title: Syntheses, biological evaluation, and molecular modeling of 18F-labeled 4-anilidopiperidines as mu-opioid receptor imaging agents.
abstract: The synthesis, evaluation, and molecular modeling of a series of 18F-labeled 4-anilidopiperidines with high affinities for the mu-opioid receptor (mu-OR) are reported. On the basis of the high brain uptake and selective retention in brain regions that contain a high concentration of the mu-OR, combined with a good metabolic stability, [18F]fluoro-pentyl carfentanil ([18F]4) and 2-(+/-)[18F]fluoropropyl-sufentanil ([18F]6) were selected as the lead compounds for further evaluation. The binding affinity to the human mu-OR was 0.74 and 0.13 nM for [18F]4 and [18F]6, respectively. In vitro autoradiography of [18F]4 and [18F]6 on rat brain sections produced patterns in accordance with the known distribution of mu-OR expression. Structure-activity relationships of the fluorinated compounds are discussed with respect to the interaction with an activated-state model of the mu-OR. Taken together, the in vivo and in vitro data indicate that [18F]4 and [18F]6 hold promise for studying the mu-opioid receptor in humans by means of positron emission tomography.
authors.affiliation: Department of Nuclear Medicine, Klinikum rechts der Isar, Technische Universität München, Ismaninger Strasse 22, D-81675 Munich, Germany. G.Henriksen@lrz.tum.de
authors.forename: Gjermund
authors.initials: G
authors.lastname: Henriksen
authors.forename: Stefan
authors.initials: S
authors.lastname: Platzer
authors.forename: János
authors.initials: J
authors.lastname: Marton
authors.forename: Andrea
authors.initials: A
authors.lastname: Hauser
authors.forename: Achim
authors.initials: A
authors.lastname: Berthele
authors.forename: Markus
authors.initials: M
authors.lastname: Schwaiger
authors.forename: Luciana
authors.initials: L
authors.lastname: Marinelli
authors.forename: Antonio
authors.initials: A
authors.lastname: Lavecchia
authors.forename: Ettore
authors.initials: E
authors.lastname: Novellino
authors.forename: Hans-Jürgen
authors.initials: HJ
authors.lastname: Wester
mesh_terms: D000814:Aniline Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D005462:Fluorine Radioisotopes; D006801:Humans; D066298:In Vitro Techniques; D007553:Isotope Labeling; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008958:Models, Molecular; D010880:Piperidines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D049268:Positron-Emission Tomography; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017450:Receptors, Opioid, mu / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: D000814:Aniline Compounds; D005462:Fluorine Radioisotopes; D010880:Piperidines; D019275:Radiopharmaceuticals; D017450:Receptors, Opioid, mu