RESUMO
We compared the influence of three different catechol-O-methyltransferase (COMT) inhibitors (CGP 28014, OR-611 and Ro 40-7592) on the metabolism of no-carrier-added (NCA) 6-[18F]fluoro-L-dopa (6-FDOPA) in one Rhesus monkey. All three COMT inhibitors improved 6-FDOPA availability in plasma, increased the specific uptake in the brain and thus improved 6-FDOPA uptake measurements using positron emission tomography (PET). Best results were obtained with Ro 40-7592.
Assuntos
Inibidores de Catecol O-Metiltransferase , Di-Hidroxifenilalanina/análogos & derivados , Inibidores Enzimáticos/farmacologia , Amidinas/farmacocinética , Amidinas/farmacologia , Animais , Benzofenonas/farmacocinética , Benzofenonas/farmacologia , Disponibilidade Biológica , Encéfalo/efeitos dos fármacos , Encéfalo/enzimologia , Encéfalo/metabolismo , Catecóis/farmacocinética , Catecóis/farmacologia , Di-Hidroxifenilalanina/metabolismo , Di-Hidroxifenilalanina/farmacocinética , Avaliação Pré-Clínica de Medicamentos/métodos , Inibidores Enzimáticos/farmacocinética , Feminino , Radioisótopos de Flúor , Macaca mulatta , Nitrilas , Nitrofenóis , Piridonas/farmacocinética , Piridonas/farmacologia , Tolcapona , Tomografia Computadorizada de EmissãoRESUMO
Using the copper assisted halogen exchange the MAO-B inhibitor Ro 43-0463, N-(2-aminoethyl)-5-iodo-2-pyridinecarboxamide, was labelled with 123I as well as with 125I to allow in vitro and in vivo investigations including SPET with healthy volunteers. Ro 43-0463 is known to inhibit reversibly and specifically MAO-B, having an IC50 of 3 x 10(-8) Mol/L. The labeling in the presence of CuSO4 and ascorbic acid was optimised, varying time (30 to 105 min), precursor concentration (1-3.5 mg) and temperature (130-200 degrees C). The labeling yield ranged between 60 and 70%. Purification was achieved with Lichrosorb RP-18 (5 micron, 250 x 8 mm) and 1.5 mL/min 0.36 M H3PO4/EtOH 97/3 [0.01 M (NH4)2HPO4]. After neutralisation and sterile filtration the final activity concentration ranged between 18.5 and 37 MBq/mL. Biodistribution studies showed a brain to blood ratio greater than 1 within 1 h p.i. The main radiation burden calculated from these animal data is to alimentary and excretory organs and the ovaries. Autoradiography was performed using rat brain slices and 5 nM [125I]Ro 43-0463 in TRIS-buffer pH 7.4 for 90 min at 20 degrees C. Its radioactivity pattern corresponds to the known distribution of MAO-B in the rat brain. By displacement with L-deprneyl the highly specific binding of R0 43-0463 was proven in vitro. SPECT studies with normal volunteers corresponded with the pattern found in autoradiography.