title: Imaging of cerebral α4β2* nicotinic acetylcholine receptors with (-)-[(18)F]Flubatine PET: Implementation of bolus plus constant infusion and sensitivity to acetylcholine in human brain.
abstract: The positron emission tomography (PET) radioligand (-)-[(18)F]flubatine is specific to α4β2(⁎) 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 α4β2(⁎) nAChR quantification with bolus plus constant infusion (B/I) (-)-[(18)F]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 (-)-[(18)F]flubatine. The metabolite-corrected input function in arterial blood was measured. Free-fraction corrected distribution volumes (VT/fP) 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; 1.5mg over 60min beginning 5min prior to radiotracer injection); 2. A single scan B/I paradigm (n=7) lasting up to 240min with 1.5mg physostigmine administered over 60min beginning at 125min of radiotracer infusion. Changes in VT/fP were measured. Baseline VT/fP values were 33.8±3.3mL/cm(3) in thalamus, 12.9±1.6mL/cm(3) in cerebellum, and ranged from 9.8 to 12.5mL/cm(3) in other gray matter regions. The B/I paradigm with equilibrium analysis at 120min yielded comparable VT/fP values with compartment modeling analysis of bolus data in extrathalamic gray matter regions (regional means <4% different). Changes in VT/fP 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 (-)-[(18)F]flubatine VT/fP in 120min, and suggest possible sensitivity of (-)-[(18)F]flubatine binding to physostigmine-induced changes in acetylcholine levels.
authors.affiliation: Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, United States; Yale PET Center, Yale University School of Medicine, New Haven, CT, United States. Electronic address: ansel.hillmer@yale.edu.
authors.forename: A T
authors.initials: AT
authors.lastname: Hillmer
authors.affiliation: Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, United States; Yale PET Center, Yale University School of Medicine, New Haven, CT, United States; Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States.
authors.forename: I
authors.initials: I
authors.lastname: Esterlis
authors.affiliation: Yale PET Center, Yale University School of Medicine, New Haven, CT, United States.
authors.forename: J D
authors.initials: JD
authors.lastname: Gallezot
authors.affiliation: Yale PET Center, Yale University School of Medicine, New Haven, CT, United States.
authors.forename: F
authors.initials: F
authors.lastname: Bois
authors.affiliation: Yale PET Center, Yale University School of Medicine, New Haven, CT, United States.
authors.forename: M Q
authors.initials: MQ
authors.lastname: Zheng
authors.affiliation: Yale PET Center, Yale University School of Medicine, New Haven, CT, United States.
authors.forename: N
authors.initials: N
authors.lastname: Nabulsi
authors.affiliation: Yale PET Center, Yale University School of Medicine, New Haven, CT, United States.
authors.forename: S F
authors.initials: SF
authors.lastname: Lin
authors.affiliation: Department of Pharmacology and Therapeutics, University of Florida, Gainesville, FL, United States.
authors.forename: R L
authors.initials: RL
authors.lastname: Papke
authors.affiliation: Yale PET Center, Yale University School of Medicine, New Haven, CT, United States.
authors.forename: Y
authors.initials: Y
authors.lastname: Huang
authors.affiliation: Department of Nuclear Medicine, University of Leipzig, Leipzig, Germany.
authors.forename: O
authors.initials: O
authors.lastname: Sabri
authors.affiliation: Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, United States; Yale PET Center, Yale University School of Medicine, New Haven, CT, United States.
authors.forename: R E
authors.initials: RE
authors.lastname: Carson
authors.affiliation: Department of Radiology and Biomedical Imaging, Yale University School of Medicine, New Haven, CT, United States; Yale PET Center, Yale University School of Medicine, New Haven, CT, United States; Department of Psychiatry, Yale University School of Medicine, New Haven, CT, United States; Department of Neurobiology, Yale University School of Medicine, New Haven, CT, United States.
authors.forename: K P
authors.initials: KP
authors.lastname: Cosgrove
mesh_terms: D000109:Acetylcholine / Q000378:metabolism*; D000328:Adult; D001549:Benzamides / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism*; D019086:Bridged Bicyclo Compounds, Heterocyclic / Q000008:administration & dosage / Q000493:pharmacokinetics*; D003198:Computer Simulation; D006801:Humans; D007090:Image Interpretation, Computer-Assisted / Q000379:methods; D057967:Infusions, Intraventricular; D008657:Metabolic Clearance Rate; D008875:Middle Aged; D008959:Models, Neurological; D057054:Molecular Imaging / Q000379:methods*; D018377:Neurotransmitter Agents / Q000378:metabolism; D049268:Positron-Emission Tomography / Q000379:methods*; D019275:Radiopharmaceuticals / Q000008:administration & dosage / Q000493:pharmacokinetics; D011978:Receptors, Nicotinic / Q000378:metabolism*; D015203:Reproducibility of Results; D012680:Sensitivity and Specificity; D014018:Tissue Distribution; D055815:Young Adult
chemical_list: D001549:Benzamides; D019086:Bridged Bicyclo Compounds, Heterocyclic; D018377:Neurotransmitter Agents; D019275:Radiopharmaceuticals; D011978:Receptors, Nicotinic; C115362:fluoronorchloroepibatidine; C403531:nicotinic receptor alpha4beta2; D000109:Acetylcholine