Preclinical comparison of four [18F, natGa]rhPSMA-7 isomers: influence of the stereoconfiguration on pharmacokinetics
Alexander Wurzer, Mara Parzinger, Matthias Konrad, Roswitha Beck, Thomas Günther Pomorski, Veronika Felber, Stefanie Felicitas Färber, Daniel Di Carlo, Hans‐Jürgen Wester
Abstract
Abstract Introduction Radiohybrid (rh) ligands, a novel class of prostate-specific membrane antigen (PSMA)-targeted radiopharmaceuticals, can be labeled either with [ 18 F]fluorine via isotopic exchange or with radiometals (such as [ 68 Ga]Gallium, [ 177 Lu]Lutetium, [ 225 Ac]Actinium). Among these, [ 18 F, nat Ga]rhPSMA-7 has recently entered clinical assessment. Aim Since [ 18 F, nat Ga]rhPSMA-7 is composed of four stereoisomers ([ 18 F, nat Ga]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 [ 19 F, nat Ga]rhPSMA-7 isomers has been developed. The comparative evaluation of the four isomers comprised human serum albumin binding, lipophilicity, IC 50 , 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 [ 18 F, nat Ga]rhPSMA-7.1 to -7.4 in LNCaP tumor-bearing mice. Results Cell studies revealed high PSMA affinity and internalization for [ 18/19 F, nat Ga]rhPSMA-7.2, -7.3 and -7.4, whereas [ 18/19 F, nat Ga]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, [ 18 F, nat Ga]rhPSMA-7.3 was identified as the preferred isomer and transferred into clinical studies. Conclusion [ 18 F, nat Ga]rhPSMA-7.3 has been selected as a lead compound for clinical development of a [ 18 F]rhPSMA-based candidate. The intraindividual differential uptake and excretion analysis in vivo allowed for an accurate comparison and assessment of radiopharmaceuticals.