A Series of 18F‐Labelled Pyridinylphenyl Amides as Subtype‐Selective Radioligands for the Dopamine D3 Receptor

Abstract

Synthesis, biological activity, and structure–selectivity relationship (SSR) studies of a novel series of potential dopamine D3 receptor radioligands as imaging agents for positron emission tomography (PET) are reported. Considering a structurally diverse library of D3 ligands, SSR studies were performed for a new series of fluorinated pyridinylphenyl amides using CoMFA and CoMSIA methods. The in vitro D3 affinities of the predicted series of biphenyl amide ligands 9 a–d revealed single‐digit to sub‐nanomolar potencies (K_i=0.52–1.6 nM), displaying excellent D3 selectivity over the D2 subtype of 110‐ to 210‐fold for the test compounds 9 a–c. Radiofluorination by nucleophilic substitution of Br or NO₂ by ¹⁸F led to radiochemical yields of 66–92 % for [¹⁸F]9 a–d. However, the specific activities of [¹⁸F]9 b and [¹⁸F]9 d were insufficient, rendering their use for in vivo studies impossible. Biodistribution studies of [¹⁸F]9 a and [¹⁸F]9 c using rat brain autoradiography revealed accumulation in the ventricles, thus indicating insufficient biokinetic properties of [¹⁸F]9 a and [¹⁸F]9 c for D3 receptor imaging in vivo.