Specific binding of [18F]fluoroethyl-harmol to monoamine oxidase A in rat brain cryostat sections, and compartmental analysis of binding in living brain

摘要

We investigated [18 F]fluoroethyl-harmol ([18 F]FEH) as a\udreversible 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 (K D = 3 nM), and density (B max\ud; 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\udshowed high permeability to brain (K 1 ; 0.32 mL/g/min) and\udslow washout (k 2 ; 0.024/min), resulting in a uniformly high equilibrium distribution volume (V D ; 20 mL/g). Using this V D 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 K D was globally close to 300 nM and B max 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\udbrain. Based on a synthesis of findings, we calculate the\udendogenous dopamine concentration to be 0.4 lM in the\udstriatal 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