Gallium-68 and zirconium-89 complexes of DFO-analogs for molecular imaging applications using PET/CT

The β⁺-emitters gallium-68 (⁶⁸Ga) and zirconium-89 (⁸⁹Zr) are among the most widely used metallic radionuclides in nuclear medicine for diagnostic imaging by Positron Emission Tomography (PET). Inspired by nature's bacterial siderophore desferrioxamine-B (DFO), a number of structurally related oligohydroxamate-based chelators have been studied for the complexation of both radiometals and for applications in nuclear medicine. We report here the solid phase (sp) synthesis of a new member of this family of acyclic chelators, DFO*^sp 3, and its comparison with DFO 1 (control) and DFO-analogs DFO* 2, and oxoDFO* 4 in vitro and in vivo.

DFO*^sp 3 and oxoDFO* 4 were synthesized efficiently on solid support by applying different protective group strategies. The [⁶⁸Ga]Ga- and [⁸⁹Zr]Zr-labeled chelators 1-4 were obtained with high radiochemical yield and purity. They were also found to be of favorable hydrophilicity (logP <-2,2), high stability in the media tested, and low protein binding (with the exception of [⁶⁸Ga]Ga-DFO 5 and [⁶⁸Ga]Ga-DFO* 6). In vivo, the radiometal complexes 5-12 showed good serum stability, fast clearance predominantly by renal excretion and low uptake in organs and tissues. In vivo PET/CT imaging confirmed the results of the ex vivo biodistribution studies, leading to the acquisition of high-quality PET/CT images with a low signal-to-noise ratio.

The excellent in vitro and in vivo characteristics of [⁶⁸Ga]Ga- and [⁸⁹Zr]Zr-complexes of hydroxamate-based chelators 1-4 support their use in radiopharmaceutical development and diagnostic PET-imaging applications in nuclear medicine.