PET Brain imaging of α7-nAChR with [18F]ASEM

Abstract The α7 nicotinic acetylcholine receptor (nAChR) increasingly has been implicated in normal brain physiology, as well as in neuropsychiatric disorders. The α7-nAChR primarily is located in cerebral cortex and sub-cortical regions, compared to the α4β2 nAChR subtype that has a more subcortical distribution. The highly cortical distribution suggests a role of α7-nAChR in cognition. We expanded the first-in-human PET imaging of α7-nAChR with [ 18 F]ASEM from five to 21 healthy non-smoking volunteers and added preliminary evidence of binding in six male patients with schizophrenia. Study aims included 1) confirmation of test-retest reproducibility of [ 18 F]ASEM binding in normal volunteers, 2) demonstration of specificity of [ 18 F]ASEM binding by competition with DMXB-A, an α7-nAChR partial agonist previously tested in clinical trials of patients with schizophrenia, 3) estimation of [ 18 F]ASEM binding potentials and α7-nAChR density in vivo in humans, and 4) α7-nAChR binding in patients with schizophrenia compared to healthy volunteers. Test-retest PET confirmed reproducibility (>90%) (variability ≤ 7%) of [ 18 F]ASEM volume of distribution ( V T ) estimates in healthy volunteers. Repeated sessions of PET in five healthy subjects included baseline and effect of inhibition after oral administration of 150 mg DMXB-A. From reduction of binding potentials, we estimated the dose-dependent occupancy of α7-nAChR by DMXB-A at 17–49% for plasma concentrations at 60–200 nM DMXB-A. In agreement with evidence post-mortem, α7-nAChR density ( B max ) averaged 0.67–0.82 nM and inhibitor affinity constant ( K I ) averaged 170–385 nM. Median V T in the six patients with schizophrenia was lower than in healthy volunteers in cingulate cortex, frontal cortex, and hippocampus. Mann-Whitney test identified cingulate cortex and hippocampus as regions with significantly lower median V T in patients than in healthy volunteers when a single outlier patient was excluded from analysis (P = 0.02, corrected for multiple comparisons).