title: N-(3-[18F]fluoropropyl)-N-nordiprenorphine: synthesis and characterization of a new agent for imaging opioid receptors with positron emission tomography.
abstract: A series of N-fluoroalkyl (1-5) and N-alkyl (6-8) analogues of the high-affinity opioid receptor antagonist diprenorphine (9) has been synthesized and evaluated with in vitro binding assays. Three of the N-fluoroalkyl compounds were prepared with the positron-emitting radionuclide 18F (1a, 2a, 5a), and their biodistribution was determined in rats. Compounds 2a and 5a were made by using a two-step labeling procedure, [18F]fluoride displacement of an iodoalkyl triflate followed by N-alkylation, that required 2 h and proceeded in 4-6% overall radiochemical yield at the end of synthesis. The effective specific activity of compounds 2a and 5a, determined by competitive receptor binding assay, was 840-1820 Ci/mmol. Compound 1a was made by the same two-step procedure, with the bromoalkyl triflate, in 0.3-0.6% radiochemical yield at an effective specific activity of 106-264 Ci/mmol. Specificity of binding in vivo was measured as the percent injected dose/gram of striatal tissue divided by the percent injected dose/gram of cerebellar tissue. The best striatum to cerebellum ratio (3.32 +/- 0.74 at 30 min) was achieved with N-(3-[18F]-fluoropropyl)-N-nordiprenorphine (2a, [18F]FPND). The high specific binding demonstrated by this compound indicates that it may be useful for in vivo imaging of opioid receptors with positron emission tomography.
authors.affiliation: Division of Radiation Sciences, Edward Mallinckrodt Institute of Radiology, Washington University School of Medicine, St. Louis, Missouri 63110.
authors.forename: P L
authors.initials: PL
authors.lastname: Chesis
authors.forename: D R
authors.initials: DR
authors.lastname: Hwang
authors.forename: M J
authors.initials: MJ
authors.lastname: Welch
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D055598:Chemical Phenomena; D002621:Chemistry; D004174:Diprenorphine / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000378:metabolism / Q000493:pharmacokinetics; D005260:Female; D005462:Fluorine Radioisotopes; D007553:Isotope Labeling; D008024:Ligands; D009019:Morphinans / Q000138:chemical synthesis*; D051381:Rats; D011919:Rats, Inbred Strains; D011957:Receptors, Opioid / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution; D014055:Tomography, Emission-Computed
chemical_list: D005462:Fluorine Radioisotopes; D008024:Ligands; D009019:Morphinans; D011957:Receptors, Opioid; C063368:N-(3-fluoropropyl)-N-nordiprenorphine; D004174:Diprenorphine