title: Specific binding of [(18)F]fluoroethyl-harmol to monoamine oxidase A in rat brain cryostat sections, and compartmental analysis of binding in living brain.
abstract: We investigated [(18)F]fluoroethyl-harmol ([(18)F]FEH) as a reversible and selective ligand for positron emission tomography (PET) studies of monoamine oxidase A (MAO-A). Binding of [(18)F]FEH in rat brain cryostat sections indicated high affinity (KD = 3 nM), and density (Bmax; 600 pmol/g). The plasma free fraction was 45%, and untransformed parent constituted only 13% of plasma radioactivity at 10 min after injection. Compartmental analysis of PET recordings in pargyline-treated rats showed high permeability to brain (K1; 0.32 mL/g/min) and slow washout (k2; 0.024/min), resulting in a uniformly high equilibrium distribution volume (VD; 20 mL/g). Using this VD to estimate unbound ligand in brain of untreated rats, the binding potential ranged from 4.2 in cerebellum to 7.2 in thalamus. We also calculated maps of rats receiving [(18)F]FEH at a range of specific activities, and then estimated saturation binding parameters in the living brain. In thalamus, striatum and frontal cortex KD was globally close to 300 nM and Bmax was close to 1600 pmol/g; the 100-fold discrepancy in affinity suggests a very low free fraction for [(18)F]FEH in the living brain. Based on a synthesis of findings, we calculate the endogenous dopamine concentration to be 0.4 μM in the striatal compartment containing MAO-A, thus unlikely to exert competition against [(18)F]FEH binding in vivo. In summary, [(18)F]FEH has good properties for the detection of MAO-A in the rat brain by PET, and may present logistic advantages for clinical research at centers lacking a medical cyclotron. We made a compartmental analysis of [(18)F]fluoroethylharmol ([(18)F]FEH) binding to monoamine oxidase A (MAO-A) in living rat brain and estimated the saturation binding parameters from the binding potential (BPND). The Bmax was of comparable magnitude to that in vitro, but with apparent affinity (300 nM), it was 100-fold lower in vivo. PET imaging with [(18) F]FEH is well suited for quantitation of MAO-A in living brain.
authors.affiliation: Laboratory of Molecular Imaging and Radiochemistry, Department of Nuclear Medicine, Friedrich Alexander University, Erlangen, Germany.
authors.forename: Simone
authors.initials: S
authors.lastname: Maschauer
authors.affiliation: Laboratory of Molecular Imaging and Radiochemistry, Department of Nuclear Medicine, Friedrich Alexander University, Erlangen, Germany.
authors.forename: Adelina
authors.initials: A
authors.lastname: Haller
authors.affiliation: Department of Chemistry, Universitetet i Oslo & Norsk Medisinisk Syklotronsenter AS, Oslo, Norway.
authors.forename: Patrick J
authors.initials: PJ
authors.lastname: Riss
authors.affiliation: Laboratory of Molecular Imaging and Radiochemistry, Department of Nuclear Medicine, Friedrich Alexander University, Erlangen, Germany.
authors.forename: Torsten
authors.initials: T
authors.lastname: Kuwert
authors.affiliation: Laboratory of Molecular Imaging and Radiochemistry, Department of Nuclear Medicine, Friedrich Alexander University, Erlangen, Germany.
authors.forename: Olaf
authors.initials: O
authors.lastname: Prante
authors.affiliation: Department of Neuroscience and Pharmacology, Copenhagen University, Copenhagen, Denmark.|Department of Neuropsychiatry and Psychosomatic Medicine, OUS-Rikshospitalet, Oslo, Norway.
authors.forename: Paul
authors.initials: P
authors.lastname: Cumming
mesh_terms: D000818:Animals; D001345:Autoradiography; D001921:Brain / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D006247:Harmine / Q000031:analogs & derivatives* / Q000097:blood / Q000493:pharmacokinetics; D066298:In Vitro Techniques; D008024:Ligands; D008297:Male; D008995:Monoamine Oxidase / Q000378:metabolism*; D008996:Monoamine Oxidase Inhibitors / Q000097:blood / Q000493:pharmacokinetics*; D049268:Positron-Emission Tomography; D011485:Protein Binding / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors
chemical_list: C000599711:7-(2-fluoroethoxy)-1-methyl-9H-beta-carboline; D008024:Ligands; D008996:Monoamine Oxidase Inhibitors; D006247:Harmine; D008995:Monoamine Oxidase
keywords: MAO-A; PET; fluorine-18; fluoroethyl-harmol; β-carbolines