Brain and Whole-Body Imaging of Nociceptin/Orphanin FQ Peptide Receptor in Humans Using the PET Ligand ¹¹C-NOP-1A

Abstract

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 (VT; 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 VT 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. 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 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 µSv/MBq), and the effective dose was 4.3 µSv/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.

Social defeat disrupts reward learning and potentiates striatal nociceptin/orphanin FQ mRNA in rats

“…Brain autoradiography studies in rodents have revealed a very high concentration of NOP receptors in the frontal cortex, and there are particularly high levels of NOP receptors in the cingulate cortex (Neal et al 1999; Sim and Childers 1997; Sim et al 1996). Consistent with these rodent findings, human positron emission tomography (PET) and post-mortem autoradiography studies have also reported high distribution of NOP receptors in the cingulate cortex and striatum (Berthele et al 2003; Lohith et al 2014; Lohith et al 2012). Moreover, NOP receptors are localized on dopaminergic nuclei in the VTA, and administration of a NOP receptor agonist inhibited dopamine neurotransmission in the VTA and NAc (Koizumi et al 2004a; Koizumi et al 2004b; Murphy et al 1996; Murphy and Maidment 1999; Murphy et al 2004).…”

Occupancy of Nociceptin/Orphanin FQ Peptide Receptors by the Antagonist LY2940094 in Rats and Healthy Human Subjects

“…We have recently discovered both labeled and unlabeled NOP receptor tracers with subnanomolar binding affinities with no intrinsic activity (i.e., antagonists), high selectivity, CNS penetration, and low nonspecific binding (Pedregal et al, 2012). 5 was safe, with favorable kinetics and reproducibility (Lohith et al, 2012(Lohith et al, , 2014, and exhibited distribution volume (V T ) consistent with known NOP density distribution (Berthele et al, 2003).…”

“…Parent fraction was measured by high-performance liquid chromatography (HPLC) to determine the metabolite corrected plasma input function, as previously described in more details (Lohith et al, 2012). Sample chromatogram can be found in (Supplemental Figure 4).…”

Nociceptin and the nociceptin receptor in learning and memory

“…At a translational level, the use of radiolabeled molecules that bind the NOP receptor in the brain (Hostetler et al, 2013; Kimura et al, 2011; Linz et al, 2014; Lohith et al, 2014; Lohith et al, 2012; Pedregal et al, 2012; Pike et al, 2011; Thomsen et al, 2000) could provide insight into the association between N/OFQ-NOP receptor levels, human learning and memory, and brain disorders (e.g. Posttraumatic stress disorder, Alzheimer, Parkinson, etc.).…”