Evaluation of a Novel Hexadentate 1,2-Hydroxypyridinone-based Acyclic Chelate, HOPO-O6-C4, for 43sc/47sc, 68ga, and 45ti Radiopharmaceuticals

Introduction: Chelators play a crucial role in the development of metal-based radiopharmaceuticals, and with the continued interest in Ga-68 and increasing availability of new radiometals such as Sc-43/Sc-47 and Ti-45, there is a growing demand for tailored chelators that can form stable complexes with these metals. This work reports the synthesis and characterization of a hexadentate tris-1,2-hydroxypyridonone chelator HOPO-O-6-C4 and its in vitro and in vivo evaluation with the above mentioned radiometals. Methods: To investigate the affinity of HOPO-O-6-C4, macroscopic studies were performed with Sc3+, and Ga3+ followed by DFT structural optimization of the Sc3+, Ga3+ and Ti4+ complexes. Further tracer studies with Sc-43 (and Sc-47), Ti-45, and Ga-68 were performed to determine the potential for positron emission tomography (PET) imaging with these complexes. In vitro stability studies followed by in vivo imaging and biodistribution studies were performed to understand the kinetic stability of the resultant radiometal-complexes of HOPO-O-6-C4. Results: Promising radiolabeling results with HOPO-O-6-C4 were obtained with Sc-43, Sc-47, Ti-45, and Ga-68 radionuclides; rapid radiolabeling was observed at 37 C and pH 7 in under 30-min. Apparent molar activity measurements were performed for radiolabeling of HOPO-O6-C4 with 43Sc (4.9 +/- 0.26 GBq/jimol), 47Sc (1.58 +/- 0.01 GBq/jimol), 45Ti (11.5 +/- 1.6 GBq/jimol) and 68Ga (5.74 +/- 0.7 GBq/jimol), respectively. Preclinical in vivo imaging studies resulted in promising results with [68Ga]Ga-HOPO-O6-C4 indicating a rapid clearance through hepatic excretion route and no decomplexation whereas [Sc-43]Sc-HOPO-O6-C4, [Sc-47]Sc-HOPO-O-6-C4 and [Ti-45] Ti-HOPO-O-6-C4 showed modest and significant evidence of decomplexation, respectively. Conclusions: The tris-1,2-HOPO chelator HOPO-O-6-C4 is a promising scaffold for elaboration into a 68Ga- based radiopharmaceutical.