Discovery of a dopamine D4 selective PET ligand candidate taking advantage of a click chemistry based REM linker.
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).
Tietze
Rainer
R
Laboratory of Molecular Imaging, Clinic of Nuclear Medicine, Schwabachanlage 6, D-91054 Erlangen, Germany.
Löber
Stefan
S
Hübner
Harald
H
Gmeiner
Peter
P
Kuwert
Torsten
T
Prante
Olaf
O
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
D001372:Aza Compounds; D005462:Fluorine Radioisotopes; D007211:Indoles; D019275:Radiopharmaceuticals; D050638:Receptors, Dopamine D4