PSMA-targeted ¹⁸F-labeled Radiohybrid Inhibitors: Labeling chemistry and automated GMP production of ¹⁸F-rhPSMA-7

Objectives: With the aim to produce ¹⁸F-labeled peptide and peptide-like radiopharmaceuticals in the same fast and efficient manner as established for radiometal complexation, we have synthesized a novel class of radiopharmaceuticals, named radiohybrids (rh). A unique feature of such radiohybrids is that both, fluorine and the metal, are always present in the ligand, but only one of them is radioactive (e.g. [¹⁸F][^natGa]rhPSMA or [¹⁹F][⁶⁸Ga]rhPSMA). To be able to introduce ¹⁸F-fluoride into unprotected complex-conjugated biovectors, we utilize the Silicon Fluoride Acceptor (SiFA) technology developed by Schirrmacher, Jurkschat and colleagues [1] in combination with a cartridge-based drying method for ¹⁸F-fluoride, formerly developed in our group. Here we present the results of the ¹⁸F-labeling of rh-compounds with the most promising PSMA-targeted tracer [¹⁸F][^natGa]rhPSMA-7 as exemplary compound.

Methods: [¹⁸F][^natGa]rhPSMA-7 includes a urea-based binding motif linked to a spacer with a SiFA moiety and a DOTAGA chelator in close proximity. The direct ¹⁸F-labeling of [¹⁹F][^natGa]rhPSMA-7 by isotopic exchange (IE) was optimized in laboratory scale by variation of precursor amount, reaction time, temperature as well as the final tracer purification (specific activity). These results were used for the set-up of a fully automated large scale production of [¹⁸F][^natGa]rhPSMA-7 in a clinical GMP environment.

Results: Optimized conditions (150 nmol precursor, 5 min, rt, 680 µL MeCN/DMSO) for manual ¹⁸F-labeling of [¹⁹F][^natGa]rhPSMA-7 resulted in RCY of 80±5% and RCP of >97% (overall 15 min, up to 2 GBq). After dilution with PBS, tracer formulation was performed by cartridge purification. This process was transferred to a simple cassette very similar to a ⁶⁸Ga-labeling cassette. The fully automated GMP production is completed within approx. 15 min. On a 50 GBq level (3000 MBq/mL), [¹⁸F][^natGa]rhPSMA-7 proofed to be radiolytically stable for at least 8 h. Since its implementation in routine production in October 2017, >250 GMP productions on activity levels between 50-100 GBq have been routinely carried out (RCY: 50±7%, SA: 330-660 GBq/µmol @EOS).

Conclusions: By combination of SiFA technology and radiometal chelators a novel and powerful class of PSMA tracers has been developed, that either allows for production of identical F/Ga-twins or of true theranostic pairs of tracers (F/Lu-rhPSMA). ¹⁸F-labeling of these tracers is simple, fast and very robust. In addition, the rh-technology can be adapted to all typically used radiometals.