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 18F as a radioisotope. Finally, radiosynthesis resulted in formation of the radioligand [18F]7h that showed optimal log D7.4 of 2.8 and was determined to be highly stable in human serum. Thus, [18F]7h represents a promising dopamine D4 selective radioligand for positron emission tomography (PET).