The Renaissance of the 68Ge/68Ga Radionuclide Generator Initiates New Developments in 68Ga Radiopharmaceutical Chemistry

Ge-68/Ga-68 radionuclide generators have been investigated for almost fifty years now, since the cyclotron-independent availability of positron emitting Ga-68 via the Ge-68/Ga-68 system had always attracted researches working in basic nuclear chemistry as well as radiopharmaceutical chemistry. However, it took decades and generations of research (and researchers) to finally approach a reliable level of Ge-68/Ga-68 generator designs, adequate to the modern requirements of radiometal labeling chemistry. Ga-68 radiopharmacy now is awaking from a sort of hibernation. The exciting perspective for the Ge-68/Ga-68 generator, now - more than ever, asks for systematic chemical, radiochemical, technological and radiopharmaceutical efforts, to guarantee reliable, highly-efficient and medically approved Ge-68/Ga-68 generator systems. The expected future broad clinical impact of Ga-68-labelled radiopharmaceuticals - beyond the Ga-68-DOTA-octreotide derivatives - for imaging tumors and many organs, on the other hand, identifies the development of sophisticated Ga-III chelating structures to be a key factor. Today, open chain complexing agents have almost completely been displaced by macrocyclic DOTA and NOTA-derived conjugates. Structures of chelating moieties are being optimized in terms of thermodynamic stability and kinetic inertness, in terms of labeling efficacies at different, even acidic pH, and in terms of synthetic options towards bifunctionality, directed to sophisticated covalent coupling strategies to a variety of biologically relevant targeting vectors. Today, one may expect that the Ge-68/Ga-68 radionuclide generator systems could contribute to and facilitate the clinical impact of nuclear medicine diagnoses for PET in a dimension comparable to the established Mo-99/Tc-99m generator system for SPECT.