Evaluation of a novel hexadentate 1,2-hydroxypyridinone-based acyclic chelate, HOPO-O6-C4, for 43Sc/47Sc, 68Ga, and 45Ti radiopharmaceuticals

Abstract

IntroductionChelators play a crucial role in the development of metal-based radiopharmaceuticals, and with the continued interest in 68Ga and increasing availability of new radiometals such as 43Sc/47Sc and 45Ti, 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-O6-C4 and its in vitro and in vivo evaluation with the above mentioned radiometals. MethodsTo investigate the affinity of HOPO-O6-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 43Sc (and 47Sc), 45Ti, and 68Ga 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-O6-C4. ResultsPromising radiolabeling results with HOPO-O6-C4 were obtained with 43Sc, 47Sc, 45Ti, and 68Ga 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/μmol), 47Sc (1.58 ± 0.01 GBq/μmol), 45Ti (11.5 ± 1.6 GBq/μmol) and 68Ga (5.74 ± 0.7 GBq/μmol), 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 [43Sc]Sc-HOPO-O6-C4, [47Sc]Sc-HOPO-O6-C4 and [45Ti]Ti-HOPO-O6-C4 showed modest and significant evidence of decomplexation, respectively. ConclusionsThe tris-1,2-HOPO chelator HOPO-O6-C4 is a promising scaffold for elaboration into a 68Ga- based radiopharmaceutical.