Automated radiosynthesis of (S)-[¹¹C]LY2795050 for imaging κ-opioid receptors in nonhuman primate brain

Objectives Central κ-opioid receptors (KOR) in brain play a vital role in sensory processing, mood transition and behavioral responses to drugs of abuse and also are involved in several neurological disorders including depression, anxiety, alcoholism and AD. In vitro and initial animal evaluation suggested (S)-[¹¹C]LY2795050 is a potent and selective KOR antagonist. Here, we report the automated radiosynthesis in TRASIS AIO module and PET imaging studies of (S)-[¹¹C]LY2795050 for imaging KOR in nonhuman primate (NHP) brain.

Methods TRASIS AIO is an automated radiosynthesis module that produces GMP grade PET radiopharmaceuticals for human injections. Based on reported method, (S)-[¹¹C]LY2795050 was synthesized and automated in a TRASIS AIO module with slight modifications. Briefly, the enatiomerically pure iodoaryl precursor underwent Pd-catalyzed [¹¹C]cyanation at 85°C for 3 min, followed by base assisted hydrolysis then HPLC purification and C18 cartridge elution to afford (S)-[¹¹C]LY2795050. To demonstrate the validity of the synthesized radiotracer, PET imaging studies were conducted on adult male rhesus monkeys. BPND were determined using the SRTM model. Specificity studies were performed by pretreating monkey with the non-radioactive (S)-LY2795050 prior to radiotracer injection.

Results (S)-[¹¹C]LY2795050 was synthesized with high radiochemical purity (>99%) and high specific activity (~2600 mCi/µmol, n >10) with 28% radiochemical yield, decay corrected to EOS. The total time required for the synthesis, including [¹¹C]HCN production, two-step reaction, purification and formulation was ~40 min. Baseline scans suggested the radiotracer distribution is consistent with KOR densities and pretreatment with the blocker (S)-LY2795050 decreased the receptor region uptake, demonstrating that the synthesized (S)-[¹¹C]LY2795050 specifically binds to KOR in NHP brain.

Conclusions We report the automated radiolabeling procedure for (S)-[¹¹C]LY2795050 with high radiochemical yield, purity and specific activity in TRASIS AIO module that can be directly translated and easily adapted to any automated modules for human injections and clinical trials. We further validated the radioactive uptake and specificity in brains of rhesus monkeys using PET imaging studies.