Brain PET Imaging of α7-nAChR with [18F]ASEM: Reproducibility, Occupancy, Receptor Density, and Changes in Schizophrenia

Background: The alpha 7 nicotinic acetylcholine receptor increasingly has been implicated in normal brain physiology, as well as in neuropsychiatric disorders. The highly cortical distribution of alpha 7 nicotinic acetylcholine receptor suggests a role in cognition. Methods: We expanded the first-in-human PET imaging of alpha 7 nicotinic acetylcholine receptor with [F-18]ASEM from 5 to 21 healthy nonsmoking volunteers and added a feasibility study in 6 male patients with schizophrenia. Study aims included: (1) confirmation of test-retest reproducibility of [F-18]ASEM binding, (2) demonstration of specificity by competition with DMXB-A, an alpha 7 nicotinic acetylcholine receptor partial agonist, (3) estimation of [F-18]ASEM binding potentials and a7 nicotinic acetylcholine receptor density in vivo in humans, and (4) demonstrating the feasibility of studying alpha 7 nicotinic acetylcholine receptor as a target for schizophrenia. Results: Test-retest PET confirmed reproducibility (> 90%) (variability <= 7%) of [F-18]ASEM volume of distribution (V-T) estimates in healthy volunteers. Repeated sessions of PET in 5 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 alpha 7 nicotinic acetylcholine receptor by DMXB-A at 17% to 49% for plasma concentrations at 60 to 200 nM DMXB-A. In agreement with evidence postmortem, alpha 7 nicotinic acetylcholine receptor density averaged 0.67 to 0.82 nM and inhibitor affinity constant averaged 170 to 385 nM. Median V-T in a feasibility study of 6 patients with schizophrenia was lower than in healthy volunteers in cingulate cortex, frontal cortex, and hippocampus (P = 0.02, corrected for multiple comparions, Mann-Whitney test). Conclusions: The current results confirm the reproducibility of [F-18]ASEM V-T estimates and the specificity of the tracer for alpha 7 nicotinic acetylcholine receptor. Preliminary findings from our feasibility study of [F-18]ASEM binding in patients with schizophrenia are suggestive and provide guidance for future studies with more subjects.