Eleventh international symposium on radiopharmaceutical chemistry: Abstracts

Abstract

Aniracetam ( I-p-anisoyl-2-pyrrolidinone) is one of the piracetam-like nootropics which exhibit memory enhancing properties1 . Although the therapeutic potentials of aniracetam in patients with senile cognitive disorders such as Alzheimer's disease has been evaluated2 and this drug is now used in clinical trials in Europe, the mechanism of action is not fully understood. Recently, aniracetam has been shown to increase the conductance of a-amino-3-hydroxy-5methyl4isoxazole propionate (AMPA) receptor, but not to Kainate and N-methyl-D-asparatate (NMDA) receptors3, all of which are subtypes of glutamate receptors. This potentiation has been suggested to be due to a reduced rate of desensitization of the receptor in the presence of aniracetam4. The glutamate receptors are known to mediate excitatory neurotransmission in brains and are important in memory acquisition, learning, and some neurodegenerative disorders. Due to the lack of potent and selective antagonists, however, the characterization of AMPA receptor is less advanced compared with that of NMDA receptor. The purpose of this study is to clear in vivo distribution characteristic of aniracetam in rodent brains by employing a positron-emitter labelled aniracetam and positron emission tomography (PET), and this study might offer a promising prospect of developing the radioligands for studying AMPA receptor by PET. Here we report the radiosynthesis of carbon-1 1 labelled aniracetam ([ k1aniracetam)along with its brain biodistribution in mice.Aniracetam and a precursor (IJ for the radiosynthesis were synthesized as shown in Scheme 1.Reaction of equimolar amounts of p-anisoylchloride, 2-pyrrolidone, and triethylamine in dry ether (reflux for 2 4 h) and subsequent silica gel column chromatography (CHC13) gave aniracetam. The precursor (lJ was prepared by demethylation of aniracetam with boron tribromide (3 equivalent, -10°Cr.t. for 14 h)5 in dry CH2Cl2 and subsequent purification by silica gel column chromatography (CHClglethyl acetate = 91 1). The chemical structures of these compounds were identified by spectral analyses6. Carbon-I 1 labelling has been achieved by Omethylation of 1 (1 mg) with I 11C]iodomethane7 in DMF (500 pl) in the presence of NaH (ca 5 pmol) at 50°C for 5 min.HPLC purification (Megapak SIL C18, JASCO Co.; 35% CH3CN; 3 ml1min) of the crude lCreaction mixture gave radiochemically and chemically pure (>99%) [ 1 lC]aniracetam. The identity of amposium Abstracts 413These compounds are all fairly lipophilic and can be synthesized with fluorine groups away from the active binding elements of the molecule using one of the new nucleophilicfluorination methods recently developed." The pharmacology has been performed with the standard methods described below to determine the specificity and potency of the compounds after fluorination.Coronal slices from rat brain (500 pm) were hemisected at the midpoint and again from cortex to mid brain to give wedge shaped sections. The sections were placed across a grease seal in a dual chambered bath containing CsF...