title: Brain and whole-body imaging in rhesus monkeys of 11C-NOP-1A, a promising PET radioligand for nociceptin/orphanin FQ peptide receptors.
abstract: Our laboratory developed (S)-3-(2'-fluoro-6',7'-dihydrospiro[piperidine-4,4'-thieno[3,2-c]pyran]-1-yl)-2-(2-fluorobenzyl)-N-methylpropanamide ((11)C-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 (11)C-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 (11)C-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 (11)C-NOP-1A. In all scans, arterial blood was sampled to measure the parent radioligand (11)C-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 (11)C-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.
  
  
  CONCLUSIONS
  (11)C-NOP-1A is a useful radioligand for quantifying NOP receptors in the monkey brain, and its radiation dose is similar to that of other (11)C-labeled ligands for neuroreceptors. (11)C-NOP-1A appears to be a promising candidate for measuring NOP receptors in the human brain.
authors: Molecular Imaging Branch, National Institute of Mental Health, National Institutes of Health, Bethesda, Maryland 20892-1026, USA.
authors: Yasuyuki
authors: Y
authors: Kimura
authors: Masahiro
authors: M
authors: Fujita
authors: Jinsoo
authors: J
authors: Hong
authors: Talakad G
authors: TG
authors: Lohith
authors: Robert L
authors: RL
authors: Gladding
authors: Sami S
authors: SS
authors: Zoghbi
authors: Johannes A
authors: JA
authors: Tauscher
authors: Nancy
authors: N
authors: Goebl
authors: Karen S
authors: KS
authors: Rash
authors: Zhaogen
authors: Z
authors: Chen
authors: Concepcion
authors: C
authors: Pedregal
authors: Vanessa N
authors: VN
authors: Barth
authors: Victor W
authors: VW
authors: Pike
authors: Robert B
authors: RB
authors: Innis
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002250:Carbon Radioisotopes; D003508:Cycloheptanes / Q000008:administration & dosage; D006801:Humans; D008253:Macaca mulatta; D008297:Male; D009292:Narcotic Antagonists; D010880:Piperidines / Q000008:administration & dosage; D049268:Positron-Emission Tomography / Q000379:methods*; D011869:Radioligand Assay; D019275:Radiopharmaceuticals; D011957:Receptors, Opioid / Q000097:blood / Q000378:metabolism*; D013141:Spiro Compounds; D051598:Whole Body Imaging / Q000379:methods*; D000094942:Nociceptin Receptor
chemical_list: C568161:3-(2'-fluoro-6',7'-dihydrospiro(piperidine-4,4'-thieno(3,2-c)pyran)-1-yl)-2-(2-fluorobenzyl)-N-methylpropanamide; D019086:Bridged Bicyclo Compounds, Heterocyclic; D002250:Carbon Radioisotopes; D003508:Cycloheptanes; D009292:Narcotic Antagonists; D010880:Piperidines; D019275:Radiopharmaceuticals; D011957:Receptors, Opioid; D013141:Spiro Compounds; C482404:cis-1-methyl-7-((4-(2,6-dichlorophenyl)piperidin-1-yl)methyl)-6,7,8,9-tetrahydro-5H-benzocyclohepten-5-ol; D000094942:Nociceptin Receptor