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

Autor: Michael A. McDonald, Elise M. Weerts, James Robert Brašić, Babak Behnam Azad, Joshua Roberts, Akira Sawa, Kelly Kitzmiller, Robert Freedman, Albert Gjedde, Chakradhar Mishra, Noble George, Lorena Gapasin, Nicola G. Cascella, Wojtek Lesniak, Jenny A. Phan, Ayon Nandi, Hiroto Kuwabara, Daniel P. Holt, Robert F. Dannals, Dean F. Wong, Andrew G. Horti, William R. Kem, Gary S. Wand, Heather Valentine
Jazyk: angličtina
Rok vydání: 2018
Předmět:
Zdroj: Wong, D F, Kuwabara, H, Horti, A G, Roberts, J M, Nandi, A, Cascella, N, Brasic, J, Weerts, E M, Kitzmiller, K, Phan, J A, Gapasin, L, Sawa, A, Valentine, H, Wand, G, Mishra, C, George, N, McDonald, M, Lesniak, W, Holt, D P, Azad, B B, Dannals, R F, Kem, W, Freedman, R & Gjedde, A 2018, ' Brain PET Imaging of α7-nAChR with [18F]ASEM : Reproducibility, Occupancy, Receptor Density, and Changes in Schizophrenia ', International Journal of Neuropsychopharmacology, vol. 21, no. 7, pp. 656-667 . https://doi.org/10.1093/ijnp/pyy021
International Journal of Neuropsychopharmacology
Wong, D F, Kuwabara, H, Horti, A G, Roberts, J M, Nandi, A, Cascella, N, Brasic, J, Weerts, E M, Kitzmiller, K, Phan, J A, Gapasin, L, Sawa, A, Valentine, H, Wand, G, Mishra, C, George, N, McDonald, M, Lesniak, W, Holt, D P, Azad, B B, Dannals, R F, Kem, W, Freedman, R & Gjedde, A 2018, ' Brain PET imaging of α7-nAChR with [18F]ASEM : Reproducibility, occupancy, receptor density, and changes in schizophrenia ', International Journal of Neuropsychopharmacology, vol. 21, no. 7, pp. 656-667 . https://doi.org/10.1093/ijnp/pyy021
Popis: Background: The α7 nicotinic acetylcholine receptor increasingly has been implicated in normal brain physiology, as well as in neuropsychiatric disorders. The highly cortical distribution of α7 nicotinic acetylcholine receptor suggests a role in cognition. Methods: We expanded the first-in-human PET imaging of α7 nicotinic acetylcholine receptor with [18F]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 [18F]ASEM binding, (2) demonstration of specificity by competition with DMXB-A, an α7 nicotinic acetylcholine receptor partial agonist, (3) estimation of [18F]ASEM binding potentials and α7 nicotinic acetylcholine receptor density in vivo in humans, and (4) demonstrating the feasibility of studying α7 nicotinic acetylcholine receptor as a target for schizophrenia. Results: Test-retest PET confirmed reproducibility (>90%) (variability ≤7%) of [18F]ASEM volume of distribution (VT) 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 α7 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, α7 nicotinic acetylcholine receptor density averaged 0.67 to 0.82 nM and inhibitor affinity constant averaged 170 to 385 nM. Median VT 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 [18F]ASEM VT estimates and the specificity of the tracer for α7 nicotinic acetylcholine receptor. Preliminary findings from our feasibility study of [18F]ASEM binding in patients with schizophrenia are suggestive and provide guidance for future studies with more subjects.
Databáze: OpenAIRE
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