Radiohalogenated Neopentyl Derivatives: A Novel Scaffold for Radioiodinated and astatinated Compounds of High Stability to In Vivo Dehalogenation

Abstract

Astatine-211 (211At) is an α-emitting radionuclide appropriate for medical use. To expand the application of 211At-labeled compounds to radiotheranostics, we developed neopentyl derivatives as a novel scaffold for radioiodination and astatination. The stability, biodistribution, and metabolism of 125I-labeled neopentyl derivatives were evaluated. The biodistribution of a 211At-labeled compound was compared with its 125I-labeled counterpart. Two iodinated neopentyl derivatives with a nitroimidazole group were synthesized; N-[2,2-bis(hydroxymethyl)-2-(iodomethyl)ethyl]-2-nitroimidazole (BHIN) and N-[2,2-diethyl2-(iodomethyl)ethyl]-2-nitroimidazole (DEIN). The radioiodination was conducted by reacting their sulfonyl precursors with Na[125I]I. The stability to the nucleophilic substitution was evaluated in a 10 mM glutathione solution at pH 7.4 for 24 h. The biodistribution of [125I]BHIN or [125I]DEIN was evaluated in normal male mice. Urine samples collected for 6 h after injection were analyzed by a reversed-phase HPLC. [211At]N-[2,2-bis(hydroxymethyl)2-(astatomethyl)ethyl]-2-nitroimidazole ([211At]BHAN) was prepared under the procedure similar to [125I]BHIN and was subjected to biodistribution study in normal male mice. Both 125I-labeled compounds were obtained in 40 to 90% radiochemical yields and over 98% radiochemical purities after HPLC purification. Both 125I-labeled compounds remained stable after incubation in a glutathione solution for 24 h (>95%), indicating that the two radioiodinated compounds possess high stability to the nucleophilic substitution reaction. In biodistribution study, while [125I]DEIN showed high radioactivity levels in the neck (10.60 ± 0.03 %ID at 24 h), such radioactivity was hardly observed with [125I]BHIN (0.03 ± 0.02 %ID at 24 h). Both radioiodinated compounds were mainly excreted into urine. The analysis of urine samples indicated that while the majority of the radioactivity was present as [125I]I- for [125I]DEIN, [125I]BHIN showed the majority of the radioactivity as the glucuronide-conjugate. [211At]BHAN was obtained in about 14% radiochemical yields and over 98% radiochemical purities after HPLC purification. [211At]BHAN exhibited the pharmacokinetics similar to [125I]BHIN with low radioactivity levels in the neck and the stomach. Both 125I-labeled compounds possessed high stability to the nucleophilic substitution. The presence of the hydroxyl groups in BHIN provided further stabilization to the enzymatic dehalogenation reaction. [125I]BHIN and [211At]BHAN exhibited similar pharmacokinetics each other with dehalogenation being hardly observed. These findings indicate that the neopentyl derivatives would serve as a useful scaffold to develop a radiotheranostic pair consisting of radioiodinated and 211At-labeled compounds.