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A Third Generation Potentially Bifunctional Trithiol Chelate, Its ^nat,1XXSb(III) Complex, and Selective Chelation of Radioantimony (¹¹⁹Sb) from Its Sn Target.

ABSTRACT: The therapeutic potential of the Meitner-Auger- and conversion-electron emitting radionuclide ¹¹⁹Sb remains unexplored because of the difficulty of incorporating it into biologically targeted compounds. To address this challenge, we report the development of ¹¹⁹Sb production from electroplated tin cyclotron targets and its complexation by a novel trithiol chelate. The chelation reaction occurs in harsh solvent conditions even in the presence of large quantities of tin, which are necessary for production on small, low energy (16 MeV) cyclotrons. The ¹¹⁹Sb-trithiol complex has high stability and can be purified by HPLC. The third generation trithiol chelate and the analogous stable ^natSb-trithiol compound were synthesized and characterized, including by single-crystal X-ray diffraction analyses.

SUBMITTER: Olson AP

PROVIDER: S-EPMC8800004 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:Introduction: Radiohybrid (rh) ligands, a novel class of prostate-specific membrane antigen (PSMA)-targeted radiopharmaceuticals, can be labeled either with [18F]fluorine via isotopic exchange or with radiometals (such as [68Ga]Gallium, [177Lu]Lutetium, [225Ac]Actinium). Among these, [18F, natGa]rhPSMA-7 has recently entered clinical assessment.Aim: Since [18F, natGa]rhPSMA-7 is composed of four stereoisomers ([18F, natGa]rhPSMA-7.1, -7.2, -7.3 and -7.4), we initiated a preclinical selection process to identify the isomer with the most favorable pharmacokinetics for further clinical investigation.Methods: A synthetic protocol for enantiopure [19F, natGa]rhPSMA-7 isomers has been developed. The comparative evaluation of the four isomers comprised human serum albumin binding, lipophilicity, IC50, internalization and classical biodistribution studies and competition experiments in LNCaP tumor-bearing CB-17 SCID mice. In addition, a radio high-performance liquid chromatography-based method was developed allowing quantitative, intraindividual comparison of [18F, natGa]rhPSMA-7.1 to -7.4 in LNCaP tumor-bearing mice.Results: Cell studies revealed high PSMA affinity and internalization for [18/19F, natGa]rhPSMA-7.2, -7.3 and -7.4, whereas [18/19F, natGa]rhPSMA-7.1 showed approximately twofold lower values. Although the biodistribution profile obtained was typical of PSMA inhibitors, it did not allow for selection of a lead candidate for clinical studies. Thus, an intraindividual comparison of all four isomers in LNCaP tumor-bearing mice was carried out by injection of a diastereomeric mixture, followed by analysis of the differential uptake and excretion pattern of each isomer. Based on its high tumor accumulation and low uptake in blood, liver and kidneys, [18F, natGa]rhPSMA-7.3 was identified as the preferred isomer and transferred into clinical studies.Conclusion: [18F, natGa]rhPSMA-7.3 has been selected as a lead compound for clinical development of a [18F]rhPSMA-based candidate. The intraindividual differential uptake and excretion analysis in vivo allowed for an accurate comparison and assessment of radiopharmaceuticals.

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A Third Generation Potentially Bifunctional Trithiol Chelate, Its ^nat,1XXSb(III) Complex, and Selective Chelation of Radioantimony (¹¹⁹Sb) from Its Sn Target.

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A Third Generation Potentially Bifunctional Trithiol Chelate, Its nat,1XXSb(III) Complex, and Selective Chelation of Radioantimony (119Sb) from Its Sn Target.

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A Third Generation Potentially Bifunctional Trithiol Chelate, Its ^nat,1XXSb(III) Complex, and Selective Chelation of Radioantimony (¹¹⁹Sb) from Its Sn Target.