 min to about 35 hours, about 5 min to about 40 hours, about 5 min to about 45 hours, about 30 min to about 1 hour, about 30 min to about 5 hours, about 30 min to about 10 hours, about 30 min to about 15 hours, about 30 min to about 20 hours, about 30 min to about 25 hours, about 30 min to about 30 hours, about 30 min to about 35 hours, about 30 min to about 40 hours, about 30 min to about 45 hours, about 1 hour to about 5 hours, about 1 hour to about 10 hours, about 1 hour to about 15 hours, about 1 hour to about 20 hours, about 1 hour to about 25 hours, about 1 hour to about 30 hours, about 1 hour to about 35 hours, about 1 hour to about 40 hours, about 1 hour to about 45 hours, about 1 hour to about 48 hours, about 5 hours to about 10 hours, about 5 hours to about 15 hours, about 5 hours to about 20 hours, about 5 hours to about 25 hours, about 5 hours to about 30 hours, about 5 hours to about 35 hours, about 5 hours to about 40 hours, about 5 hours to about 45 hours, about 5 hours to about 48 hours, about 10 hours to about 15 hours, about 10 hours to about 20 hours, about 10 hours to about 25 hours, about 10 hours to about 30 hours, about 10 hours to about 35 hours, about 10 hours to about 40 hours, about 10 hours to about 45 hours, about 10 hours to about 48 hours, about 20 hours to about 25 hours, about 20 hours to about 30 hours, about 20 hours to about 35 hours, about 20 hours to about 40 hours, about 20 hours to about 45 hours, about 20 hours to about 48 hours, about 30 hours to about 35 hours, about 30 hours to about 40 hours, about 30 hours to about 45 hours, about 30 hours to about 48 hours, about 40 hours to about 45 hours, or about 40 hours to about 48 hours.

[0106] In some embodiments, reacting the compound of Formula (IV) with the compound of Formula (V) is carried out in the presence of an additive. In some embodiments, the additive is K2CO3.

[0107] In some embodiments, reacting the compound of Formula (IV) with the compound of Formula (V) is carried out in the presence of an activator. In some embodiments, the activator is KF.

[0108] In some embodiments, the process can further comprise reacting the compound of Formula (I):313156387v3with a solution of HCl in dioxane to produce the compound of Formula (I) where

[0109] Although preferred embodiments have been depicted and described in detail herein, it will be apparent to those skilled in the relevant art that various modifications, additions, substitutions, and the like can be made without departing from the spirit of the invention and these are therefore considered to be within the scope of the invention as defined in the claims which follow. EXAMPLES

[0110] The following Examples are presented to illustrate various aspects of the present disclosure, but are by no means intended to limit its scope. Example 1 – Materials and Methods

[0111] Full experimental methods, including the synthesis and characterization of radiolabeled compounds and non-radioactive standards, are described in Example 2. Representative synthetic procedures are described below. General Procedure for One-Pot Radioiodination of Aryl Boron Compounds

[0112] Arylboronic acid (5a) or potassium aryl trifluoroborate (5c) (2 µmol) and bismacycle Bi(III) compound 4 (1.0 mg, 1.8 µmol) were weighed and transferred into a clean 313156387v3and dried glass reaction vial equipped with a stir bar and dissolved in 900 µL of anhydrous acetonitrile. The reaction mixture was stirred for 1-4 hours at room temperature. Then, a solution of oxidant, SelectFluor™ (F-TEDA) or 2,6-dichloro-1-fluoropyridinium triflate (Cl2FPyOTf) (1.6 µmol), in 100 µL acetonitrile was added to the reaction mixture, and the solution was stirred for 15 min at room temperature. An 800 µL aliquot of the reaction mixture was removed and stored at -20 ⁰C as a Bi(V) stock solution. To the remaining 200 µL was added a solution of Na[125I]I (Revvity, USA) containing 7.4 MBq in 0.1 M NaOH, diluted to 10 µL with acetonitrile. The resulting reaction mixture was stirred at room temperature, and the progress of the reaction was monitored by radio-HPLC at 30 min intervals from 30 min to 2 hours. If unreacted [125I]iodide was observed after 2 hours, another 100 µL of the Bi(V) stock solution was added to the reaction mixture, and reaction progress was monitored by radio-HPLC. The radiochemical conversion was calculated by comparing the peak area of aryl [125I]iodide to the peak area of unreacted [125I]iodide in the radiochromatogram. The identity of the radiolabeled compound was confirmed by co-injection with a non-radioactive standard. The aryl [125I]iodide was purified and isolated by semi-prep HPLC. Chromatographic details are available in Example 2. General Procedure for One-Pot Radiobromination of Aryl Boron Compounds

[0113] The Bi(V) stock solution was prepared as described above. To the remaining 200 µL of Bi(V) solution was added a solution of NH4[77Br]Br (obtained through the US Department of Energy Isotope Program) containing 7.4 MBq in 0.1 M NH4OH, diluted to 10 µL with acetonitrile. The resulting reaction mixture was stirred at 80 ⁰C, and the progress of the reaction was monitored by radio-HPLC at 30 min intervals from 30 min to 2 hours. If unreacted [77Br]bromide was observed after 2 hours, another 200 µL of the Bi(V) stock solution was added to the reaction mixture, and the progress of the reaction was monitored by radio-HPLC. The radiochemical conversion was calculated as described above. The identity of the radiolabeled compound was confirmed by co-injection with a non-radioactive standard. The aryl [77Br]bromide was purified and isolated by semi-prep HPLC. Chromatographic details are available in Example 2. General Procedure for One-Pot Radioastatination of Aryl Boron Compounds

[0114] The Bi(V) stock solution was prepared as described above. To the remaining 200 µL of Bi(V) solution was added a solution of Na[211At]At (obtained through the US Department of Energy Isotope Program) containing 7.4 MBq in 0.1 M NaOH, diluted to 10 µL with acetonitrile. The resulting reaction mixture was stirred at room temperature, and the progress of the reaction was monitored by radio-HPLC at 30 min intervals from 30 min to 2 hours. If unreacted [211At]astatide was observed after 2 hours, another 200 µL of the Bi(V) stock solution 313156387v3was added to the reaction mixture, and the completion of the reaction was monitored by radio- HPLC. The identity of the radiolabeled compound was confirmed by co-injection with a non- radioactive iodide standard. The aryl [211At]astatide was purified and isolated by semi-prep HPLC. Chromatographic details are available in Example 2. Synthesis of [124I]MIP-1095

[0115] Potassium aryl trifluoroborate 21 (7.1 mg, 10 µmol) and bismacycle Bi(III) compound 4 (5.2 mg, 9 µmol) were weighed and transferred into a clean and dried glass reaction vial equipped with a stir bar and dissolved in 1.8 mL of anhydrous acetonitrile. The reaction mixture was stirred for 1 hour at room temperature. Then, a solution of Cl2FPyOTf (2.5 mg, 8 µmol) in 200 µL acetonitrile was added to the reaction mixture, and the solution was stirred for 10 min at room temperature. Upon completion of the reaction, a 1.5 mL aliquot of the reaction mixture was removed and stored at -20 ⁰C as a Bi(V) stock solution. To the remaining 500 µL of Bi(V) solution was added a solution of Na[124I]I (Revvity, USA) containing 150 MBq in 0.3 M NaOH and 0.3 M sodium thiosulfate, diluted to 50 µL with acetonitrile. The resulting reaction mixture was stirred at room temperature, and the progress of the reaction was monitored by radio-HPLC. After 1 hour, an additional 250 µL of the Bi(V) stock solution was added to the reaction mixture which was stirred for another 1 hour to achieve >90% radiochemical conversion. The radiolabeled intermediate was purified by semi-prep HPLC. Chromatographic details are available in Example 2. The fraction containing the compound was collected and passed through a pre-conditioned Sep-Pak C18 plus short cartridge (Waters, USA). The radiolabeled compound was eluted with 1 mL acetonitrile into a glass reaction vial. The acetonitrile was evaporated under nitrogen flow at room temperature, and the resulting residue was dissolved in 0.5 mL 4 N HCl in dioxane and stirred for 1 hour at room temperature. Upon completion of the reaction, the mixture was diluted with water (20 mL) and passed through a pre-conditioned C18 cartridge as described above. The retained material was eluted with 1 mL ethanol into a glass reaction vial. The ethanol was slowly evaporated to a volume of approximately 0.2 mL under nitrogen flow at room temperature. The resulting solution was diluted with 1.8 mL saline and passed through a 0.2 µm Millex® nylon syringe filter (Millipore Sigma, USA), yielding [124I]MIP-1095 in 64% ndcRCY and >99% radiochemical and chemical purity. The identity of the radiolabeled compound was confirmed by co-injection with a non- radioactive standard. The total synthesis time was 4 hours from mixing compounds 4 and 21. Chromatographic details and a flow diagram depicting the radiosynthesis are available in Example 2. 313156387v3PET Imaging

[0116] Male athymic nu / nu mice (Charles River, USA) were implanted subcutaneously with 1x106LNCaP cells (ATCC, USA) in Matrigel on the shoulder or knee. Once tumors reached approximately 200 mm3, the mice (n=4) were administered 100 µL of a solution of 3.7- 4.4 MBq [124I]MIP-1095 in 10% v / v ethanol / saline by tail vein injection. The mice were imaged by microPET / CT (Siemens Inveon™), under isoflurane (1.5% in oxygen) at 1 hour post injection. A 30 min PET acquisition was preceded by a 5 min CT acquisition for attenuation correction and anatomical co-registration. Image processing was performed using the AMIDE freeware. Computational Modeling

[0117] The structure optimization and frequency calculations were performed in Gaussian 16 (Gaussian, Inc, USA) using the B3LYP / LanL2DZ basis. Radiochemistry

[0118] All radiochemistry work was performed behind the lead shield and under the ventilation hood. Example 2 – Synthetic Methods and Experimental Section General Information

[0119] Unless otherwise stated, all experiments were performed in closed containers using dried solvents, but no other efforts were made to exclude air or moisture. All glassware and the NMR tubes were oven-dried at 120 ⁰C for at least 12 hours before use. The reaction vial was charged with a Teflon-coated magnetic stir bar. Reagents, e.g., 1-chloromethyl-4-fluoro-1,4- diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (SelectfluorTM), 1-fluoro-2,6- dichloropyridinium tetrafluoroborate, 1-fluoro-2,6-dichloropyridinium triflate, 1- fluoropyridinium tetrafluoroborate, 1-fluoro-2,4,6-trimethylpyridinium tetrafluoroborate, arylboronic acids, arylboronic acid pinacol esters, potassium aryltrifluoroborates, iodoarene, and bromoarene standards were obtained from Millipore Sigma, Fisher Scientific, Oakwood Chemicals, AmBeed, and A2B Chemicals and used without further purification. Anhydrous solvents were purchased from Sigma Aldrich in a sure-sealed bottle and stored under argon atmosphere. Sodium [125I]iodide was purchased from Revvity as a solution in 0.1 M NaOH with a specific activity of ~630 GBq / mg. Sodium [124I]iodide was purchased from 3D Imaging, LLC (Little Rock, USA) and supplied as a solution in 0.3 M NaOH and 0.3 M sodium thiosulfate with a specific activity of ~1100 GBq / µmol. [77Br]Bromine and [211At]astatine were supplied by the U.S. Department of Energy Isotope Program, managed by the Office of Isotope R&D and 313156387v3Production. Potassium aryl trifluoroborates were prepared from commercially available arylboronic acids by following a previously reported experimental procedure (Vedejs et al., “Conversion of Arylboronic Acids into Potassium Aryltrifluoroborates: Convenient Precursors of Arylboron Difluoride Lewis Acids,” J. Org. Chem.60:3020–3027 (1995), which is hereby incorporated by reference in its entirety).

[0120] All NMR experiments were recorded at 25 °C using a 500 MHz spectrometer (Bruker) in deuterated chloroform (CDCl3) or deuterated acetonitrile (CD3CN) at the NMR Core facility at the Weill Cornell Medicine. Deuterated solvents were purchased from Cambridge Isotope Laboratories.1H NMR spectra (500 MHz) were referenced to the residual protons of the deuterated solvents, and13C NMR spectra (125 MHz) were referenced internally to the D- coupled13C resonances of the NMR solvent.19F NMR spectra (470 MHz) are reported in deuterated chloroform or acetonitrile without external reference. Chemical shifts (δ) and coupling constants (J) are reported in ppm and Hz, respectively, and chemical shifts are reported relative to the calibrated residual deuterated solvent peak. A high-resolution mass was determined using an ESI-MS fragmentation experiment. The percentage of radiochemical conversion, yield, and purity were determined by radio-HPLC by measuring the comparing the peak area of the activity eluted with the same retention time as the non-radioactive standard with the total peak areas of all radioactive species. The activity of I-124, I-125, and At-211 was measured using a CRC-12 dose calibrator (Capintec). The settings used for I-125 and I-124 were 319 and 570, respectively, and the setting used for At-211 was 48. The activity of Br-77 was measured on an ATOMLAB™ 500 dose calibrator (Biodex). Activities were assessed at the start of the reaction and after the isolation of the purified product. Synthesis of 10-Aryl-10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide (2a)

[0121] A 250 mL Schlenk flask equipped with a magnetic stir bar was charged with BiBr3(2.50 g, 5.5 mmol) and BiPh3(1.23 g, 2.8 mmol) under N2atmosphere. The mixture was dissolved in 50 ml diethyl ether at room temperature and stirred for 3 hours, at which point a yellow precipitate was observed.20 mL THF was added to dissolve the yellow precipitate. The 313156387v3resulting solution was cooled to -78 ⁰C. In a separate 500 mL Schlenk flask, n-butyllithium (11.28 mL, 18.0 mmol, 1.6 M in hexanes, 2.2 eq.) was added to a solution of diphenyl sulfone (1.79 g, 8.20 mmol) in 100 mL THF at -78 °C for 1 hour. The cooled dibromo(phenyl)bismuthane solution was added dropwise to the reaction mixture at -78 °C with continuous stirring, and the resulting solution was slowly warmed to room temperature and stirred for an additional 6 hours. The reaction was quenched with brine (25 mL), and the organic material was extracted with EtOAc (3 × 80 mL). The organic solvents were dried over sodium sulfate, filtered, and evaporated under reduced pressure to obtain a dark yellow gum. The crude product was purified by flash chromatography (silica, hexane:EtOAc = 90:10 to 50:50) to obtain bismacyle Bi(III) 2a as a white solid (2.42 g, 59% yield).1H NMR (500 MHz, CD3CN): δ 8.31- 8.29 (dd, J = 7.5 Hz, J = 1.0 Hz, 2H, CH), 7.92-7.90 (J = 7.5 Hz, J = 1.5 Hz, 2H, CH), 7.75-7.73 (J = 6.5 Hz, J = 1.5 Hz, 2H, CH), 7.46-7.39 (m, 6H, CH), 7.37-7.34 (m, 1H, CH).13C NMR (125 MHz, CD3CN): δ 166.56, 159.96, 141.60, 138.17, 137.72, 133.10, 130.29, 127.99, 127.94, 125.98. HRMS (ESI, m / z): calcʼd for C18H13BiO2SNa+[M+Na]+525.1364; found 525.1359. Preparation of 5,5-Dioxido-10H-dibenzo[b,e][1,4]thiabismin-10-yl trifluoromethanesulfonate (4) Synthesis of 10-Iodo-10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide (31)

[0122] The synthesis was carried out according to previously reported methods (Suzuki et al., “Synthesis and Reactions of Some New Heterocyclic Bismuth -(iii) and -(v) Compounds. 5, 10- Dihydrobenzo[b,e]bismine and Related Systems,” J. Chem. Soc. Perkin Trans.1, 1593– 1600 (1992); Sakurai and Mukaiyama, “A New Preparative Method of Aryl Sulfonate Esters by Using Cyclic Organobismuth Reagents,” Heterocycles 74:771–790 (2007); which are hereby incorporated by reference in their entirety). Briefly, compound 2a (1.01 g, 2.0 mmol) was weighed, transferred into a 50 mL round bottom flask, and dissolved in 10 mL anhydrous diethyl ether at room temperature. Iodine chunks (0.25 g, 0.98 mmol) were weighed and added in small portions with continuous stirring at room temperature. Upon the addition of iodine, the color of the resultant solution turned reddish. The resulting reaction mixture was stirred for 2 hours at room temperature. The reaction was deemed complete when the color of the solution became colorless. The solvent was evaporated under reduced pressure, and the resulting mass was 313156387v3washed with toluene to obtain a light yellow solid. The solid was recrystallized to obtain 0.9 g (82% yield) of compound 31 as a yellow crystalline solid.1H NMR (500 MHz, CD3CN): δ 9.23 – 9.21 (dd, J = 7.5 Hz, 0.5 Hz, 2H, CH), 8.31-8.29 (dd, J = 7.5 Hz, 1.0 Hz, 2H, CH), 7.62-7.59 (td, J = 7.5 Hz, 1.5 Hz 2H, CH), 7.50-7.47 (td, J = 7.5 Hz, 1.0 Hz, 2H, CH).13C NMR (125 MHz, CD3CN): δ 163.65, 140.30, 140.10, 135.90, 128.77, 127.61. HRMS (ESI, m / z): calcʼd for C12H8BiO2S[M]+425.23; found 425.14. Synthesis of 5,5-Dioxido-10H-dibenzo[b,e][1,4]thiabismin-10-yl Trifluoromethanesulfonate (4)

[0123] Compound 31 (0.500 g, 0.90 mmol) was weighed, transferred into a 50 mL Schlenk tube, and placed under nitrogen atmosphere. The compound was dissolved in anhydrous acetonitrile (20mL) at room temperature. Silver trifluoromethanesulfonate (0.236 g, 0.91 mmol) was added in small portions to the reaction mixture with continuous stirring under a nitrogen atmosphere. A yellow precipitate was observed over the course of the reaction. The reaction mixture was stirred for 16 hours at room temperature. The yellow precipitate was filtered, the filtrate was transferred to a round bottom flask, and the organic solvent was evaporated under reduced pressure to obtain a light yellow solid. The crude product was dissolved in CH2Cl2(20 mL), sonicated, and filtered to remove the residual yellow solid. The filtrate was dried under reduced pressure to obtain compound 4 (0.42 g, 80%) as a white solid.1H NMR (500 MHz, CD3CN): δ 8.908 (broad doublet, 2H), 8.467- 8.452 (d, J = 7.5 Hz, 2H), 7.912 - 7.882 (t, J = 7.5 Hz, 2H, CH), 7.603-7.573 (t, J = 7.5 Hz, 2H, CH).13C NMR (125 MHz, CD3CN): 191.74, 139.93, 136.01, 135.01, 128.96, 128.80, 118.10 (q, J = 316.25).19F NMR (470 MHz, CD3CN): δ -79.26. HRMS (ESI, m / z): calcʼd for C12H8BiO2S[M]+425.23; found 425.14. Synthesis of 5,5-Dioxido-10H-dibenzo[b,e][1,4]thiabismin-10-yl Trifluoromethanesulfonate (4) via One Step Synthesis313156387v3

[0124] The synthesis of compound 4 was carried out according to the previously published method (Planas et al., “Bismuth-Catalyzed Oxidative Coupling of Arylboronic Acids with Triflate and Nonafolate Salts,” J. Am. Chem. Soc.142(26):11382 – 11387 (2020), which is hereby incorporated by reference in its entirety). Phenylbismine (2.5 mmol) was weighed and transferred into a clean and dried Schlenk flask, which was kept under a nitrogen atmosphere. Compound 4 was dissolved in anhydrous CH2Cl2,and trifluoromethanesulfonic acid (TfOH) (2.75 mmol, 1.1 equiv.) added dropwise into the solution of compound 4 under a nitrogen blanket at room temperature with continuous stirring. The resultant reaction mixture was stirred for 2 hours at room temperature. The organic solvent was removed under vacuum, and the remaining solid was washed with a 20% CH2Cl2in pentane solution. The obtained white solid was dried under vacuum overnight.1H NMR (500 MHz, CD2Cl2): δ 9.016 - 9.001 (d, J = 7.5 Hz, 2H), 8.520 -8.504. (d, J = 8.0 Hz, 2H), 7.986 - 7.956 (t, J = 7.5 Hz, 2H, CH), 7.62 -7.59 (t, J = 7.5 Hz, 2H, CH).13C NMR (125 MHz, CD2Cl2): 191.74, 138.83, 136.92, 134.94, 130.09, 129.49, 118.95 (q, J = 316.25 Hz).19F NMR (470 MHz, CD2Cl2): δ -77.68. MS (ESI, m / z): calcʼd for [C12H8BiO2S]+425.14; found 425.23. General Procedure for Transmetalation of Aryl Rings

[0125] Organoboron compounds 5a-5e (0.2 mmol) and bismacycle Bi(III) trifluoromethanesulfonate 4 (115 mg, 0.2 mmol) were weighed and transferred into a shell vial equipped with a stir bar and dissolved in 750 µL of CD3CN with continuous stirring at room temperature. KF (12 mg, 0.2 mmol) or K2CO3(83 mg, 0.6 mmol) were added in small portions to the reaction mixture as indicated in FIG.3. The resulting reaction mixture was stirred for 30 min to 24 hours, and the progress of the reaction was monitored by1H-NMR. Upon completion of the reaction, an off-white precipitate was observed. The CD3CN was evaporated under reduced pressure to obtain an off-white solid. The crude product was dissolved in 3 mL EtOAc and washed with water (3x1 mL). EtOAc was evaporated under reduced pressure to obtain a 313156387v3white residue, which was purified by column chromatography (silica, hexane:EtOAc = 5:95 to 40:60) to obtain compounds 2a-2c as white solids in 79-95% yield. 10-Phenyl-10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide (2a)

[0126] Following the general procedure, 2a was obtained in 95% yield as colorless crystals.1H NMR (500 MHz, CD3CN): δ 8.31 – 8.29 (dd, J = 7.5 Hz, J = 1.0 Hz, 2H, CH), 7.92 – 7.90 (J = 7.5 Hz, J = 1.5 Hz, 2H, CH), 7.75 - 7.73 (J = 6.5 Hz, J = 1.5 Hz, 2H, CH), 7.46 – 7.39 (m, 6H, CH), 7.37-7.34 (m, 1H, CH).13C NMR (125 MHz, CD3CN): δ 141.60, 138.17, 137.72, 133.10, 130.29, 127.99, 127.94, 125.98. HRMS (ESI, m / z): calcʼd for C18H13BiO2SNa+[M+Na]+525.1364; found 525.1359. 10-(4-Methoxyphenyl)-10H-dibenzo[b,e][1,4]thiabismine 5,5-dioxide (2b)

[0127] Following the general procedure, 2b was obtained in 95% yield as colorless crystals.1H NMR (500 MHz, CD3CN): δ 8.30-8.28 (d, J = 7.5 Hz, 2H, CH), 7.92-7.90 (J = 7.0 Hz, 2H, CH), 7.63-7.61 (m, 2H, CH), 7.46-7.39 (m, 4H, CH), 6.94-6.93 (m, 2H, CH), 3.76 (s, 3H, OMe).13C NMR (125 MHz, CD3CN): δ 159.79, 141.93, 140.14, 138.06, 133.37, 128.28, 126.23, 116.46, 54.73. HRMS (ESI, m / z): calcʼd for C19H15BiO3S[M]+533.3664; found 533.3658. 10-(4-(Trifluoromethyl)phenyl)-10H-dibenzo[b,e][1,4]thiabismine 5,5-Dioxide (2c)

[0128] Following the general procedure, 2c was obtained in 79% yield as a white solid.1H NMR (500 MHz, CD2Cl2): δ 8.35 – 8.33 (dd, J = 7.5 Hz, J = 1.0 Hz, 2H, CH), 7.90 – 7.87 (J = 7.5 Hz, J = 1.5 Hz, 2H, CH), 7.85 – 7.83 (J = 7.5 Hz, J = 1.5 Hz, 2H, CH), 7.62 - 7.60 (dd, J = 313156387v37 Hz, J = 1.5 Hz, 2H, CH), 7.43 – 7.40 (td, J = 7 Hz, J = 1.5 Hz, 2H, CH), 7.38 – 7.35 (td, J = 7 Hz, J = 1.5 Hz, 2H, CH).13C NMR (125 MHz, CD2Cl2): δ 166.61, 138.37, 135.77, 134.13, 130.55, 130.28, 128.48 (q, J = 276 Hz),126.82 (q, J = 3.7 Hz), 125.02, 123.71, 123.68, (q, J = 33.6 Hz). HRMS (ESI, m / z): calcʼd for C19H12BiF3O2S[M]+571.3386; found 571.3378. General Procedure for Oxidation of Bi (III) to Bi(V)F-TEDA Cl2FPyOTf

[0129] Bismacycle Bi(III) compound 2a (10 mg, 0.02 mmol) was weighed and transferred into a shell vial equipped with a stir bar and dissolved in 750 µL CD3CN with continuous stirring at room temperature. Either SelectFluor™ (F-TEDA) or 2,6-dichloro-1- fluoropyridinium triflate (Cl2FPyOTf), (0.02 mmol) was added to the reaction mixture in small portions with continuous stirring at room temperature. The reaction mixture was stirred for 10 min and the progress of the reaction was monitored by1H-NMR. The oxidation of Bi(III) to Bi(V) was determined by comparing the chemical shift and peak integral of the signal from an aromatic proton of the Bi(V) complex with the signal from the corresponding proton of the Bi(III) compound.

[0130] 1H NMR (500 MHz, CD3CN): δ 8.31 – 8.25 (d, J = 7.5 Hz, 7.5 Hz, 4H, CH), 7.99 – 7.97 (J = 7 Hz, 2H, CH), 7.84 – 7.81 (t, J = 7 Hz, 2H, CH), 7.73 – 7.64 (m, 5H, CH).1H NMR data matched those previously reported (Magre and Cornella, “Redox-Neutral Organometallic Elementary Steps at Bismuth: Catalytic Synthesis of Aryl Sulfonyl Fluorides,” J. Am. Chem. Soc.143(51):21497–21502 (2021), which is hereby incorporated by reference in its entirety).19F NMR (470 MHz, CD3CN): δ -151.4. The fluorine atom bound to bismuth is not visible. 313156387v3General Procedure for Two-Step, One-Pot Radioiodination of Aryl Rings2a: R = H 6a: R = H 2b: R = OMe6b: R = OMe2c: R = CF3 6c: R = CF3

[0131] Bismacycle Bi(III) compounds 2a-2c (0.2 µmol) were transferred into a glass reaction vial equipped with a stir bar and dissolved in 150 µL of anhydrous acetonitrile. A solution of the oxidizing agent (F-TEDA or Cl2FPyOTf; 0.16 µmol) in 100 µL acetonitrile was added dropwise to the solution of 2a-2c with continuous stirring at room temperature. The mixture was stirred for 10 min at room temperature. In a separate glass reaction vial, a solution of Na[125I]I containing 7.4 MBq in 10 µL was prepared by diluting the solution of Na[125I]I in 0.1 M NaOH with anhydrous acetonitrile. After 1 hour of stirring, the Na[125I]I solution was added dropwise to the reaction vial containing the Bi(V) mixture with continuous stirring at room temperature. The resulting reaction mixture was stirred at room temperature, and the progress of the reaction was monitored by radio-HPLC at 30 min intervals from 30 min to 2 hours. The identity of the radiolabeled product was confirmed by co-injection with the non- radioactive standard. [125I]Iodoarene (6a-6c) was purified and isolated by radio-HPLC.

[0132] For these analyses, compounds were injected onto a Symmetry C18, 5 µm, 4.6x50 mm column (Waters) attached to a dual pump Agilent 1200 Series HPLC equipped with a variable wavelength detector and a HERM LB 500 flow cell radiodetector (Berthold Technologies). Compounds were detected at 230 nm and 254 nm. The mobile phases used were 0.01% v / v trifluoroacetic acid (TFA) / H2O (solvent A) and 0.01% v / v TFA / acetonitrile (solvent B). Elution of the column was performed at a flow rate of 2 mL / min using the gradient reported in Table 1 below. 313156387v3Table 1. Chromatographic Conditions for HPLC Purification of Compounds 6a-6c Stationary phase: Symmetry C18, 5 µm, 4.6x50 mm column Mobile phase gradient: Time (min) Mobile Phase A (%) Mobile Phase B (%) 0.0 100 0 1.0 100 0 8.0 5 95 9.0 5 95 10.0 100 0 11.0 100 0 UV detection wavelengths: 230 and 254 nm Flow rate: 2 mL / min Procedure for the Three-Step One Pot Synthesis in Cold Conditions and Monitoring the Progress of Reaction in an NMR Tube for Iodination of Aryl Rings

[0133] Potassium trifluoroborate (5c) (0.02 mmol) and bismacycle Bi(III) compound (4) (0.019) were weighed and transferred into an NMR tube and dissolved in 750 µL of CD3CN and the mixture was vortexed for 5 minutes at room temperature. Progress of the reaction was monitored by1H-NMR after 30 minutes and observed that transmetalation was completed in stoichiometric amount. Oxidation: T-FEDA (0.0198 mmol) was weighed and transferred to the NMR tube with small portion and the resultant solution was vortexed for five minutes at room temperature. The progress of the reaction was monitored by1H-NMR. Reductive elimination: Tetrabutylammonium iodide (TBAI) (0.021 mmol) was weighed and transferred into the NMR tube containing Bi(V) complex, and the resultant mixture was vortexed for 5 minutes at room temperature. The progress of the reaction was monitored by1H-NMR. 313156387v3General Procedure for Three-Step, One-Pot Radioiodination of Aryl Rings5a: X = B(OH)25b: X = Bpin5c: X = BF3K

[0134] First step (transmetalation): Arylboronic acid (5a), pinacol borane (5b), or potassium trifluoroborate (5c) (2 µmol) and bismacycle Bi(III) compound (4) (1.0 mg, 1.8 µmol) were weighed and transferred into a glass reaction vial equipped with a stir bar and dissolved in 900 µL of anhydrous acetonitrile with continuous stirring at room temperature. The reaction mixture was stirred for 1 to 4 hours at room temperature, depending on the aryl boron precursor (2 hours using boronic acid 5a, 4 hours using pinacol borane 5b, and 1 hour using trifluoroborate 5c).

[0135] Second step (oxidation): A solution of T-FEDA or Cl2FPyOTf (1.6 µmol) in 100 µL acetonitrile was added to the reaction mixture and the resulting solution was stirred for 10 min at room temperature. Then, an 800 µL aliquot was removed from the reaction vial and stored at -20 ⁰C. The remaining 200 µL of the reaction mixture was used as a Bi(V) precursor for reaction with Na[125I]I.

[0136] Third step (reductive elimination): A solution of Na[125I]I containing 7.0 MBq in 10 µL was prepared by diluting the stock solution with anhydrous acetonitrile and adding dropwise to the reaction vial with continuous stirring. The resulting reaction mixture was stirred at room temperature, and the progress of the reaction was monitored by radio-HPLC at 30 min intervals from 30 min to 2 hours. If unreacted [125I]iodide was observed after 2 hours, another 200 µL aliquot of the Bi(V) stock solution was added, and the reaction was stirred for completion. [125I]Iodobenzene (6a) was purified and isolated by radio-HPLC using method reported in Table 1.

[0137] A representative chromatogram is shown in FIG.4.1-Iodobenzene was co- injected to confirm the identity of 6a. 313156387v3General Procedure for Three-Step, One-Pot Radiobromination of Aryl Rings

[0138] The synthesis was performed as described above for the three-step, one-pot radioiodination of aryl rings, with the exception of the reductive elimination step, which was undertaken at 80 ⁰C for 4 hours. Compounds 17a-h were purified by HPLC and isolated in 27- 88% non-decay corrected radiochemical incorporation. The chromatographic conditions are given in Table 2. Table 2. Chromatographic Conditions for HPLC Purification of Compounds 17a-h Stationary phase: Symmetry C18, 5 µm, 4.6x50 mm column Mobile phase gradient: Time (min) Mobile Phase A (%) Mobile Phase B (%) 0.0 100 0 2.0 100 0 8.0 5 95 9.0 5 95 10.0 100 0 11.0 100 0 UV wavelengths for detection: 230 and 254 nm Flow rate: 2 mL / min

[0139] A representative chromatogram is provided in FIG.5.2-Bromo-1,3,5- trimethylbenzene was co-injected to confirm the identity of 17b. Competitive Study for the Bond Formation of Aryl-Iodide vs Aryl-OH via Reductive Elimination From Bi(V) Complexes

[0140] Bismacycle Bi(III) compound 2a (0.02 mmol) was transferred into a glass reaction vial equipped with a stir bar and dissolved in 0.5 ml acetonitrile-D3. A solution of the oxidizing agent (F-TEDA) (0.19 mmol) in 80 µL acetonitrile-D3was added dropwise to the solution of 2a with continuous stirring at room temperature. The mixture was stirred for 10 min 313156387v3at room temperature and monitored the completion of reaction by1H-NMR.1H-NMR evident the completion of the oxidation to form Bi(V) complexes.

[0141] In a separate glass reaction vial, a solution mixture of TBAI (0.02 mmol in 50 µL) and NaOH (0.02 mmol in 70 µL) was prepared. The solution mixture was added to the Bi(V) species with continuous stirring at room temperature. The resultant reaction mixture was stirred for 30 min at room temperature and monitored the completion of reaction by1H-NMR. General Procedure for Three-Step, One-Pot Synthesis of Radioastatination of Aryl Rings

[0142] The synthesis was performed as described above for the three-step, one-pot radioiodination of aryl rings. Compounds 18a-d were purified by HPLC and isolated in 53-78% non-decay corrected radiochemical incorporation using the chromatographic conditions described in Table 3 below. Table 3. Chromatographic Conditions for HPLC Purification of Compounds 18a-d Stationary phase: Symmetry C18, 5 µm, 4.6x50 mm column Mobile phase gradient: Time (min) Mobile Phase A (%) Mobile Phase B (%) 0.0 100 0 2.0 100 0 8.0 5 95 9.0 5 95 10.0 100 0 11.0 100 0 UV wavelengths for detection: 230 and 254 nm Flow rate: 2 mL / min

[0143] A representative chromatogram is depicted FIG.6.2-Iodo-1,3,5-trimethylbenzene was co-injected to confirm the identity of compound 18b. Synthesis of Radiopharmaceuticals and Their Precursors and Standards Boc- and Urea-Protected Meta-[125I]Iodobenzylguanidine ([125I]MIBG) 313156387v3RCC = 80% RCY = 53%

[0144] The synthesis was performed as described above for the three-step, one-pot radioiodination of aryl rings. The protected [125I]MIBG intermediate was purified by HPLC and isolated in 80% non-decay corrected radiochemical incorporation, 53% non-decay corrected radiochemical yield, and greater than 99% radiochemical purity. A representative chromatogram is depicted FIG.7. The identity of the radiolabeled product was confirmed by co-injection with the non-radioactive standard. Table 4. Chromatographic Conditions for HPLC Purification of Boc- and urea-protected meta-[125I]iodobenzylguanidine ([125I]MIBG) Stationary phase: Symmetry C18, 5 µm, 4.6x50 mm column Mobile phase gradient: Time (min) Mobile Phase A (%) Mobile Phase B (%) 0.0 100 0 1.0 100 0 8.0 5 95 9.0 5 95 10.0 100 0 11.0 100 0 UV wavelengths for detection: 230 and 254 nm Flow rate: 2 mL / min

[0145] Potassium aryl trifluoroborate 21 (1.4 mg, 2 µmol) and bismacycle Bi(III) compound 4 (1.0 mg, 1.8 µmol) were weighed and transferred into a clean and dried glass reaction vial equipped with a stir bar and dissolved in 900 µL of anhydrous acetonitrile with continuous stirring at room temperature. The reaction mixture was stirred for 1 hour at room temperature. Then, a solution of Cl2FPyOTf (0.5 mg, 1.6 µmol) in 100 µL acetonitrile was added 313156387v3to the reaction mixture, and the solution was stirred for 10 min at room temperature. Then, 800 µL aliquot was removed from the reaction vial and stored at -20 ⁰C as a Bi(V) stock solution. To the remaining 200 µL of Bi(V) solution was added a solution of Na[125I]I containing 7.5 MBq in 0.1 M NaOH, diluted to 50 µL with acetonitrile. The resulting reaction mixture was stirred at room temperature, and the progress of the reaction was monitored by radio-HPLC. After 1 hour of stirring, another 200 µL of the Bi(V) stock solution or freshly prepared Bi(V) solution was added to the reaction mixture, and the completion of the reaction was monitored by radio-HPLC. The identity of the radiolabeled compound was confirmed by co-injection with a non-radioactive standard (FIG.8). The radioiodinated intermediate was purified by HPLC using the conditions described below. The isolated radiolabeled compound was hydrolyzed with 0.3 mL 4 N HCl in dioxane to yield [125I]MIP-1095 with 92% radiochemical incorporation, 65% non-decay corrected radiochemical yield, and >99% radiochemical and chemical purity. Table 5. Chromatographic Conditions for HPLC Purification of [125I]MIP-1095 Stationary phase: Symmetry C18, 5 µm, 4.6x50 mm column Mobile phase gradient: Time (min) Mobile Phase A (%) Mobile Phase B (%) 0.0 100 0 2.0 100 0 8.0 5 95 9.0 5 95 10.0 100 0 11.0 100 0 UV wavelengths for detection: 230 and 254 nm Flow rate: 2 mL / min [124I]MIP-1095

[0146] Potassium aryl trifluoroborate 21 (7.1 mg, 10 µmol) and bismacycle Bi(III) compound 4 (5.2 mg, 9 µmol) were weighed and transferred into a clean and dried glass reaction vial equipped with a stir bar and dissolved in 1.8 mL of anhydrous acetonitrile with continuous stirring at room temperature. The reaction mixture was stirred for 1 hour at room temperature. Then, a solution of Cl2FPyOTf (2.5 mg, 8 µmol) in 200 µL acetonitrile was added to the reaction mixture, and the solution was stirred for 10 min at room temperature. Upon completion of the reaction, 1.5 mL of the contents of the vial were removed and stored at -20 ⁰C as a Bi(V) stock solution. To the remaining 500 µL of Bi(V) solution was added a solution of Na[124I]I containing 130 MBq in 0.3 M NaOH and 0.3 M sodium thiosulfate, diluted to 50 µL with acetonitrile. The resulting reaction mixture was stirred at room temperature, and the progress of the reaction was monitored by radio-HPLC. After 1 hour of stirring, another 250 µL of the Bi(V) stock solution was added to the reaction mixture with stirring, and the completion of the reaction was 313156387v3monitored by radio-HPLC. The radiolabeled intermediate was purified by semi-prep HPLC using the method outlined in Table 6 below (Chromatogram provided in FIG.9). Table 6. Chromatographic Conditions for HPLC Purification of Radiolabeled Intermediate Stationary phase: Luna C18, 10 µm, 10x250 mm column Mobile phase gradient: Time (min) Mobile Phase A (%) Mobile Phase B (%) 0.0 90 10 2.0 90 10 11.0 10 95 14.0 10 95 16.0 90 10 17.0 90 10 UV wavelengths for detection: 230 and 254 nm Flow rate: 8 mL / min

[0147] The fraction containing the desired compound was collected and passed through a preconditioned Sep-Pak C18 plus short cartridge (Waters, USA). The radiolabeled compound was eluted with 1 mL of acetonitrile into a glass reaction vial. The acetonitrile was evaporated under nitrogen flow, and the resulting residue was dissolved in 0.5 mL 4 N HCl in dioxane and stirred for 1 hour at room temperature. Upon completion of the reaction, the crude reaction mixture was diluted with water (20 mL) and passed through a preconditioned C18 cartridge as described above. The cartridge was washed with 5 mL H2O and the retained material was eluted with 1 mL absolute ethanol into a glass reaction vial. The ethanol was slowly evaporated to a volume of approximately 0.2 mL under nitrogen flow at room temperature. The resulting solution was diluted with 1.8 mL saline and passed through a 0.2 µm Millex® nylon syringe filter (Millipore Sigma, USA) to afford [124I]MIP-1095 in 64% non-decay corrected radiochemical yield and >99% radiochemical and chemical purity. The identity of the radiolabeled compound was confirmed by co-injection with a non-radioactive standard. The total synthesis time was 4 hour. The analytical chromatographic method is outlined below and the chromatograph is provided in FIG.10. Table 7. Chromatographic Conditions for HPLC Purification of [124I]MIP-1095 Stationary phase: Symmetry C18, 5 µm, 4.6x50 mm column Mobile phase gradient: Time (min) Mobile Phase A (%) Mobile Phase B (%) 0.0 100 0 2.0 100 0 8.0 5 95 9.0 5 95 10.0 100 0 11.0 100 0 UV wavelengths for detection: 230 and 254 nm Flow rate: 2 mL / min 313156387v3

[0148] A flow diagram showing the key radiosynthetic steps following addition of Na[124I]I to the reaction mixture is provided in FIG.11. Di-tert-Butyl (((S)-6-(3-(4-([77Br]bromophenyl)ureido)-1-(tert-butoxy)-1-

[0149] The synthesis was carried out as described above for the three-step, one-pot radioiodination of aryl rings using 70 MBq NH4[77Br]Br. The reductive elimination reaction was carried out at 80 ⁰C. Compound 22 was purified by HPLC using the method described below and isolated in 59% non-decay corrected radiochemical yield and >99% radiochemical purity. The identity of the radiolabeled product was confirmed by co-injection with a non-radioactive standard (FIG.12). Table 8. Chromatographic Conditions for HPLC Purification of Compound 22 Stationary phase: Symmetry C18, 5 µm, 4.6x50 mm column Mobile phase gradient: (flow rate: 2 ml / min) Time (min) Mobile Phase A (%) Mobile Phase B (%) 0.0 100 0 2.0 100 0 8.0 5 95 9.0 5 95 10.0 100 0 11.0 100 0 UV wavelengths for detection: 230 and 254 nm Flow rate: 2 mL / min Di-tert-Butyl (((S)-6-(3-(4-([211At]astatophenyl)ureido)-1-(tert-butoxy)-1-

[0150] The synthesis was carried out as described above for the three-step, one-pot radioiodination of aryl rings using 10 MBq Na[211At]At. Compound 23 was purified by HPLC using the method described below and isolated in 42% non-decay corrected radiochemical yield and >99% radiochemical purity. The identity of the radiolabeled product was confirmed by co- injection with the non-radioactive iodinated standard (FIG.13). 313156387v3Table 9. Chromatographic Conditions for HPLC Purification of Compound 23 Stationary phase: Symmetry C18, 5 µm, 4.6x50 mm column Mobile phase gradient: Mobile Phase A (%) Mobile Phase B (%)100 0 2.5 100 0 8.0 5 95 9.0 5 95 10.0 100 0 11.0 100 0 UV wavelengths for detection: 230 and 254 nm Flow rate: 2 mL / min Synthesis of tert-Butyl (E)-(((tert-butoxycarbonyl)imino)(3,5-dimethyl-4-oxo-

[0151] The compound was synthesized according to previously published methods (Hu et al., “A Practical, Automated Synthesis of meta-[18F]Fluorobenzylguanidine for Clinical Use,” ACS Chemical Neuroscience 6(11):1870-1879 (2015), which is hereby incorporated by reference in its entirety) and obtained as a white solid (252.5 mg, 74% yield).1H NMR (500 MHz, CD3CN): δ 7.38-7.37 (d, J = 7.0 Hz, 1H, CH), 7.35 (s, 1H, CH), 7.15-7.12 (t, J = 7.5 Hz, 1H, CH), 7.07-7.05 (d, J = 7.5 Hz, 1H, CH), 4.91 (broad s, CH), 4.44 (broad s, 4H, CH2), 4.03 (broad s, 1H, CH), 2.60 (broad s, 6H, CH3),1.49 (s, 9H, CH3),1.43 (s, 9H, CH3).13C NMR (125 MHz, CD3CN): 158.94, 156.59, 152.03, 151.10, 133.92, 132.32, 132.31, 131.28, 126.86, 126.17, 81.72, 79.68, 60.60, 51.60, 32.09, 27.41, 27.31.19F NMR (470 MHz, CD3CN): δ -142.36.1H NMR,13C NMR, and19F NMR data matched those previously reported (Hu et al., “A Practical, Automated Synthesis of meta-[18F]Fluorobenzylguanidine for Clinical Use,” ACS Chemical Neuroscience 6(11):1870-1879 (2015), which is hereby incorporated by reference in its entirety). Synthesis of tert-Butyl (E)-(((tert-butoxycarbonyl)imino)(3,5-dimethyl-4-oxo- 1,3,5-triazinan-1-yl)methyl)(3-(5,5-dioxido-10H-dibenzo[b,e][1,4]thiabismin-10 yl)benzyl)carbamate (25) 313156387v3

[0152] Transmetalation was performed as described above and the product was obtained as colorless crystals (46 mg, 96% yield).1H NMR (500 MHz, CD3CN): δ 8.31-8.29 (dd, J = 7.5 Hz, J = 1.5 Hz, 2H, CH), 7.93-7.92 (J = 6.5 Hz, 2H, CH), 7.76 (s, 1H, CH), 7.67-7.66 (d, J = 7.5 Hz, 1H, CH), 7.46-7.40 (m, 5H, CH), 7.38-7.37 (d, J = 7.0 Hz, 1H, CH), 4.36 (broad s, 4H, CH2), 2.62 (broad s, 6H, CH3),1.42 (s, 9H, CH3),1.34 (s, 9H, CH3).13C NMR (125 MHz, CD3CN): 158.39, 156.01, 151.53, 150.23, 141.61, 138.36, 137.93, 137.84, 137.69, 133.20, 130.64, 128.96, 128.04, 126.10, 81.72, 79.46, 60.21, 51.70, 31.94, 26.97, 26.91. HRMS (ESI, m / z): calcʼd for C35H42BiN5O7S [M+] 885.2658; found 885.2660. Synthesis of Di-tert-butyl ((1-(tert-butoxy)-1-oxo-6-(3-(4-(4,4,5,5-tetramethyl-

[0153] A clean and dried 20 mL glass reaction flask equipped with a magnetic stir bar was charged with urea 26 (195 mg, 0.4 mmol) and isocyanate 27 (98 mg, 0.4 mmol) and dissolved in 5 mL dichloromethane at room temperature. Triethyl amine (41.5 mg, 0.41 mmol) was weighed and added into the reaction mixture solution at room temperature with continuous stirring. The resultant reaction mixture was stirred for 3 hours. The organic solvents were removed under reduced pressure and the crude residue was dissolved in 2 mL acetonitrile and purified by preparative HPLC to obtain the product as a white solid (144 mg, 72% yield). The chromatographic conditions are described below.1H NMR (500 MHz, CD3CN): δ 7.58-7.56 (2H, m, CH), 7.42-7.39 (2H, m, CH), 7.39 (1H, s, NH), 5.54-5.52 (1H, d, NH), 5.43-5.40 (2H, m, NH), 4.16-4.13 (1H, m, CH), 4.08-4.05 (1H, m, CH), 3.17-3.15 (2H, m, CH2), 2.26-2.22 (2H, m, CH2), 1.95-1.93 (1H, m, CH), 1.73-1.69 (2H, m, CH2), 1.63-1.61 (1H, m, CH), 1.50-1.47 (2H, m, CH2), 1.41 (27H, s, CH3), 1.38-1.35 (2H, m, CH2), 1.29 (12H, s, CH3).13C NMR (125 313156387v3MHz, CD3CN): 172.01, 171.57, 157.18, 154.89, 142.97, 135.04, 116.83, 83.17, 81.02, 80.51, 79.64, 53.33, 52.63, 38.64, 31.37, 30.85, 28.96, 27.31, 26.97, 26.88, 26.86, 23.87, 22.07. HRMS (ESI, m / z): calcʼd for C37H61BN4O10[M+] 732.2658; found 732.2686. Table 10. Chromatographic Conditions for HPLC Purification of Compound 28 Stationary phase: Luna C18, 5 µm (Phenyl-Hexyl), 150 × 21.20 mmFlow rate: 20 mL / min Synthesis of Di-tert-Butyl ((1-(tert-butoxy)-1-oxo-6-(3-(4-(trifluoro-l4-

[0154] The conversion of the pinacol borane to the trifluoroborate salt was carried out according to previously published methods (Vedejs et al., “Conversion of Arylboronic Acids into Potassium Aryltrifluoroborates: Convenient Precursors of Arylboron Difluoride Lewis Acids,” J. Org. Chem.60:3020–3027 (1995), which is hereby incorporated by reference in its entirety). Briefly, pinacol borane 28 (50 mg, 0.06 mmol) was dissolved in 8 mL methanol in a 20 mL glass reaction vial. An aqueous solution of potassium hydrogen fluoride (53 mg (60 mmol) in 1.2 ml H2O) was added dropwise into the reaction vial and was stirred continuously at room temperature overnight. The organic solvent was evaporated under reduced pressure, and the reaction mixture was dried azeotropically with acetonitrile. The resultant residue was extracted with 100 mL acetonitrile. The solvent was evaporated under reduced pressure to give trifluoroborate 21 as a white solid (46 mg, 95% yield).1H NMR (500 MHz, CD3CN): δ 7.31- 7.30 (2H, d, CH), 7.12-7.10 (2H, d, CH), 7.00 (1H, s, NH), 5.62-5.60 (1H, d, NH), 5.47-5.46 (1H, d, NH), 5.29-5.27 (1H, t, NH), 4.15-4.11 (1H, m, CH), 4.07-4.05 (1H, m, CH), 3.15-3.10 (2H, m, CH2), 2.25-2.21 (2H, m, CH2), 1.74-1.68 (2H, m, CH2), 1.64-1.58 (1H, m, CH), 1.50- 313156387v31.46 (2H, m, CH2), 1.42 (27H, s, CH3), 1.38-1.35 (2H, m, CH2).13C NMR (125 MHz, CD3CN): 172.16, 171.93, 171.75, 157.22, 155.89, 136.82, 131.48, 118.05, 80.95, 80.54, 79.71, 53.31, 52.59, 38.69, 31.30, 30.87, 29.16, 27.33, 26.97, 26.90, 26.88, 23.82, 21.96.19F NMR (470 MHz, CD3CN): - 141.37. HRMS (ESI, m / z): calcʼd for C31H49BF3N4O8[M+] 673.3645; found 673.3648. Synthesis of Di-tert-Butyl ((1-(tert-butoxy)-6-(3-(4-iodophenyl)ureido)-1- oxohexan-2-yl)carbamoyl)glutamate (29)

[0155] The compound was synthesized as previously reported (Maresca et al., “A Series of Halogenated Heterodimeric Inhibitors of Prostate Specific Membrane Antigen (PSMA) as Radiolabeled Probes for Targeting Prostate Cancer,” Journal of Medicinal Chemistry 52(2):347- 357 (2009), which is hereby incorporated by reference in its entirety) and compound 29 was obtained as white solid (36 mg, 76%).1H NMR (500 MHz, CD3CN): δ 7.55-7.52 (2H, m, CH), 7.306 (1H, s, NH), 7.25-7.22 (2H, m, CH), 5.51-5.49 (1H, d, NH), 5.41-5.38 (2H, m, NH), 4.16- 4.13 (1H, m, CH), 4.08-4.05 (1H, m, CH), 3.17-3.12 (2H, m, CH2), 2.26-2.22 (2H, m, CH2), 1.95-1.93 (1H, m, CH), 1.76-1.74 (2H, m, CH2), 1.63-1.59 (1H, m, CH), 1.49-1.46 (2H, m, CH2), 1.41 (27H, s, CH3), 1.38-1.35 (2H, m, CH2).13C NMR (125 MHz, CD3CN): 172.34, 171.91, 157.47, 155.21, 140.42, 137.51, 120.44, 83.24, 81.33, 80.85, 79.98, 53.62, 52.95, 39.02, 31.74, 31.18, 29.26, 27.67, 27.31, 27.21, 27.19, 22.37. HRMS (ESI, m / z): calcʼd for C31H49IN4O8[M+] 732.2617; found 732.2624. Synthesis of Di-tert-butyl ((6-(3-(4-bromophenyl)ureido)-1-(tert-butoxy)-1-313156387v3

[0156] A clean and dried 20 mL glass reaction flask equipped with a magnetic stir bar was charged with urea 26 (98 mg, 0.2 mmol) and (4-bromophenyl)isocyanate (40 mg, 0.2 mmol). The compounds were dissolved in 5 mL CH2Cl2at room temperature. Triethyl amine (21.2 mg, 0.21 mmol) was weighed and added into the reaction mixture solution at room temperature with continuous stirring. The resulting reaction mixture was stirred for 3 hours. The organic materials were evaporated under reduced pressure and the crude residue was dissolved in 2 mL acetonitrile and purified by preparative HPLC to obtain compound 30 as a white solid (105 mg, 75% yield). The chromatographic method is described below.1H NMR (500 MHz, CD3CN): δ 7.43 (1H, broad singlet, NH) 7.38 (4H, m, CH), 5.58-5.57 (1H, m, NH), 5.50-5.49 (2H, m, NH), 4.20 - 4.17 (1H, m, CH), 4.10-4.09 (1H, m, CH), 3.19-3.17 (2H, m, CH2), 2.29-2.25 (2H, m, CH2), 1.99-1.95 (1H, m, CH), 1.78-1.72 (2H, m, CH2), 1.65-1.58 (1H, m, CH), 1.49-1.45 (2H, m, CH2), 1.44 (27H, s, CH3), 1.37-1.33 (2H, m, CH2).13C NMR (125 MHz, CD3CN): 172.40, 172.34, 171.91, 157.54, 155.30, 139.82, 131.46, 120.08, 81.37, 80.85, 79.99, 53.68, 52.98, 39.03, 31.75, 31.19, 29.29, 27.67, 27.31, 27.21, 27.20, 22.43. HRMS (ESI, m / z): calcʼd for C31H49BrN4O8[M+] (685.6125; found 685.6122) and (687.5012; found 687.5009). Table 11. Chromatographic Conditions for HPLC Purification of Compound (30) Stationary phase: Luna C18, 5 µm (Phenyl-Hexyl), 150 × 21.20 mm Mobile phase gradient: Time (min) Mobile Phase A (%) Mobile Phase B (%) 0.0 90 10 2.0 90 10 11.0 10 90 14.0 10 90 16.0 90 10 17.0 90 10 UV wavelengths for detection: 230 and 254 nm Flow rate: 20 mL / min

[0157] Chromatograms of radiolabeled compounds are provided in FIGs.14-52. Unless otherwise indicated, the chromatograms display the radioHPLC (top) and UV chromatogram (230 nm, bottom) of a co-injection of the indicated purified radiolabeled compound and its non- radioactive standard. Example 3 – Results and Discussion

[0158] Aryl rings can be transferred to nucleophiles at room temperature via regioselective reductive elimination from Bi(V) compounds (FIG.1A) (Debnath et al., “Regioselective Reductive Elimination from Bismuth(V) Compounds for Aryl Transfer to Nucleophile,” Advanced Synthesis & Catalysis 366(5):1128-1136 (2024), which is hereby 313156387v3incorporated by reference in its entirety). This method exploits the comparatively easy synthesis of these non-toxic compounds, which are highly stable with a weakly coordinating fifth ligand (e.g., OTf) and are readily reduced to Bi(III) in the presence of a strongly coordinating nucleophilic ligand. The regioselectivity of nucleophile transfer is governed by relative orientations of the recipient aryl ring and the incoming nucleophile, but requires ortho- substitution on the aryl ring (Debnath et al., “Regioselective Reductive Elimination from Bismuth(V) Compounds for Aryl Transfer to Nucleophile,” Advanced Synthesis & Catalysis 366(5):1128-1136 (2024); which is hereby incorporated by reference in its entirety). Rationale for a Bridged Bismacycle Ligand System

[0159] Treatment of (2,6-dimethylaryl)triphenylbismuth(V) compounds (Fig.1A, compounds 1a-1c) with two equivalents of tetrabutylammonium iodide at room temperature eliminates 1,3-dimethyl-substituted iodoarenes in nearly quantitative conversion within 4 hours (Debnath et al., “Regioselective Reductive Elimination from Bismuth(V) Compounds for Aryl Transfer to Nucleophile,” Advanced Synthesis & Catalysis 366(5):1128-1136 (2024), which is hereby incorporated by reference in its entirety). When the same substrates were treated with Na[125I]I, radiochemical conversion (RCC) was only 30-45% even after 16 hours. This finding highlights the challenge of translating this approach to radiochemistry, for which the nucleophile is present in significantly sub-stoichiometric quantities (~1,000 to 10,000-fold molar deficit). Nearly quantitative RCC was achieved in 4-6 hours at 80 °C, but regioselectivity was compromised in the absence of the two ortho-methyl substituents.

[0160] Inspired by the demonstration of a tethered bis-aryl sulfoximine and sulfone bridged ligand to functionalize (-F, -OTfa) aryl rings (FIG.1B) (Planas et al., “Fluorination of Arylboronic Esters Enabled by Bismuth Redox Catalysis,” Science 367:313-317 (2020); Planas et al., “Mechanism of the Aryl–F Bond-Forming Step from Bi(V) Fluorides,” J. Am. Chem. Soc. 144(32):14489–14504 (2022); Planas et al., “Bismuth-Catalyzed Oxidative Coupling of Arylboronic Acids with Triflate and Nonafolate Salts,” J. Am. Chem. Soc.142(26):11382–11387 (2020), which are hereby incorporated by reference in their entirety), it was hypothesized that a bridging ligand system would conformationally restrain the Bi(V) complex and facilitate the regioselective transfer of aryl groups with or without ortho substituents to (radio)halides. Conformational restraint around the Bi(V) center would ensure the orthogonal alignment of the recipient aryl ring to the halide nucleophile and confer maximal regioselectivity even in the absence of ortho substituents. This hypothesis is consistent with the regioselectivity recently reported by Ball and coworkers (Jurrat et al., “Modular Bismacycles for the Selective C–H Arylation of Phenols and Naphthols,” Nat. Chem.12(3):260–269 (2020); Senior et al., “Meta- 313156387v3Selective C-H Arylation of Phenols Via Regiodiversion of Electrophilic Aromatic Substitution,” Nat Chem.15(3):386-394 (2023); Ruffell et al., “Bismuth-Mediated α-Arylation of Acidic Diketones with Ortho-Substituted Boronic Acids,” Angewandte Chemie International Edition 61(40):e202210840 (2022); Ruffell et al., “Umpolung Synthesis of Pyridyl Ethers by Bi(V)- Mediated O-Arylation of Pyridones,” Angewandte Chemie International Edition 61(51):e202212873 (2022), which are hereby incorporated by reference in their entirety) for the arylation of phenols, naphthols, 1,3-diones, and pyridones using sulfone-bridged Bi(III) bismacycles and by Cornella and colleagues for fluorination of arylboronic acids using bridged sulfoximine and sulfone bismacyle ligand systems (Planas et al., “Fluorination of Arylboronic Esters Enabled by Bismuth Redox Catalysis,” Science 367:313-317 (2020); Planas et al., “Mechanism of the Aryl–F Bond-Forming Step from Bi(V) Fluorides,” J. Am. Chem. Soc. 144(32):14489–14504 (2022), which are hereby incorporated by reference in their entirety) (Fig. 1B). It was reasoned that this innovation would significantly expand the range of drugs and radiopharmaceuticals accessible by bismuth-mediated radiohalogenation, allow multiple radiohalogenated compounds to be synthesized from a single precursor, and advance the possibility of using radiohalides as theranostic pairs.

[0161] The fluorination reactions reported by Planas and colleagues were used stoichiometric amounts of electrophilic halide (fluorine) source and required 16 hours at 90 ⁰C or treating the isolated Bi(V) difluorides with BF3·OEt2at room temperature (Planas et al., “Fluorination of Arylboronic Esters Enabled by Bismuth Redox Catalysis,” Science 367:313-317 (2020); Planas et al., “Mechanism of the Aryl–F Bond-Forming Step from Bi(V) Fluorides,” J. Am. Chem. Soc.144(32):14489–14504 (2022), which are hereby incorporated by reference in their entirety) and therefore unsuitable for radiofluorination. Given the enhanced reactivity of larger halides, especially bromide, iodide, and astatide, in metal-mediated reductive elimination reactions (Winston et al., “Halide-Dependent Mechanisms of Reductive Elimination from Gold(III),” J. Am. Chem. Soc.137(24):7921–7928 (2015); Roy and Hartwig, “Directly Observed Reductive Elimination of Aeyl Halides from Arylpalladium(II) Halide Complexes,” J. Am. Chem. Soc.25(46):13944–13945 (2003), which are hereby incorporated by reference in its entirety), it was envisioned that replacing one fluoride ligand of the Bi(V) with a larger nucleophilic (radio)halide would promote reductive elimination of the corresponding aryl halide under milder conditions (Fig.1C).

[0162] Iodine-125 was used as a representative radionuclide to assess the conformationally restrained bismacycle for the synthesis of aryl (radio)halides. The initial proof- of-concept efforts demonstrated that sulfone-bridged triaryl bismacycle 2a, previously 313156387v3synthesized by Suzuki and Mukaiyama (Suzuki et al., “Synthesis and Reactions of Some New Heterocyclic Bismuth -(iii) and -(v) Compounds.5, 10- Dihydrobenzo[b,e]bismine and Related Systems,” J. Chem. Soc. Perkin Trans.11593–1600 (1992); Sakurai and Mukaiyama, “A New Preparative Method of Aryl Sulfonate Esters by Using Cyclic Organobismuth Reagents,” Heterocycles 74:771–790 (2007); Murafuji et al., “Bismuth Heterocycles Based on a Diphenyl Sulfone Scaffold: Synthesis and Substituent Effect on the Antifungal Activity Against Saccharomyces cerevisiae,” Eur. J. Med. Chem.46(2):519-525 (2011), which is hereby incorporated by reference in its entirety), undergoes oxidation to Bi(V) (3b) with SelectFluor™ in 10 minutes, followed by reductive elimination upon treatment with Na[125I]I at room temperature over 2 hours to obtain [125I]iodobenzene in 74-84% RCC (Fig.1D, n=2). The observation is consistent with the results reported by Suzuki while treating a similar triaryl sulfone-bridged bismacycle with iodine in cold chemistry (Suzuki et al., “Synthesis and Reactions of Some New Heterocyclic Bismuth -(iii) and -(v) Compounds.5, 10- Dihydrobenzo[b,e]bismine and Related Systems,” J. Chem. Soc. Perkin Trans.11593–1600 (1992), which is hereby incorporated by reference in its entirety). Optimization of (Radio)iodoarene Synthesis

[0163] As previously reported, transmetalation of the aryl ring from arylboronic acid to the bridged Bi(III) complex occurred in PhMe / water (99:1) at room temperature to 60 ⁰C (Jurrat et al., “Modular Bismacycles for the Selective C–H Arylation of Phenols and Naphthols,” Nat. Chem.12(3):260–269 (2020); Senior et al., “Meta-Selective C-H Arylation of Phenols Via Regiodiversion of Electrophilic Aromatic Substitution,” Nat. Chem.15(3):386-394 (2023), which is hereby incorporated by reference in its entirety), aryl boronic acids, pinacol borane esters, and potassium trifluoroborates were investigated as substrates to identify reactions that could be accomplished at room temperature (Fig.3) in acetonitrile. Electrophilic bismacycle Bi(III) triflate 4 was prepared by treating bismacycle(III) iodide with silver triflate at room temperature. Modest transmetalation of phenylboronic acid 5a (Fig.3, entries 1-4) and poor transmetalation of pinacol borane 5b (Fig.3, entries 5-7) to 4 was observed at 2 hours. Consistent with published reports (Planas et al., “Fluorination of Arylboronic Esters Enabled by Bismuth Redox Catalysis,” Science 367:313-317 (2020), which is hereby incorporated by reference in its entirety), addition of KF (1 equivalent) improved transmetalation yield (Fig.3, entries 3 and 6), while, in contrast to reports (Jurrat et al., “Modular Bismacycles for the Selective C–H Arylation of Phenols and Naphthols,” Nat. Chem.12(3):260–269 (2020); Senior et al., “Meta-Selective C-H Arylation of Phenols Via Regiodiversion of Electrophilic Aromatic Substitution,” Nat. Chem.15(3):386-394 (2023), which is hereby incorporated by reference in its 313156387v3entirety), K2CO3(1 equivalent) had a slight effect (Fig.3, entries 4 and 7) in the absence of H2O. Nearly quantitative transmetalation of potassium aryl trifluoroborates 5c and 5d to 4 was observed within 1 hour at room temperature (Fig.3, entries 8 and 9). Under identical reaction conditions, electron-deficient aryl trifluoroborate 5e underwent transmetalation with a 17% yield (Fig.3, entry 10), which improved to 26% in the presence of KF (Fig.3, entry 11) in 2 hours, however, 90% transmetalation can be achieved in 48 hours without the presence of KF (Fig.3, entry 12).

[0164] Compound 2a was oxidized within 10 min with one equivalent of F-TEDA (SelectFluor™) or 2,6-dichloro-1-fluoropyridinium triflate (Cl2FPyOTf). However, isolation of Bi(V) compounds 3a and 3b was unsuccessful, plausibly due to the rapid exchange of the fifth ligand and the decomposing nature during the workup and isolation process at room temperature. This suggested a one-pot synthesis as a method of radiohalogenation that maximizes the reactivity of the transiently available Bi(V) species. A two-step, one-pot radiosynthesis of electron-neutral, electron-rich, and electron-deficient [125I]iodoarenes was initially performed at room temperature using Na[125I]I as the nucleophile source (Fig.53A). RCC was determined by radio-HPLC. Significantly, although Na[125I]I is dissolved in an excess of NaOH, selective incorporation of [125I]iodide rather than hydroxide into the recipient aryl ring was observed. The formation of [¹²⁵I]iodoarene was confirmed by co-injection with the non-radioactive standard in HPLC, comparing peaks from both the UV and radio detectors. A competitive study under non- radioactive conditions was conducted by treating Bi(V) complexes (3a and 3b) with a mixture of TBAI and aqueous NaOH (1 equivalent each). Reaction progress monitored by ¹H NMR showed exclusive formation of iodobenzene as the reductive elimination product, along with Bi(III)-F as the byproduct (Fig.54A). Even in the presence of excess aqueous NaOH (10 equivalents), only iodobenzene was formed. This outcome highlights the advantage of bismuth-mediated radioiodination, which remains effective under highly basic aqueous conditions, unlike copper- mediated methods that are incompatible with large amounts of water and strong base (Zhou et al., “A Practical Protocol for Large-scale Copper-mediated Radioiodination of Organoboronic Precursors: Radiosynthesis of [123 I]KX-1 for Auger Radiotherapy,” J. Labelled Comp. Radiopharm.66(13):435-439 (2023), which is hereby incorporated by reference in its entirety).

[0165] Excess or stoichiometric amounts of oxidant decreased RCC (Fig.53A, entries 1- 2 and 6-7), while 0.8 equivalents improved radioiodine incorporation (Fig.53A, entries 3 and 8). It was postulated that in the presence of excess oxidant, the unreacted oxidant reacts with iodide to form short-lived iodine monofluoride, which then undergoes disproportionation to yield I₂ and IF₅. During this process, the Bi(V) complex is reduced back to the Bi(III) starting material, as 313156387v3confirmed by ¹H NMR, leading to reduced RCC. Notably, the addition of 5% D2O in CD3CN suppressed the undesired reverse reduction of Bi(V) to Bi(III) starting material, instead promoted the forward reductive elimination from Bi(V), resulting in improved iodobenzene formation (95% yield), which is consistent with the observation in radiochemistry. RCC was consistently higher when Cl2FPyOTf was used as an oxidant (Fig.53A, entries 6-10). After the addition of Na[125I]I, the reductive elimination step was completed within 2 hours. Under these conditions, RCC to [125I]iodobenzene exceeded 99% (Fig.53A, entry 8). Comparable conversion was also observed for the electron-rich 4-methoxyphenyl ring (Fig.53A, entry 9), while 91% RCC was observed for the electron-deficient 4-trifluoromethylphenyl group (Fig.53A, entry 10).

[0166] To expand the applications of this methodology, a three-step, one-pot synthesis was developed (Fig.53B). A stoichiometric excess of bismacycle 4 decreased RCC (Fig.53B, entries 1, 2, 6, and 7), so 0.9 equivalents of Bi(III) complex and 0.8 equivalents of oxidizing agent were used. Using this stoichiometry, RCC ≥ 95% was achieved using either 5a or 5c as the starting material (Fig.53B, entries 3, 7, 11, and 12). The addition of K2CO3or KF imposed a detrimental effect on RCC (Fig.53B, entries 4, 9, and 10). The transmetalation reaction was carried out for 2 hours using 5a, for 4 hours using 5b, and for 1 hour using 5c. Remarkably, even though the prior studies indicate that transmetalation of 5a and 5b to the Bi(III) complex 4 is incomplete after 2 hours (Fig.3A, entries 1 and 5), it was still possible to achieve 99% and 81% RCC, respectively, to [125I]iodobenzene in the one-pot reaction (Fig.53B, entries 7 and 11). This highlights that despite inefficient transmetalation, upon oxidation, it produces sufficient Bi(V) complex to react with [125I]iodide to yield [125I]iodobenzene with excellent yield. The postulated reaction mechanism is depicted in Fig.54A, which is consistent with the mechanism proposed by Cornella and coworkers for the Bi-catalyzed coupling of arylboronic acid and triflate salts (Planas et al., “Bismuth-Catalyzed Oxidative Coupling of Arylboronic Acids with Triflate and Nonafolate Salts,” J. Am. Chem. Soc.142(26):11382 – 11387 (2020), which is hereby incorporated by reference in its entirety). Each step of the reaction was monitored by1H- NMR in cold chemistry, and the formation of iodobenzene and Bi(III)-F byproduct were confirmed by comparing the relevant standards. Collectively, these experiments demonstrate that a three-step, one-pot synthesis is a feasible route to radiolabeled iodobenzene production even when [125I]iodide is present as a substantially limiting reagent (~1,000 to 10,000 fold molar deficit). Mechanistic Observation of Regioselectivity

[0167] To rationalize the regioselectivity of reductive elimination (RE), the geometry and orientation of aryl rings around the Bi(V) complex was investigated by computational modeling. 313156387v3Previous work showed that the 2,6-dimethyl substituted aryl ring imparted regioselectivity to the RE step by inducing an orthogonal orientation between the nucleophile and the recipient aryl ring (Debnath et al., “Regioselective Reductive Elimination from Bismuth(V) Compounds for Aryl Transfer to Nucleophile,” Advanced Synthesis & Catalysis 366(5):1128-1136 (2024), which is hereby incorporated by reference in its entirety).

[0168] Therefore, it was investigated whether the sulfone bridge conformationally restrained the nucleophile and receptor aryl ring to optimal geometry for transfer (Fig.54B). Bi(V) bismacycle 7a was selected as a model compound. Compound 7a demonstrated a distorted trigonal bipyramidal geometry where the sulfone-bridged aryl rings occupied one axial and one equatorial position, and the unbridged aryl receptor ligand was positioned in an equatorial coordination site (Fig.56B). The larger iodide and smaller fluoride ligands occupied the remaining equatorial and axial coordination sites, respectively (Fig.54B). The unbridged equatorial aryl ligand can undergo free rotation to align orthogonally to the axial coordination plane, resulting in reactive confirmation for reductive elimination. Furthermore, the equatorial iodide ligand can undergo Berry pseudo-rotation (Ugi et al., “Berry Pseudorotation and Turnstile Rotation,” Acc. Chem. Res.4(8):288–296 (1971), which is hereby incorporated by reference in its entirety) to the axial position by overcoming a 5.70 kcal / mol energy barrier. It was hypothesized that the axial iodide sterically hinders further rotation of the unbridged aryl ring to ensure HOMO-LUMO orbital overlap between iodide and ipso carbon of the aryl ring, respectively. It was further hypothesized that fluoroarene formation was not observed because the axial fluoride does not restrict the rotation of the unbridged aryl ring and has a higher energy HOMO that makes orbital overlap, and, consequently, reductive elimination less favorable. Modeling shows that ortho-substitution of the unbridged aryl ring in Bi(V) bismacycle 7b decreases the energetic barrier to iodine Berry pseudo-rotation to 1.25 kcal / mol (Fig.54C). This observation is consistent with our experimental observations, where the ortho-substituted aryl rings transferred to [125I]iodide faster (1-2 hours) than the unsubstituted aryl rings (4-6 hours). Evaluation of Substrate Scope and Functional Group Tolerance for Bismuth- Mediated [125I]Iodination

[0169] The substrate scope of the one-pot, three-step reaction was explored using aryl and heteroaryl boron compounds with different functional group substituents (Fig.55A). [125I]Iodide (t1 / 2= 60 d) was the model radioisotope for these studies, but the reactions were tested under conditions and reaction times suitable for other isotopes of iodine. Bi(V) complexes were prepared in sealed containers using dried solvents, with no additional precautions taken to exclude air or moisture. The complexes were then reacted with Na[¹²⁵I]iodide in a 0.1 N 313156387v3NaOH(aq) solution. [125I]Iodide incorporation into 2,6-dimethylaryl rings with para substituents occurred with quantitative RCC at room temperature within 4 hours, irrespective of the nature of the substituent (Fig.55A, 8a-8g). However, the reaction was more rapid (complete within 1-2 hours) when electron-neutral (8a) or electron-withdrawing para substituents (8c-8g) were present.1,3-Dichloro- (9a) and 1-bromo-3-chloro-2-[125I]iodobenzene (9b) formed after 2 hours with 88% and ≥99% RCC, respectively. However, RCC for 1,3-difluoro analog 9c was only 39% and 67% after 2 hours and 6 hours, respectively, of reaction time. The lower RCC was attributed to the high electron density of the fluorine atoms adjacent to the ipso carbon of the receptor arene interfering with aryl transfer to iodide. Reactions with aryl trifluoroborate substrates bearing a variety of single ortho substituents, including methyl (9d, ≥99%), isopropyl (9e, ≥99%), bromo (9f, 83%), ester (9g, 99%), and methoxy (9h, ≥99%) groups proceeded with good conversion in 4 hours. These reaction times, as compared to 1-2 hours achievable with the 2,6-dimethyl arenes 8a and 8c-8g, indicate that a single ortho substituent is not enough to guarantee optimized orthogonal ring orientation for the aryl group transfer. An electron-withdrawing substituent at the para position slightly compromised RCC (6c, 69% and 6d, 58%), which was attributed to poor transmetalation. The Boc-protected indole (10, 83%), naphthalene (11, ≥99%), and 6-fluoro-2- methyl substituted pyridine (12, 99%) groups all demonstrated excellent incorporation of [125I]iodide. To further investigate substrate scope, the reactions of aryl boronic acids were also explored and nearly quantitative RCC was observed after 4 hours of reductive elimination with electron-rich (8h, 6b, 13) or electron-deficient (14) aryl rings when T-FEDA was used as the oxidant. These results agreed with the trends observed with the trifluoroborate substrates and additionally highlighted that meta-substitution is well tolerated. The [125I]iodination of boronic acids of quinoline (35, 31%) and pyridine (36, 35%) in electron-poor position resulted in lower RCC, seemingly due to the poor transmetalation. Bismuth-Mediated [77Br]Bromination and [211At]Astatination of Aryl Boron Compounds

[0170] To test the suitability of the sulfone-bridged bismacycle for general radiohalogenation, incorporation of [77Br]bromine (t1 / 2= 56 h) and [211At]astatine (t1 / 2= 7.2 h) via the one-pot reaction was determined. These radioisotopes decay by emission of an Auger electron and alpha particle, respectively, and are potential agents for targeted radionuclide therapy (Idrissou et al., “Targeted Radionuclide Therapy Using Auger Electron Emitters: The Quest for the Right Vector and the Right Radionuclide,” Pharmaceutics 13:980 (2021); Guérard et al., “Production of [(211)At]-astatinated Radiopharmaceuticals and Applications in Targeted α-particle Therapy,” Cancer Biother. Radiopharm.28(1):1-20 (2013), which are hereby 313156387v3incorporated by reference in their entirety). The use of 5c resulted in 17% [77Br]bromide incorporation at room temperature after 8 hours of reductive elimination. However, when the reductive elimination was performed at 80 ⁰C, the RCC increased to 88% after 4 hours (Fig.55B, 17a). Heating was likely necessary to overcome the poorer HOMO-LUMO overlap of the bromine and ipso carbon of the aryl ring caused by the smaller size and higher HOMO energy of bromide compared to iodide. Under these conditions, 2,6-dimethylaryl rings containing para substituents, such as methyl (17b, 50%), aldehyde (17c, 27%), cyano (17d, 72%), and methoxy (17g, 83%) groups, were [77Br]brominated at lower RCC than was observed for the [125I]iodination reactions but with sufficient conversion for preparation of radiopharmaceuticals. Larger ortho substituents were well-tolerated (17e, 72%). In the absence of ortho substituents, an electron-donating para-methoxy substituent (17h, 88%) increased RCC compared to the electron-withdrawing trifluoromethane substituent (17f, 56%). This trend mirrors what was observed with iodine as the nucleophile. Although RCC could likely be increased by further optimization of the reaction conditions, these proof-of-concept studies highlight the suitability of the method for radiobromination. [211At]Astatination of 5a and 5c was accomplished in comparable RCC (78% and 79%, respectively) at room temperature (Fig.55C, 18a). Reductive elimination was initially restricted to 2 hours for these trials due to the short half-life of astatine- 211. Ortho substitution decreased aryl transfer to [211At]astatide (Fig.55C, 18b: 63%, 18c: 53%) even after allowing the reductive elimination step to proceed for 4 hours. It was proposed that the larger size of astatine reduces reaction rate due to steric hindrance with the ortho aryl substituents that prevents optimal HOMO-LUMO overlap. This reactivity trend is the reverse of iodine, for which ortho substitution increased the RCC of reductive elimination. In both cases, regioselectivity was preserved, as only the unbridged aryl ring was transferred to the radiohalogen. The electron-rich para-methoxy group (18d) facilitated [211At]astatide incorporation in 72% RCC after 2 hours. Therefore, while less efficient than radioiodination, these representative examples confirm that the one-pot bismuth-mediated radioastatination of aryl rings is feasible in short reaction times at room temperature. Bismuth-Mediated [18F]Fluorination of Unsubstituted Arenes

[0171] To test the universality of this method for radiohalogenation, bismuth-mediated aryl transfer reaction to [18F]fluoride was explored. Using bismacyle 2a as the precursor, no incorporation of [18F]fluorine was evident after 1 hour, even after heating to 120 °C (Fig.55D). This outcome was not surprising, given the absence of non-radioactive fluorine incorporation in the previous experiments. Prior bismuth-mediated fluorination in cold chemistry was accomplished using an electrophilic fluorine source with 16 hours at 90 ⁰C or treating the 313156387v3isolated Bi(V) difluorides with BF3·OEt2at room temperature (Planas et al., “Fluorination of Arylboronic Esters Enabled by Bismuth Redox Catalysis,” Science 367:313-317 (2020); Planas et al., “Mechanism of the Aryl–F Bond-Forming Step from Bi(V) Fluorides,” J. Am. Chem. Soc. 144(32):14489–14504 (2022), which are hereby incorporated by reference in their entirety), therefore, those conditions are incompatible for [18F]fluorination (t1 / 2= 109 min) of aryl rings. Next-generation ligand design may enable the bismuth-mediated [18F]fluoride incorporation into aryl rings with state of the art supplied nucleophilic [18F]fluoride. Preparation of Radiopharmaceuticals

[0172] To demonstrate the suitability of the method for preparing radiopharmaceuticals, two model compounds were selected whose synthesis could be accomplished in low yields by conventional methods or required the use of toxic organometallic precursors. [125I]Iodine incorporation into a protected precursor of meta-iodobenzylguanidine (MIBG) (Shapiro and Gross, “Radiochemistry, biochemistry, and kinetics of131I-metaiodobenzylguanidine (MIBG) and123I-MIBG: Clinical implications of the use of123I-MIBG,” Med. Pediatr. Oncol.15:170-177 (1987), which is hereby incorporated by reference in its entirety) (Fig.56A) was 80%, and the compound was isolated in 53% non-decay corrected radiochemical yield (ndcRCY) and ≥99% radiochemical purity (RCP). Further work will establish whether radiohalogenation can be achieved in the absence of protecting groups. The final deprotection step was not performed in this proof-of-concept study.

[0173] Radiohalide incorporation into a t-butyl protected precursor of MIP-1095 (Barrett et al., “First-in-Man Evaluation of 2 High-Affinity PSMA-Avid Small Molecules for Imaging Prostate Cancer,” J. Nucl. Med.54:380-387 (2013), which is hereby incorporated by reference in its entirety) was also highly successful (Fig.56B). The incorporation of [77Br]bromine to 22 required heating at 80 ⁰C for 4 hours and resulted in 59% ndcRCY, whereas [211At]astatination and [124 / 125I]iodination occurred at room temperature. [211At]Astatinated compound 23 was isolated in 42% ndcRCY and ≥99% RCP. The radiolabeled intermediates of [124 / 125I]MIP-1095 were purified by semi-prep HPLC and deprotected to afford [124 / 125I]MIP-1095 in 64% averaged ndcRCY (n=3) and ≥99% RCP. Molar activity exceeded 250 GBq / µmol. The purified products were also chemically pure because the non-radiolabeled precursors and by-products, including the boron trifluoride and boronic acid precursors, unreacted Bi(III) compound, oxidizing agent, and Bi(V) complex, have significantly shorter retention times on the C18 reverse-phase column than the radiolabeled compound.

[0174] As further validation of the synthetic method disclosed herein, microPET / CT imaging studies of LNCaP xenograft mice were conducted using [124I]MIP-1095 prepared by the 313156387v3bismuth-mediated radiohalogenation protocol (Fig.56C). The compound was well tolerated by the mice, and the distribution of [124I]MIP-1095 in these studies agrees with previously published images (Hillier et al., “Preclinical Evaluation of Novel Glutamate-Urea-Lysine Analogues That Target Prostate-Specific Membrane Antigen as Molecular Imaging Pharmaceuticals for Prostate Cancer,” Cancer Res.69:6932-6940 (2009), which is hereby incorporated by reference in its entirety). These studies confirm that, even without further optimization, the radiosynthesis method effectively incorporates radiohalides into complex drug molecules. This demonstrates the robustness of the bismuth-mediated radiohalogenation technique in the presence of water in basic solution and its suitability for radiopharmaceutical synthesis intended for in vivo studies.

[0175] Disclosed herein is a robust, three-step, one-pot method for regioselective bismuth-mediated radiohalogenation of aryl boron compounds that leads to high incorporation of isotopes of bromine, iodine, and astatine under mild conditions. This method is effective with electron-rich, deficient, neutral, and sterically crowded aryl and heteroaryl rings. Electron- deficient positions in aryl rings showed lower radiochemical incorporation, evidently attributed to poor transmetalation. Theoretical evidence for regioselectivity, which can be explained by the geometry at the Bi(V) center is provided. The synthetic method exhibits broad substrate scope and functional group tolerance and can be used to prepare radiopharmaceuticals that are otherwise inaccessible under such mild conditions or without using toxic organometallic reagents. This method provides a new tool for the synthesis of radiohalogenated radiopharmaceuticals for nuclear imaging and radiotherapy in preclinical and clinical laboratories.

[0176] Although preferred embodiments have been depicted and described in detail herein, it will be apparent to those skilled in the relevant art that various modifications, additions, substitutions, and the like can be made without departing from the spirit of the invention and these are therefore considered to be within the scope of the invention as defined in the claims which follow. 313156387v3

Claims

WHAT IS CLAIMED IS:

1. A process for preparation of a compound of Formula (I):whereinis a point of attachment of ring A to ring B or, if ring B is absent, to R1or R2group; is a single or a double bond; ring B is optional and, if present, is aryl or heteroaryl; Hal is halogen or radioisotope of halogen; X is independently selected at each occurrence from C, N, NH, O, or S; R1is optional and, if present, is selected from the group consisting of H, halogen, CN, C1-6alkyl, -OC1-6alkyl, CF3, -C(O)H, -C(O)C1-6alkyl, -C(O)OC1-6alkyl,R2is optional and, if present, is selected from the group consisting of H, halogen, CN, C1-6alkyl, -OC1-6alkyl, CF3, -C(O)H, -C(O)C1-6alkyl, -C(O)OC1-6alkyl, 313156387v3R3is optional and, if present, is selected from the group consisting of H, halogen, CN, C1-6alkyl, -OC1-6alkyl, CF3, -C(O)H, -C(O)C1-6alkyl, -C(O)OC1-6alkyl,R4is optional and, if present, is selected from the group consisting of H, halogen, CN, C1-6alkyl, -OC1-6alkyl, CF3, -C(O)H, -C(O)C1-6alkyl, -C(O)OC1-6alkyl, 313156387v3,R5is optional and, if present, is selected from the group consisting of H, halogen, CN, C1-6alkyl, -OC1-6alkyl, CF3, -C(O)H, -C(O)C1-6alkyl, -C(O)OC1-6alkyl,n is independently selected at each occurrence from 1, 2, 3, 4, or 5; said process comprising: providing a compound of Formula (IIa) or (IIb):wherein R is halogen; 313156387v3R´ is optional and, if present, is independently H, OCH3, or CF3; and X1is OTf or BF4; providing a compound of Formula (III): R6-Hal (III), wherein R6is Na, K, Cs, NH4, or (C1-6alkyl)4N; and reacting the compound of Formula (IIa) or (IIb) with the compound of Formula (III) under conditions effective to produce the compound of Formula (I).

2. A process for preparation of a compound of Formula (I):whereinis a point of attachment of ring A to ring B; is a single or a double bond; ring B is optional and, if present, is selected from the group consisting of C5aryl, C6aryl, C4heteroaryl, C5heteroaryl, and C6heteroaryl; Hal is halogen or radioisotope of halogen; X is independently selected at each occurrence from C or N; 313156387v3R1is optional and, if present, is selected from the group consisting of H, halogen, CN, C1-6alkyl, -OC1-6alkyl, CF3, -C(O)H, -C(O)C1-6alkyl, -C(O)OC1-6alkyl,R2is optional and, if present, is selected from the group consisting of H, halogen, CN, C1-6alkyl, -OC1-6alkyl, CF3, -C(O)H, -C(O)C1-6alkyl, -C(O)OC1-6alkyl,R3is optional and, if present, is selected from the group consisting of H, halogen, CN, C1-6alkyl, -OC1-6alkyl, CF3, -C(O)H, -C(O)C1-6alkyl, -C(O)OC1-6alkyl,R4is optional and, if present, is selected from the group consisting of H, halogen, CN, C1-6alkyl, -OC1-6alkyl, CF3, -C(O)H, -C(O)C1-6alkyl, -C(O)OC1-6alkyl,313156387v3R5is optional and, if present, is selected from the group consisting of H, halogen, CN, C1-said process comprising: providing a compound of Formula (IIa) or (IIb):wherein R is halogen; and X1is OTf or BF4; providing a compound of Formula (III): R6-Hal (III), wherein R6is Na, K, or (CH3CH2CH2CH2)4N; and reacting the compound of Formula (IIa) or (IIb) with the compound of Formula (III) under conditions effective to produce the compound of Formula (I).

3. The process according to claim 1 or 2, wherein Hal is selected from the group consisting of I, Br, Cl, F,18F,123I,76Br,77Br,124I,125I,131I,34mCl, and211At.

4. The process according to claim 1 or 2, wherein ring A is selected from the group consisting313156387v35. The process according to claim 1 or claim 2, wherein R1, R2, R3, R4, or R5is6. The process according to claim 1, wherein R1, R2, R3, R4, or R5is ,7. The process according to claim 1 or claim 2, wherein the compound of Formula (I) is 313156387v38. The process according to claim 1, wherein the compound of Formula (I) is9. The process according to claim 1 or 2, wherein the compound of Formula (I) has a Formula (I´): 313156387v3Hal R5X X 4 X X R X R2R3(I´).

10. The process according to any one of claims 1-9, wherein the compound of Formula (III) is selected from the group consisting of tetrabutylammonium iodide, tetrabutylammonium fluoride, tetrabutylammonium chloride, tetrabutylammonium bromide, tetraethylammonium iodide, tetraethylammonium fluoride, tetraethylammonium chloride, tetraethylammonium bromide, NaF, NaBr, NaI, Na[18F], Na[123I], Na[76Br], Na[77Br], Na[124I], Na[125I], Na[131I], Na[34mCl] and Na[211At].

11. The process according to any one of claim 1 or 2, wherein said reacting the compound of Formula (IIa) or (IIb) with the compound of Formula (III) is carried out at a temperature of from about 0°C to about 120°C.

12. The process according to claim 11, wherein said reacting the compound of Formula (IIa) or (IIb) with the compound of Formula (III) is carried out at room temperature.

13. The process according to claim 11, wherein said reacting the compound of Formula (IIa) or (IIb) with the compound of Formula (III) is carried out at a temperature of from about 20°C to about 30°C.

14. The process according to claim 11, wherein said reacting the compound of Formula (IIa) or (IIb) with the compound of Formula (III) is carried out at a temperature of from about 70°C to about 90°C.

15. The process according to claim 1 or 2, wherein said reacting the intermediate compound of Formula (IIa) or (IIb) with the compound of Formula (III) is carried out in a solvent selected from the group consisting of acetonitrile, dioxane, tetrahydrofuran, dimethylformamide, and dimethylsulfoxide. 313156387v316. The process according to claim 1 or 2, wherein said reacting the compound of Formula (IIa) or (IIb) with the compound of Formula (III) is carried out for from about 30 min to about 24 hours.

17. The process according to claim 16, wherein said reacting the compound of Formula (IIa) or (IIb) with the compound of Formula (III) is carried out for from about 1 hour to about 5 hours.

18. The process according to claim 1 or 2, wherein R is F.

19. The process according to claim 1, wherein said providing a compound of Formula (IIa) or (IIb) comprises: providing a compound of Formula (A):providing an oxidizing agent; and reacting the compound of Formula (A) with the oxidizing agent under conditions effective to produce the compound of Formula (IIa) or (IIb).

20. The process according to claim 19, wherein said providing a compound of Formula (A) comprises: providing a compound of Formula (IV):wherein LG is a leaving group; providing a compound of Formula (V): 313156387v3wherein Y is Cl, F, or OTf ; and reacting the compound of Formula (IV) with the compound of Formula (V) under conditions effective to produce the compound of Formula (A).

21. The process according to claim 1 or claim 2, wherein said providing a compound of Formula (IIa) or (IIb) comprises: providing a compound of Formula (IV):wherein LG is a leaving group; providing a compound of Formula (V):reacting the compound of Formula (IV) with the compound of Formula (V) under conditions effective to produce the compound of Formula (IIa) or (IIb). OH B 22. The process according to claim 20 or 21, wherein LG isOH,, BF3K, or -OTf.

23. The process according to claim 21, wherein said reacting the compound of Formula (IV) with the compound of Formula (V) is carried out in the presence of an oxidizing agent. 313156387v324. The process according to claim 19 or 23, wherein the oxidizing agent is selected from the group consisting of 1-chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octane bis(tetrafluoroborate) (SelectfluorTM), 2,6-dichloro-1-fluoropyridinium triflate, and 2,6-dichloro- 1-fluoropyridinium tetrafluoroborate.

25. The process according to claim 20 or 21, wherein said reacting the compound of Formula (IV) with the compound of Formula (V) is carried out in acetonitrile or CD3CN.

26. The process according to any one of claims 20-25, wherein said reacting the compound of Formula (IV) with the compound of Formula (V) is carried out at a temperature of from about 20°C to about 40°C.

27. The process according to claim 26, wherein said reacting the compound of Formula (IV) with the compound of Formula (V) is carried out at a temperature of from about 20°C to about 30°C.

28. The process according to claim 20 or 21, wherein said reacting the compound of Formula (IV) with the compound of Formula (V) is carried out for from about 5 min to about 48 hours.

29. The process according to claim 28, wherein said reacting the compound of Formula (IV) with the compound of Formula (V) is carried out for from about 15 min to about 2 hours.

30. The process according to claim 20 or 21, wherein said reacting the compound of Formula (IV) with the compound of Formula (V) is carried out in the presence of an additive.

31. The process according to claim 30, wherein the additive is K2CO3.

32. The process according to claim 20 or 21, wherein said reacting the compound of Formula (IV) with the compound of Formula (V) is carried out in the presence of an activator.

33. The process according to claim 32, wherein the activator is KF. 313156387v334. The process according to claim 1 or 2, further comprising: reacting the compound of Formula (I):with a solution of HCl in dioxane to produce the compound of Formula (I) wherein R1,35. The process according to claim 1 or 2, wherein Hal is a radioisotope of halogen (radiohalogen). 313156387v3

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