Preparation and pharmacological evaluation of a new central muscarinic cholinergic receptor imaging agent [76Br]-4-bromodexetimide

Muscarinic cholinergic receptors (mAChR) play an important role in a number of physiological and behavioural responses. The putative role of muscarinic receptors in neurodegenerative disorders such as Alzheimer's disease, Huntington's disease and dementias associated with Parkinson's disease has generated considerable interest for the non invasive mapping of mAChR. Potential muscarinic imaging agents include 11C- and 123I-QNB analogs, 11C-scopolamine and 11C-benztropine while radiolabelled dexetimide derivatives have shown exciting potential. Simpler methods for the preparation of dexetirnide derivatives incorporating. longer lived isotopes suitable forPET studies is required. We are reporting the synthesis and the pharmacological characterisation of a bromine-76 derivative of dexetimide suitable for PET studies. The radiosynthesis of [7‘Br]-4-bromodexetimide ([7‘Br]-BDEX) was carried out by bromination via electrophilic bromodesilylation with no carrier added [76Br]NT-I4. During the preparation of this radiopharmaceutical a number of reaction conditions and reagents were examined. Oxidising agent such as peracetic acid and dichloramine-T were evaluated and found inefficient while chloramine-T appeared the reagent of choice. Peracetic acid reactions were carried out in acetic acid with radiochemical yields of 6% obtained. Dichloromi.ne~T reactions were conducted in both methanol and TFA solvent with radiochemical yields of 10% and 24% respectively. The choramine-T reactions were most efficient but were also concentration and solvent dependent. The optimum labelling conditions were found to be the use of chloramine-T (10-3M) in 0.1N HC1 at room temperature for l5 min followed by addition of a sodium metabisulte solution (fig. 1). Under these conditions the radiochemical yield reaches 80%. The purification and isolation of the radiotracer from the reaction mixture was carried out by HPLC on a µ-Bondapaku-Bondapak C18 column (300 x 7.8 mm) with a mixture of acetonitrile and ammonium acetate buffer (45:55) as the mobile phase and a ow rate of 2.5 ml/min while UV absorption was measured at 239 nm. Radiochemical and chemical purities assessed by radio-TLC and HPLC were 98% with a specific activity of 11 GBq/µmol/L.

Description

Physical copy held by ANSTO Library at DDC: 616.07575/115.

Keywords

Pharmacology, Receptors, Neurology, Synthesis, Aging, Labelling, Radiopharmaceuticals, Chloramines, Concentration ratio, Reagents, Rats, Rodents, Data, Cerebral cortex, Sodium, Acetonitrile, Hippocampus

Citation

Kassiou, M., Loc'h, C., Bottlander, M., Lambrecht, R. M., Katsifis, A., Schmidm L., Ottaviani, M., Maziere, M., & Masiere, B. (1993). Preparation and pharmacological evaluation of a new central muscarinic cholinergic receptor imaging agent [76Br]-4-bromodexetimide. Paper presented to the Tenth International Symposium on Radiopharmaceutical Chemistry, Kyoto University (October 25-28, 1983), (pp. 229-231). Kyoto, Japan : Kyoto University.