Brain and whole-body imaging of nociceptin/orphanin FQ peptide receptor in humans using the PET ligand ¹¹C-NOP-1A

Nociceptin/orphanin FQ peptide (NOP) receptor is a new class of opioid receptor that may play a pathophysiologic role in anxiety and drug abuse and is a potential therapeutic target in these disorders. We previously developed a high-affinity PET ligand, ¹¹C-NOP-1A, which yielded promising results in monkey brain. Here, we assessed the ability of ¹¹C-NOP-1A to quantify NOP receptors in human brain and estimated its radiation safety profile. Methods: After intravenous injection of ¹¹C-NOP-1A, 7 healthy subjects underwent brain PET for 2 h and serial sampling of radial arterial blood to measure parent radioligand concentrations. Distribution volume (V _T; a measure of receptor density) was determined by compartmental (1- and 2-tissue) and noncompartmental (Logan analysis and Ichise's bilinear analysis [MA1]) methods. A separate group of 9 healthy subjects underwent whole-body PET to estimate whole-body radiation exposure (effective dose). Results: After ¹¹C-NOP-1A injection, the peak concentration of radioactivity in brain was high (∼5-7 standardized uptake values), occurred early (∼10 min), and then washed out quickly. The unconstrained 2-tissue-compartment model gave excellent V _T identifiability (∼1.1% SE) and fitted the data better than a 1-tissue-compartment model. Regional VT values (mL·cm ^-3) ranged from 10.1 in temporal cortex to 5.6 in cerebellum. V _T was well identified in the initial 70 min of imaging and remained stable for the remaining 50 min, suggesting that brain radioactivity was most likely parent radioligand, as supported by the fact that all plasma radiometabolites of ¹¹C-NOP-1A were less lipophilic than the parent radioligand. Voxel-based MA1 VT values correlated well with results from the 2-tissue-compartment model, showing that parametric methods can be used to compare populations. Whole-body scans showed radioactivity in brain and in peripheral organs expressing NOP receptors, such as heart, pancreas, and spleen. ¹¹C-NOP-1A was significantly metabolized and excreted via the hepatobiliary route. Gallbladder had the highest radiation exposure (21 mSv/MBq), and the effective dose was 4.3 mSv/MBq. Conclusion: ¹¹C-NOP-1A is a promising radioligand that reliably quantifies NOP receptors in human brain. The effective dose in humans is low and similar to that of other ¹¹C-labeled radioligands, allowing multiple scans in 1 subject.