Novel synthesis of [¹¹C]GVG (vigabatrin) for pharmacokinetic studies of addiction treatment

Abstract

We have shown that gamma vinyl-GABA (GVG, VigabatrinR), a selective suicide inhibitor of GABA-transaminase (GABA-T), inhibits the effects of cocaine, nicotine, heroin, alcohol and methamphetamine both biochemically (dopamine) and behaviorally in rodents and primates. These data strongly suggest that the, use of GVG may represent a new strategy for the treatment of substance abuse [l]. To better understand the mechanism associated with this inhibition and the pharmacokinetics, as well as the potential side effects of this drug, we carried 'out investigations on developing a radiosynthesis of ["CIGVG for PET studies (tll2 for C-11 = 20 min). Several synthetic routes for the preparation of GVG including radiolabeling with longlived I4C (t1n for C-14 = 5730 yr) have been published [2, 31; however, they are not suitable for C-11 radiosynthesis. For example, a procedure,to prepare the key 2oxopyrrolidine-5-carboxaldehyde precursor that would in principle allow the incorporation of C-1 1 by employing Wittig condensation with["C]methyltriphenylphosphonium iodide was not straightforward (Scheme 1) [4, 5 , Kihlberg, 1990 #6, 61, We experienced this in our initial trials and other researchers made similar observations. Difficulties encountered during the isolation of the aldehyde precursor, its instability for storage, +s well as the subsequent timeconsuming Wittig reaction prompted us to pursue another synthetic pathway. Scheme 1

28 Radiochemistry

“…4-[ 11 C]amino-acids 98 have been made in this way as has [ 11 C]vigabatgrin. 99 Reduction of the nitrile will, of course, lead to an amine, and this route has been chosen 100 Much of [ 14 C]radiochemistry is even more run of the mill than that of carbon-11. But it is interesting to report the preparation of -phenylalanine 106 and -tyrosine 107 each labelled at either the 1 or the 2 position.…”

“…Pre-treatment of the alumina substrate was found to be particularly important 41 for a gallium-68 generator, whilst a supported liquid membrane 42, 43 was used to allow the passage of just yttrium-90 from pre-treated high level reactor waste. Generators are particularly popular as a source of technetium ( 99m Tc from the decay of 99 Mo) and improvements are continually reported; some recent ideas have included zirconium-molybdenum gels 44 and the use of alumina 45 or titanium polymers 46 as adsorbants.…”