Pharmacological characterization of [125I]CHIBA-1006 binding, a new radioligand for α7 nicotinic acetylcholine receptors, to rat brain membranes

The α7 nicotinic acetylcholine receptors (nAChRs) play an important role in the pathophysiology of neuropsychiatric diseases such as schizophrenia and Alzheimer's disease. However, there are currently no suitable small molecule radioligands for imaging α7 nAChRs in the brain. In this study, we synthesized the novel radioligand [125I]4-iodophenyl 1,4-diazaicyclo[3.2.2]nonane-4-carboxylate ([125I]CHIBA-1006), a iodine-derivative of the selective α7 nAChR agonist SSR180711, and studied the characterization of [125I]CHIBA-1006 binding to rat brain membranes. The assays of [125I]CHIBA-1006 binding to rat brain membranes were performed at 4 °C. The presence of a single saturable high-affinity binding component for [125I]CHIBA-1006 in the rat brain was shown. Scatchard analysis revealed an apparent equilibrium dissociation constant (Kd) of 88.2 ± 21.4 nM and a maximal number of binding sites (Bmax) of 65.4 ± 6.8 fmol/mg protein (mean ± SEM, n = 4). The specific binding of [125I]CHIBA-1006 was inhibited by a number of α7 nAChR-selective ligands (e.g., unlabeled CHIBA-1006, SSR180711, CHIBA-1001, MG624 and A844606), suggesting a similarity among α7 nAChR pharmacological profiles. In contrast, α-bungarotoxin, MLA, and nicotine showed very weak affinity for [125I]CHIBA-1006 binding. The regional distribution of [125I]CHIBA-1006 binding to crude membranes from dissected regions of the rat brain was different from that of [125I]α-bungarotoxin binding, suggesting that [125I]CHIBA-1006 binding sites may not be identical to [125I]α-bungarotoxin binding sites in the rat brain. The present findings suggest that [125I]CHIBA-1006 would be a useful new small molecule radioligand for α7 nAChRs in the brain.

Research Highlights►The α7 nAChRs play a role in the pathophysiology of neuropsychiatric diseases. ►We developed the novel radioligand [125I]CHIBA-1006 for α7 nAChRs in rat brain. ►The presence of a high-affinity binding site for [125I]CHIBA-1006 was shown. ►[125I]CHIBA-1006 would be a new radioligand for studying α7 nAChRs in the brain.