[³H]Chiba-1001(methyl-SSR180711) has low in vitro binding affinity and poor in vivo selectivity to nicotinic alpha-7 receptor in rodent brain.

Neuronal nicotinic acetylcholine receptor (nAChR) agonists active at the alpha-7 (α-7) receptor subtype are potential therapeutics for cognitive deficits in schizophrenia, Alzheimer's disease, and other mental disorders. SSR180711, an α-7 selective partial agonist, has been shown to improve preclinical cognition. A novel positron emission tomography (PET) radioligand, ¹¹C-Chiba1001, is a close analog of SSR180711. We labeled Chiba-1001 with tritium in order to evaluate its utility as a preclinical radioligand tool. In vitro, the binding affinity of [³H]Chiba-1001 at the α-7 receptor was low (K(d) = 120-180 nM) in both HEK239 cell membranes expressing human α-7 receptor and in native rat hippocampus membranes. The α-7 selective ligands AZD0328, ARR17779, and MLA did not inhibit [³H]Chiba-1001 binding (K(i) > 10,000 nM). In rat hippocampal membranes, Chiba-1001 and SSR180711 inhibited [³H]Chiba-1001 binding (K(i) = 220 and 230 nM, respectively), consistent with the literature reports. The in vivo binding profile of the radioligand was examined in normal rat, wild type mouse, and α-7 knockout mouse brain. We found that [³H]Chiba-1001 lacks adequate and specific brain regional uptake in rat and mouse brain. No significant inhibition of the radioligand binding was obtained following pretreatment of the animal with AZ11637326, AZD0328, or MLA. Our results indicate that [³H]Chiba-1001 has low affinity for α-7 nAChRs in vitro and poor α-7 regional and pharmacological selectivity in the rodent brain.