Abstract
IntroductionRadiohybrid (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.AimSince [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.MethodsA 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.ResultsCell 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.
Highlights
Radiohybrid ligands, a novel class of prostate-specific membrane antigen (PSMA)-targeted radi‐ opharmaceuticals, can be labeled either with [18F]fluorine via isotopic exchange or with radiometals
During the last decade, advancements in the field of prostate-specific membrane antigen (PSMA)-targeting radiopharmaceuticals have had significant impact on the clinical management of patients suffering from prostate cancer [1,2,3]. [68Ga]Ga-PSMA-11 [4, 5] in particular has been the subject of extensive evaluation and has already
Analytical characterization Previously produced clinical batches of diastereomeric [19F, natGa]rhPSMA-7 (n = 6) were analyzed by high-performance liquid chromatography (HPLC) to retrospectively determine the abundance of the individual isomers [19F, natGa]rhPSMA-7.1 to -7.4
Summary
Radiohybrid (rh) ligands, a novel class of prostate-specific membrane antigen (PSMA)-targeted radi‐ opharmaceuticals, can be labeled either with [18F]fluorine via isotopic exchange or with radiometals (such as [68Ga] Gallium, [177Lu]Lutetium, [225Ac]Actinium). Due to the superior nuclear properties of the fluorine-18 radionuclide and accompanying logistic and economic advantages [10, 11], a shift of interest from 68Ga-labeled PSMA tracers toward 18F-labeled analogues has been observed in recent years [12,13,14] In this context radiohybrid (rh) PSMA ligands, developed by our group, form a novel class of radiopharmaceuticals, which combine a Silicon–Fluoride–Acceptor (SiFA) and a metal chelate (or a chelator) in a single molecule [15]. The novel tracer outperformed morphologic imaging for N-staging of high-risk primary prostate cancer, with efficacy comparable to the literature data for [68Ga]Ga-
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