title: Discovery of a dopamine D4 selective PET ligand candidate taking advantage of a click chemistry based REM linker.
abstract: Employing D4 selective azaindoles as lead compounds, a focused library of the carbocyclic arene bioisosteres 1 was synthesized when we took advantage of the click chemistry derived triazolylmethyl acrylate resin 2. Ligand binding assays on monoaminergic GPCRs led to SARs that indicated further lead structure optimizations when the attachment of alkoxy substituents provided both an improvement of the biological properties and the opportunity to introduce (18)F as a radioisotope. Finally, radiosynthesis resulted in formation of the radioligand [(18)F]7h that showed optimal logD(7.4) of 2.8 and was determined to be highly stable in human serum. Thus, [(18)F]7h represents a promising dopamine D4 selective radioligand for positron emission tomography (PET).
authors.affiliation: Laboratory of Molecular Imaging, Clinic of Nuclear Medicine, Schwabachanlage 6, D-91054 Erlangen, Germany.
authors.forename: Rainer
authors.initials: R
authors.lastname: Tietze
authors.forename: Stefan
authors.initials: S
authors.lastname: Löber
authors.forename: Harald
authors.initials: H
authors.lastname: Hübner
authors.forename: Peter
authors.initials: P
authors.lastname: Gmeiner
authors.forename: Torsten
authors.initials: T
authors.lastname: Kuwert
authors.forename: Olaf
authors.initials: O
authors.lastname: Prante
mesh_terms: D001372:Aza Compounds / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D020650:Combinatorial Chemistry Techniques; D005462:Fluorine Radioisotopes; D006801:Humans; D007211:Indoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics*; D050638:Receptors, Dopamine D4 / Q000187:drug effects*; D013329:Structure-Activity Relationship
chemical_list: D001372:Aza Compounds; D005462:Fluorine Radioisotopes; D007211:Indoles; D019275:Radiopharmaceuticals; D050638:Receptors, Dopamine D4