title: PET imaging of acetylcholinesterase inhibitor-induced effects on α4β2 nicotinic acetylcholine receptor binding.
abstract: Acetylcholinesterase inhibitors (AChEIs) are drugs that increase synaptic acetylcholine (ACh) concentrations and are under investigation as treatments for symptoms accompanying Alzheimer's disease. The goal of this work was to use PET imaging to evaluate alterations of in vivo α4β2 nicotinic acetylcholine receptor (nAChR) binding induced by the AChEIs physostigmine (PHY) and galanthamine (GAL). The α4β2 nAChR-specific radioligand [(18)F]nifene was used to examine the effects of 0.1-0.2 mg/kg PHY, 5 mg/kg GAL, and saline in three separate experiments all performed on each of two rat subjects. A 60-min bolus-infusion protocol was used with drug administered after 30 min. Data from the thalamus and cortex were analyzed with a graphical model accounting for neurotransmitter activation using the cerebellum as a reference region to test for transient competition with bound [(18) F]nifene. Significant [(18) F]nifene displacement was detected in both regions during one PHY and both GAL studies, while no significant competition was observed in both saline studies. This preliminary work indicates the viability of [(18) F]nifene in detecting increases in synaptic ACh induced by AChEIs.
authors.affiliation: Department of Medical Physics, University of Wisconsin-Madison, Madison, Wisconsin, 53705; Waisman Brain Imaging Laboratory, University of Wisconsin-Madison, Madison, Wisconsin, 53705.
authors.forename: Ansel T
authors.initials: AT
authors.lastname: Hillmer
authors.forename: Dustin W
authors.initials: DW
authors.lastname: Wooten
authors.forename: Mohammed
authors.initials: M
authors.lastname: Farhoud
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Higgins
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Lao
authors.forename: Todd E
authors.initials: TE
authors.lastname: Barnhart
authors.forename: Jogeshwar
authors.initials: J
authors.lastname: Mukherjee
authors.forename: Bradley T
authors.initials: BT
authors.lastname: Christian
mesh_terms: D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology*; D005260:Female; D005702:Galantamine / Q000494:pharmacology*; D010830:Physostigmine / Q000494:pharmacology*; D049268:Positron-Emission Tomography; D011725:Pyridines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D011978:Receptors, Nicotinic / Q000378:metabolism*
chemical_list: D002800:Cholinesterase Inhibitors; D011725:Pyridines; D011758:Pyrroles; D011978:Receptors, Nicotinic; C403531:nicotinic receptor alpha4beta2; C515562:nifene; D005702:Galantamine; D010830:Physostigmine
keywords: PET; [18F]nifene; acetylcholinesterase inhibitors; galanthamine; nicotinic acetylcholine receptor; physostigmine
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