Further validation to support clinical translation of [¹⁸F]FTC-146 for imaging sigma-1 receptors

This study aims to further evaluate the specificity and selectivity of [¹⁸F]FTC-146 and obtain additional data to support its clinical translation.

The binding of [¹⁹F]FTC-146 to vesicular acetylcholine transporter (VAChT) was evaluated using [³H]vesamicol and PC12^A123.7 cells in an in vitro binding assay. The uptake and kinetics of [¹⁸F]FTC-146 in S1R-knockout mice (S1R-KO) compared to wild-type (WT) littermates was assessed using dynamic positron emission tomography (PET) imaging. Ex vivo autoradiography and histology were conducted using a separate cohort of S1R-KO/WT mice, and radiation dosimetry was calculated from WT mouse data (extrapolated for human dosing). Toxicity studies in Sprague–Dawley rats were performed with a dose equivalent to 250× the anticipated clinical dose of [¹⁹F]FTC-146 mass.

VAChT binding assay results verified that [¹⁹F]FTC-146 displays negligible affinity for VAChT (K _i = 450 ± 80 nM) compared to S1R. PET images demonstrated significantly higher tracer uptake in WT vs. S1R-KO brain (4.57 ± 1.07 vs. 1.34 ± 0.4 %ID/g at 20–25 min, n = 4, p < 0.05). In S1R-KO mice, it was shown that rapid brain uptake and clearance 10 min post-injection, which are consistent with previous S1R-blocking studies in mice. Three- to fourfold higher tracer uptake was observed in WT relative to S1R-KO mouse brains by ex vivo autoradiography. S1R staining coincided well with the autoradiographic data in all examined brain regions (r ² = 0.85–0.95). Biodistribution results further demonstrated high [¹⁸F]FTC-146 accumulation in WT relative to KO mouse brain and provided quantitative information concerning tracer uptake in S1R-rich organs (e.g., heart, lung, pancreas) for WT mice vs. age-matched S1R-KO mice. The maximum allowed dose per scan in humans as extrapolated from mouse dosimetry was 33.19 mCi (1228.03 MBq). No significant toxicity was observed even at a 250X dose of the maximum carrier mass [¹⁹F]FTC-146 expected to be injected for human studies.

Together, these data indicate that [¹⁸F]FTC-146 binds specifically to S1Rs and is a highly promising radiotracer ready for clinical translation to investigate S1R-related diseases.