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

68Ge/68Ga radionuclide generators have been investigated for almost fifty years now, since the cyclotronindependent availability of positron emitting 68Ga via the 68Ge/68Ga 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 68Ge/68Ga generator designs, adequate to the modern requirements of radiometal labeling chemistry. 68Ga radiopharmacy now is awaking from a sort of hibernation. The exciting perspective for the 68Ge/68Ga generator, now - more than ever, asks for systematic chemical, radiochemical, technological and radiopharmaceutical efforts, to guarantee reliable, highly-efficient and medically approved 68Ge/68Ga generator systems. The expected future broad clinical impact of 68Ga-labelled radiopharmaceuticals - beyond the 68Ga-DOTA-octreotide derivatives - for imaging tumors and many organs, on the other hand, identifies the development of sophisticated GaIII 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 68Ge/68Ga radionuclide generator systems could contribute to and facilitate the clinical impact of nuclear medicine diagnoses for PET in a dimension comparable to the established 99Mo/99mTc generator system for SPECT.