Synthesis and enantiomeric evaluation of radiolabelled methyl phenidate for the study of dopamine reuptake sites
Loading...
Date
2002-04-29
Journal Title
Journal ISSN
Volume Title
Publisher
Australasian Environmental Isotope Conference
Abstract
Neurological diseases such as Parkinson's Disease and associated Movement Disorders have been characterised by reductions in the number of dopamine re-uptake sites or dopamine transporters (DAT) on presynaptic neurons in the striatum. Radiolabelled drugs which display specific and selective binding to the DAT has thus found clinical utility in medical imaging. The psychomotor stimulant methyl phenidate (MP) or Ritalin 1 and several derivatives have demonstrated high affinity binding to these DAT where they exert their pharmacological action. MP possesses two chiral centers with its pharmacological activity being attributed to the dl-threo diastereomer, the dl-erythro being inactive. Furthermore, imaging studies using Positron Emission Tomography (PET) with carbon-11 radiolabelled MP confirmed the d-threo enantiomer to be most active. In vitro studies indicate that compounds substituted with either bromine or iodine in the 3 position of the aromatic ring exhibit high affinity and selective binding to DAT and were thus targeted for radiolabelling with both the PET tracer Bromine-76 as well as the SPECT tracer lodione-123. Threo methyl phenidate and its halogenated derivatives were prepared by the condensation of 3-bromophenylacetonitrile and 2-bromopyridine according to modified literature methods. Radiohalogenation with either 76Br or 123I was achieved by halodestannylation reactions of the corresponding tributyl stannane precursor in the presence of chloramine-T as the oxidant. Purification by C-18 reverse phase HPLC gave the dl-threo product in 70-80% radiochemical yield and in greater than 95% radiochemical purity. Separation of the d and / enantiomers was achieved by chiral HPLC. Biodistribution studies in rodents indicated high uptake of radioactivity in tissues with known DAT sites. PET and SPECT imaging studies in primates indicated high uptake in the striatum compared to the cerebellum reference tissue. The synthesis, diastereomeric separation, structure activity studies, radiolabelling and biological studies of these compounds will be presented,
Description
Keywords
Aromatics, Carbon 11, Enantiomorphs, Iodine 123, Positron computed tomography, Radiopharmaceuticals, Single photon emission computed tomography, Synthesis, Bromine 76, Dopamine, Nervous system diseases
Citation
Katsifis, A., Mattner, F., Mardon, K., Dikic, B., Papazian, V., Jackson, T., & Greguric, I. (2002). Synthesis and enantiomeric evaluation of radiolabelled methyl phenidate for the study of dopamine reuptake sites. Poster presented to the France-Australia symposium on nuclear medicine : methodology, clinical applications and pharmacology : volume of proceedings, Monday 29th April 2002, Sheraton on the park, Sydney, Australia. Lucas Heights, NSW : Australian Nuclear Science and Technology Organisation, (pp. 62).