Imaging of cerebral alpha(4)beta(2)* nicotinic acetylcholine receptors with (-)-[F-18]Flubatine PET: Implementation of bolus plus constant infusion and sensitivity to acetylcholine in human brain

摘要

The positron emission tomography (PET) radioligand (-)-[F-18] flubatine is specific to alpha(4)beta(2)* nicotinic acetylcholine receptors (nAChRs) and has promise for future investigation of the acetylcholine system in neuropathologies such as Alzheimer's disease, schizophrenia, and substance use disorders. The two goals of this work were to develop a simplified method for alpha(4)beta(2)* nAChR quantification with bolus plus constant infusion (B/I) (-)-[F-18]flubatine administration, and to assess the radioligand's sensitivity to acetylcholine fluctuations in humans. Healthy human subjects were imaged following either bolus injection (n = 8) or B/I (n = 4) administration of (-)-[F-18]flubatine. The metabolite-corrected input function in arterial blood was measured. Freefraction corrected distribution volumes (V-T/f(P)) were estimated with modeling and graphical analysis techniques. Next, sensitivity to acetylcholine was assessed in two ways: 1.A bolus injection paradigm with two scans (n = 6), baseline (scan 1) and physostigmine challenge (scan 2; 1.5 mg over 60 min beginning 5 min prior to radiotracer injection); 2.A single scan B/I paradigm (n = 7) lasting up to 240 min with 1.5 mg physostigmine administered over 60 min beginning at 125 min of radiotracer infusion. Changes in V-T/f(P) were measured. Baseline V-T/f(P) values were 33.8 +/- 3.3 mL/cm(3) in thalamus, 12.9 +/- 1.6 mL/cm(3) in cerebellum, and ranged from 9.8 to 12.5 mL/cm(3) in other graymatter regions. The B/I paradigm with equilibrium analysis at 120 min yielded comparable V-T/f(P) values with compartment modeling analysis of bolus data in extrathalamic gray matter regions (regional means <4% different). Changes in V-T/f(P) following physostigmine administration were small and most pronounced in cortical regions, ranging from 0.8 to 4.6% in the two-scan paradigm and 2.8 to 6.5% with the B/I paradigm. These results demonstrate the use of B/I administration for accurate quantification of (-)-[F-18] flubatine V-T/f(P) in 120 min, and suggest possible sensitivity of (-)-[F-18] flubatine binding to physostigmine-induced changes in acetylcholine levels. (C) 2016 Elsevier Inc. All rights reserved.