title: Synthesis of a potent and selective (18)F-labeled delta-opioid receptor antagonist derived from the Dmt-Tic pharmacophore for positron emission tomography imaging.
abstract: Identification and pharmacological characterization of two new selective delta-opioid receptor antagonists, derived from the Dmt-Tic pharmacophore, of potential utility in positron emission tomography (PET) imaging are described. On the basis of its high delta selectivity, H-Dmt-Tic--Lys(Z)-OH (reference compound 1) is a useful starting point for the synthesis of (18)F-labeled compounds prepared by the coupling of N-succinimidyl 4-[ (18)F]fluorobenzoate ([(18)F]SFB) with Boc-Dmt-Tic--Lys(Z)-OH under slightly basic conditions at 37 degrees C for 15 min, deprotection with TFA, and HPLC purification. The total synthesis time was 120 min, and the decay-corrected radiochemical yield of [(18)F]- 1 was about 25-30% ( n = 5) starting from [(18)F]SFB ( n = 5) with an effective specific activity about 46 GBq/micromol. In vitro autoradiography studies showed prominent uptake of [ (18)F]- 1 in the striatum and cortex with significant blocking by 1 and UFP-501 (selective delta-opioid receptor antagonist), suggesting high specific binding of [(18)F]- 1 to delta-opioid receptors. Noninvasive microPET imaging studies revealed the absence of [(18)F]- 1 in rat brain, since it fails to cross the blood-brain barrier. This study demonstrates the suitability of [ (18)F]- 1 for imaging peripheral delta-opioid receptors.
authors.affiliation: Molecular Imaging Program at Stanford, Department of Radiology and Bio-X Program, Stanford University School of Medicine, Stanford, CA 94305, USA.
authors.forename: Eun Kyoung
authors.initials: EK
authors.lastname: Ryu
authors.forename: Zhanhong
authors.initials: Z
authors.lastname: Wu
authors.forename: Kai
authors.initials: K
authors.lastname: Chen
authors.forename: Lawrence H
authors.initials: LH
authors.lastname: Lazarus
authors.forename: Ewa D
authors.initials: ED
authors.lastname: Marczak
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Sasaki
authors.forename: Akihiro
authors.initials: A
authors.lastname: Ambo
authors.forename: Severo
authors.initials: S
authors.lastname: Salvadori
authors.forename: Chuancheng
authors.initials: C
authors.lastname: Ren
authors.forename: Heng
authors.initials: H
authors.lastname: Zhao
authors.forename: Gianfranco
authors.initials: G
authors.lastname: Balboni
authors.forename: Xiaoyuan
authors.initials: X
authors.lastname: Chen
mesh_terms: D000818:Animals; D001667:Binding, Competitive; D001921:Brain / Q000000981:diagnostic imaging; D004151:Dipeptides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D015195:Drug Design; D005462:Fluorine Radioisotopes / Q000737:chemistry; D006168:Guinea Pigs; D007553:Isotope Labeling / Q000379:methods; D008297:Male; D051379:Mice; D008968:Molecular Conformation; D049268:Positron-Emission Tomography / Q000379:methods*; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017465:Receptors, Opioid, delta / Q000037:antagonists & inhibitors*; D017450:Receptors, Opioid, mu / Q000187:drug effects; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D044005:Tetrahydroisoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*
chemical_list: C446951:2',6'-dimethyltyrosyl-1,2,3,4-tetrahydroisoquinoline-3-carboxylic acid; D004151:Dipeptides; D005462:Fluorine Radioisotopes; D019275:Radiopharmaceuticals; D017465:Receptors, Opioid, delta; D017450:Receptors, Opioid, mu; D044005:Tetrahydroisoquinolines