Brain PET Imaging of [alpha]7-nAChR with [18F]ASEM: Reproducibility, Occupancy, Receptor Density, and Changes in Schizophrenia

• Published in: The international journal of neuropsychopharmacology 2018-07, Vol.21 (7), p.656
• Main Authors: Wong, Dean F, Kuwabara, Hiroto, Ho, Roberts, Joshua M, Nandi, Ayon, Cascella, Nicola, Brasic, James, Weerts, Elise M, Kitzmiller, Kelly, Phan, Jenny A, Gapasin, Lorena, Sawa, Akira, Valentine, Heather, Wand, Gary, Mishra, Chakradhar, George, Noble, McDonald, Michael, Lesniak, Wojtek, Holt, Daniel P, Azad, Babak B, Dannals, Robert F, Kem, William, Freedman, Robert, Gjedde, Albert
• Format: Article
• Language: English
• Subjects: Brain; Medical research; Medicine, Experimental; Nervous system diseases; PET imaging; Physiological aspects; Schizophrenia
• ISSN: 1461-1457
• DOI: 10.1093/ijnp/pyy021

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 [[.sup.18]F]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 [[.sup.18]F]ASEM binding, (2) demonstration of specificity by competition with DMXB-A, an [alpha]7 nicotinic acetylcholine receptor partial agonist, (3) estimation of [[.sup.18]F]ASEM binding potentials and [alpha]7 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 [greater than or equal to]7%) of [[.sup.18]F]ASEM volume of distribution ([V.sub.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.sub.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 [[.sup.18]F]ASEM [V.sub.T] estimates and the specificity of the tracer for [alpha]7 nicotinic acetylcholine receptor. Preliminary findings from our feasibility study of [[.sup.18]F]ASEM binding in patients with schizophrenia are suggestive and provide guidance for future studies with more subjects. Keywords: PET imaging, nicotinic acetylcholine receptors, schizophrenia