Radiohybrid (rh) chemistry

Radiohybrid (rh) ligands, developed by Wester and colleagues at the Technical University of Munich, combine a silicon-fluoride-acceptor (SiFA) group with a metal chelator (typically DOTA, DOTAGA or TRAP) within a single molecule. Only one of the two binding sites carries a radioactive isotope at a time: the SiFA silicon-fluorine bond can be radiolabelled with 18F by rapid isotopic exchange (19F/18F IE, complete in around 5 minutes at room temperature owing to a low, roughly 15.7 kcal/mol, activation barrier), while the chelator can instead be loaded with a radiometal such as 68Ga, 177Lu or 225Ac. This produces chemically near-identical diagnostic (18F/natMetal) and therapeutic (19F/radiometal) 'twins' with matched pharmacokinetics, avoiding the small structural differences that can arise between separately designed PET and radiometal tracers for the same target.

The lead compound 18F-rhPSMA-7 (and its isomer rhPSMA-7.3) showed imaging quality comparable to or better than 68Ga-PSMA-11 in clinical studies of low-PSA prostate cancer recurrence, and was developed into the FDA-approved diagnostic agent flotufolastat F-18. Laboratory-scale radiolabelling achieves radiochemical yields around 58% ± 9% and molar activities of 12-60 GBq/µmol within under 20 minutes, and the reaction is compatible with cartridge-based purification suited to automated GMP synthesis modules. The SiFA moiety's lipophilicity must be offset by adding a hydrophilic chelator or linker (or newer hydrophilic SiFA variants), and to date SiFA groups are the only chemistry used to build radiohybrids, so the concept has mainly been demonstrated for PSMA and minigastrin/CCK2R ligands rather than across the whole radioligand class.