Automated cassette-based synthesis, metabolism, and dosimetry of [¹⁸F]ApaScan, a PET tracer for aldosterone synthase...

Aldosterone-producing adenomas (APAs) account for most cases of primary aldosteronism (PA), a major cause of secondary hypertension and hypokalemia. Although adrenal vein sampling (AVS) is the diagnostic gold standard, its invasiveness and limited availability underscore the need for less invasive diagnostic alternatives such as positron emission tomography (PET). We recently developed 6-chloro-5-fluoro-1-(2-[¹⁸F]fluoroethyl)-2-(pyridin-3-yl)-1H-benzo[d]imidazole ([¹⁸F]ApaScan), a highly CYP11B2-selective PET tracer for imaging APAs. This study characterizes the metabolism, biodistribution, dosimetry, and automated synthesis of [¹⁸F]ApaScan in preparation for first-in-human studies.

Metabolism was evaluated in vitro using mouse, rat, and human liver microsomes and in vivo in mouse blood following the administration of [¹⁸F]ApaScan. Biodistribution (%ID/g) was measured in mice, and human radiation doses were estimated using the MIRD schema. The automated radiosynthesis process was optimized on a cassette-based FASTlab module integrated with preparative HPLC to afford the final formulation (ca. 5% ethanol). This formulation was validated in three consecutive production runs in accordance with the in-house manufactured PET drug standards in Japan.

A single radiometabolite, identified as the pyridine N-oxide derivative of ApaScan, was observed in both in vitro liver microsome assays and in vivo mouse studies. Biodistribution studies revealed adrenal uptake peaked at 5.9%ID/g at 2 min post-injection and cleared rapidly, with no significant retention in other organs or in bone. The extrapolated human radiation doses were 13.4 μSv/MBq for males and 15.9 μSv/MBq for females, comparable to other clinically used ¹⁸F-labeled tracers. The automated radiosynthesis achieved a non-decay-corrected yield of 29.2 ± 0.5%, a molar radioactivity of 1070 ± 246 GBq/μmol, and a radiochemical purity >99%. The final product met all quality specifications, including sterility and endotoxin limits.

[¹⁸F]ApaScan undergoes oxidative metabolism while maintaining favorable adrenal kinetics and exhibiting acceptable dosimetry. We established a reproducible automated radiosynthesis of [¹⁸F]ApaScan suitable for clinical use. These findings support proceeding to first-in-human studies to evaluate the pharmacokinetics and APA imaging performance of [¹⁸F]ApaScan in patients with PA.