Brain and whole-body imaging in rhesus monkeys of ¹¹C-NOP-1A, a promising PET radioligand for nociceptin/orphanin FQ peptide receptors

Our laboratory developed (S)-3-(2′-fluoro-6′,7′- dihydrospiro [piperidine-4,4′-thieno[3,2-c]pyran]-1-yl)-2-(2-fluorobenzyl) -Nmethylpropanamide ( ¹¹C-NOP-1A), a new radioligand for the nociceptin/orphanin FQ peptide (NOP) receptor, with high affinity (K _i, 0.15 nM) and appropriate lipophilicity (measured logD, 3.4) for PET brain imaging. Here, we assessed the utility of ¹¹C-NOP-1A for quantifying NOP receptors in the monkey brain and estimated the radiation safety profile of this radioligand based on its biodistribution in monkeys. Methods: Baseline and blocking PET scans were acquired from head to thigh for 3 rhesus monkeys for approximately 120 min after ¹¹C-NOP-1A injection. These 6 PET scans were used to quantify NOP receptors in the brain and to estimate radiation exposure to organs of the body. In the blocked scans, a selective nonradioactive NOP receptor antagonist (SB-612111; 1 mg/kg intravenously) was administered before ¹¹C-NOP-1A. In all scans, arterial blood was sampled to measure the parent radioligand ¹¹C-NOP-1A. Distribution volume (V _T; a measure of receptor density) was calculated with a compartment model using brain and arterial plasma data. Radiation-absorbed doses were calculated using the MIRD Committee scheme. Results: After ¹¹C-NOP-1A injection, peak uptake of radioactivity in the brain had a high concentration (∼5 standardized uptake value), occurred early (∼12 min), and thereafter washed out quickly. V _T (mL · cm ^-3) was highest in the neocortex (∼20) and lowest in hypothalamus and cerebellum (∼13). SB-612111 blocked approximately 50%-70% of uptake and reduced V _T in all brain regions to approximately 7 mL · cm ^-3. Distribution was well identified within 60 min of injection and stable for the remaining 60 min, consistent with only parent radioligand and not radiometabolites entering the brain. Whole-body scans confirmed that the brain had specific (i.e., displaceable) binding but could not detect specific binding in peripheral organs. The effective dose for humans estimated from the baseline scans in monkeys was 5.0 μSv/MBq. Conclusion: ¹¹C-NOP-1A is a useful radioligand for quantifying NOP receptors in the monkey brain, and its radiation dose is similar to that of other ¹¹C-labeled ligands for neuroreceptors. ¹¹C-NOP-1A appears to be a promising candidate for measuring NOP receptors in the human brain.