title: Evaluation of 18F-labeled benzodioxine piperazine-based dopamine D4 receptor ligands: lipophilicity as a determinate of nonspecific binding.
abstract: Derivatization of the putative neuroleptic 1-(2,3-dihydrobenzo[1,4]dioxin-6-yl)-4-(4-fluorobenzyl)piperazine (3a) led to a series of new dopamine receptor D4 ligands displaying high affinity (Ki=1.1-15 nM) and D2/D4 subtype selectivities of about 800-6700. These ligands were labeled with the short-lived positron emitter fluorine-18 and analyzed for their potential application for imaging studies by positron emission tomography (PET). In vitro autoradiography was used to determine their nonspecific binding behavior as a result of their structural and thus physicochemical properties. The biodistribution, in vivo stability, and brain uptake of the most promising D4 radioligand candidate were determined. This proved to be 1-(2,3-dihydrobenzo[b][1,4]dioxin-6-yl)-4-((6-fluoropyridin-3-yl)methyl)piperazine ([18F]3d), which revealed an excellent binding pattern with a high selectivity and limited nonspecific binding in vitro. This analogue also exhibited a high stability and an extremely high brain uptake in vivo with specific binding in hippocampus, cortex, colliculus, and cerebellum as determined by ex vivo autoradiography. Thus, [18F]3d appears as a suitable D4 radioligand for in vivo imaging, encouraging continued evaluation by PET studies.
authors: Institute of Neuroscience and Medicine, INM-5, Nuclear Chemistry, Forschungszentrum Jülich GmbH, Jülich, Germany.
authors: Fabian
authors: F
authors: Kügler
authors: Wiebke
authors: W
authors: Sihver
authors: Johannes
authors: J
authors: Ermert
authors: Harald
authors: H
authors: Hübner
authors: Peter
authors: P
authors: Gmeiner
authors: Olaf
authors: O
authors: Prante
authors: Heinz H
authors: HH
authors: Coenen
mesh_terms: D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000378:metabolism; D004146:Dioxanes / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D005462:Fluorine Radioisotopes; D006801:Humans; D066298:In Vitro Techniques; D008024:Ligands; D051379:Mice; D010879:Piperazines / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D011869:Radioligand Assay; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017208:Rats, Wistar; D050638:Receptors, Dopamine D4 / Q000378:metabolism*; D013329:Structure-Activity Relationship; D014018:Tissue Distribution
chemical_list: C570533:1-(2,3-dihydrobenzo(b)(1,4)dioxin-6-yl)-4-((6-fluoropyridin-3-yl)methyl)piperazine; D004146:Dioxanes; D005462:Fluorine Radioisotopes; D008024:Ligands; D010879:Piperazines; D019275:Radiopharmaceuticals; D050638:Receptors, Dopamine D4