Metabolic studies of astatine- and radioiodine-labeled neopentyl derivatives

1100 Objectives: Astatine-211 (211At) is one of the most promising radionuclides for targeted α therapy of cancers and radioiodine such as iodine-123 is useful radionuclide for diagnosis. Because astatine and iodine are the same group, halogen, the same scaffolds could be used for astatination and radioiodination to prepare radiotheranostics compounds. However, the in vivo instability of 211At-labeling agents such as 211At-benzoate limits the application of 211At to various compounds. To overcome the problem and expand the application of 211At-labeled compounds to radiotheranostics, we have recently developed neopentyl derivatives as a novel scaffold for astatination and radioiodination.1 In the present study, radiotheranostics utility of neopentyl derivatives were evaluated by metabolic studies comparing with reference compounds radiolabeled with 125I or 211At via a conventional method using benzamide. Methods: The 125I-labeled neopentyl derivative with a nitroimidazole, [125I]N-(2,2-bis(hydroxymethyl)-2-(iodomethyl)ethyl)-2-nitroimidazole ([125I]BHIN) was prepared by reacting its sulfonyl precursors with Na[125I]I. [211At]N-(2,2-bis(hydroxymethyl)-2-(astatomethyl)ethyl))-2-nitroimidazole ([211At]BHAN) was prepared under the procedure similar to [125I]BHIN. The stability against nucleophilic substitution or Cytochrome P450s (CYP) metabolisms were evaluated in the solutions of glutathione or CYP-activated microsomes. [125I]BHIN, [211At]BHAN and 125I/211At-labeled benzamide derivatives were subjected to biodistribution study in normal male mice. Results: [125I]BHIN and [211At]BHAN were obtained with radiochemical yields of 72% and 14%, respectively, and with a radiochemical purity of over 98% after HPLC purification. Both compounds remained stable in glutathione solution for 24 h (>95%) and in microsomal solution for 30 min (>95%). These results indicated that both compounds possess high stability against the nucleophilic substitution reaction and CYP metabolisms. In biodistribution studies, [125I]BHIN, [211At]BHAN and 125I-labeled benzamide derivative showed lower accumulation in the stomach at 3 h postinjection (0.76 ± 0.19, 1.15 ± 0.28, 1.44 ± 0.14 %ID, respectively) compared with 211At-labeled benzamide derivative (22.9 ± 1.99 %ID). Both neopentyl derivatives, [125I]BHIN and [211At]BHAN, exhibited similar pharmacokinetics in other tissues. Conclusions: [125I]BHIN and [211At]BHAN were stable against nucleophilic substitution reaction and CYP metabolism. Both compounds exhibited similar pharmacokinetics and higher in vivo stability compared with a conventional 211At-labeled benzamide derivative. These findings indicate that the neopentyl derivatives would serve as a useful scaffold to develop radiotheranostic compounds using radioiodine and 211At. Reference: (1) Journal of Medical Imaging and Radiation Sciences, Volume 50, Issue 1, S22 - S23