Synthesis and evaluation of 5,7-dihydro-3-[2-[1-(4-[18F] fluorobenzyl)-4-piperidinyl]ethyl]-6H-pyrrolo[3,2-f]1,2-benzisoxazol-6-one for in vivo mapping of acetylcholinesterase

Objectives Acetylcholinesterase (AChE) is an important cholinergic marker for the diagnosis of Alzheimer's disease (AD). A recent study has demonstrated that C-11-labelled 5,7-dihydro-7-methyl-3-[2-[1-(phenylmethyl)4-piperidinyl]ethyl]-6H-pyrrolo[3,2-f]-1,2-benzisoxazol- 6-one (CP-126,998) shows promising results. The demethylated form of this ligand (CP-118,954) is a more potent and selective inhibitor than CP-126,998. In this study, therefore, CP-118,954 was labelled with F-18 and evaluated for the in vivo mapping of AChE. Methods The 4-fluoro (1) and 2-fluoro (2) derivatives of CP-118,954 were synthesized from 4-methyl-3-nitroanisole in 11 steps. Their in vitro binding affinities to AChE were measured using Ellman's method. The preparation of [F-18]-1 was carried out by reductive alkylation of the piperidine precursor with 4-[F-18]-fluorobenzaidehyde, followed by high-performance liquid chromatography (HPLC) purification. In vitro autoradiography was performed by incubating rat brain coronal slices with [F-18]-1. Tissue distribution studies were performed in mouse brain and the data were expressed as the percentage of the injected dose per gram of tissue (%ID-g(-1)). Results Two fluorine-substituted AChE inhibitors were synthesized and their in vitro binding data showed that the 4-fluoro and 2-fluoro derivatives (1 and 2) had similar or superior binding affinity to that of the unsubstituted ligand, CP-118,954. The F-18-labelled ligand was synthesized in 20-35% radiochemical yield (EOS) and with high effective specific activity (36-42 GBq(.)mumol(-1)). Autoradiography showed high uptake of [F-18]-1 in the striatum and this striatal uptake was completely inhibited by the unlabelled ligand 1. Tissue distribution studies demonstrated that high radioactivity was accumulated in the striatum, an AChE-rich region. Conclusions This study demonstrates that [F-18]-1 may hold promise as a radioligand for the in vivo mapping of AChE. (C) 2004 Lippincott Williams Wilkins.