Synthesis and Structure–Affinity Relationships of Selective High-Affinity 5-HT 4 Receptor Antagonists: Application to the Design of New Potential Single Photon Emission Computed Tomography Tracers

Abstract : The work described herein aims at finding new potential ligands for the brain imaging of 5-HT 4 receptors using single-photon emission computed tomography (SPECT). Starting from the non-substituted phenanthridine compound 4a exhibiting a Ki value of 51 nM on 5-HT 4 R, we explored structure-affinity in this series. We found that substitution in position 4 of the tricycle with a fluorine atom gave the best result. Introduction of an additional nitrogen atom inside the tricyclic framework led to increase both the affinity and the selectivity for 5-HT 4 R suggesting the design of the antagonist 4v exhibiting a high affinity of 0.04 nM. Several iodinated analogues were then synthesized as potential SPECT tracers. The iodinated compound 11d was able to displace the reference radioiodinated 5-HT 4 R antagonist (1-butylpiperidin-4-yl)methyl-8-amino-7-iodo[ 123 I]-2,3-dihydrobenzo[b][1,4]dioxine-5-carboxylate ([ 123 I]1, [ 123 I]SB 207710) both in vitro and in vivo in brain. Compound 11d was radiolabeled with [ 125 I]iodine, providing a potential SPECT candidate for brain imaging of 5-HT 4 R.