Targeted Alpha Therapy Symposium

Radiohalogenated neopentyl derivatives: A novel scaffold for radioiodinated and astatinated compounds of high stability to in vivo dehalogenation

Not scheduled

15m

Fairmont Château Laurier Hotel

Speaker

Dr Hiroyuki Suzuki (Graduate School of Pharmaceutical Sciences, Chiba University)

Description

**Objectives:** 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. **Methods:** 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-diethyl-2-(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. **Results:** 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. **Conclusions:** 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.