We have investigated the opioid receptor (OR) agonist (20R)-4,5-a-epoxy-6-(2-18 F-fluoroethoxy)-3-hydroxy-a,17-dimethyl-a-(2-phenyleth-1-yl)-6,14-ethenomorphinan-7-methanol ( 18 F-FE-PEO) as a candidate OR PET ligand. This tracer is attractive because it combines 18 F labeling, is suited to the slow kinetics of high-affinity ligands, and has agonist binding, which has been shown to be more sensitive to changes in OR occupation than is antagonist binding. Methods: Agonist potency and off-target binding were investigated in vitro, and autoradiographic studies on rat brain sections were used to assess binding patterns. Quantification of the tracer in vivo was investigated using small-animal PET in rats with blood sampling. Results: 18 F-FE-PEO was obtained by direct nucleophilic radiofluorination and subsequent deprotection with a yield of 28% 6 15%, a specific activity of 52-224 MBq/nmol, and a radiochemical purity of more than 97% (90 min from end of bombardment). In vitro studies showed it to be a full agonist ligand, which selectively binds to OR with high affinity, although it is not selective to a single OR subtype (inhibition constant, 0.4-1.6 nM across OR subtypes). Autoradiography binding patterns were consistent with the known distribution of OR, although nondisplaceable signal typically constituted one third of the signal in OR-dense regions. Although metabolites were present in blood (;40% of plasma radioactivity was nonparent 3 h after injection), no significant metabolite fraction was found in brain tissue, aiding PET quantification. A plasma input 2-tissue-compartment model provided good fits to the PET data, and regional distribution volumes from the latter correlated well with those from Logan plot analysis (r 2 5 0.98). The cerebellum had the lowest distribution volume, but the time-activity curve data could not be adequately fitted with a 1-tissue-compartment model. Reference tissue models using the cerebellum as the reference region did not provide good fits to the data, so blood-based kinetic analysis is recommended.
Conclusion:As the first 18 F-labeled OR agonist ligand, 18 F-FE-PEO is a useful addition to the existing OR ligand portfolio.