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, C-11-NOP-1A, which yielded promising results in monkey brain. Here, we assessed the ability of C-11-NOP-1A to quantify NOP receptors in human brain and estimated its radiation safety profile. Methods: After intravenous injection of C-11-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 (similar to 5-7 standardized uptake values), occurred early (similar to 10 min), and then washed out quickly. The unconstrained 2-tissue-compartment model gave excellent V-T identifiability (similar to 1.1% SE) and fitted the data better than a 1-tissue-compartment model. Regional V-T values (mL.cm(-3)) ranged from 10.1 in temporal cortex to 5.6 in cerebellum. VT 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 C-11-NOP-1A were less lipophilic than the parent radioligand. Voxel-based MA1 V-T 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. C-11-NOP-1A was significantly metabolized and excreted via the hepatobiliary route. Gallbladder had the highest radiation exposure (21 mu Sv/MBq), and the effective dose was 4.3 mu Sv/MBq. Conclusion: C-11-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 C-11-labeled radioligands, allowing multiple scans in 1 subject.