Wayne T. Stolle

An asymmetric synthesis of (R)‐5‐(methylamino)‐5,6‐dihydro‐4H‐imidazo‐[4,5,1‐ij]quinolin‐2(1H)‐one (1) and its [2‐14C]‐ and [6,7‐3H2]‐labeled forms

(R)-5-(Methylamino)-5,6-dihydro-4H-imidazo[4,5,1-ij]quinolin-2(1H)-one (1) is a dopamine agonist which shows selectivity for the D2 receptor subtype, and is of interest as a potential drug for the treatment of Parkinsons disease. An asymmetric epoxidation approach has been used to prepare 1 in eleven steps (15% overall yield) from 8-nitroquinoline. An advanced intermediate in this synthesis, tert-butyl (R)-methyl(8-amino-1,2,3,4-tetrahydro-3-quinolinyl)carbamate (10), has been reacted with [ 14 C]phosgene to provide a two-step synthesis of 1 labeled with carbon-14 at the C-2 position (236 μCi/mg). Bromination of 1 gave the dibromo analogue 12b which was reduced in the presence of tritium gas to give 1 labeled with tritium at the C-6 and C-7 positions (28.5 Ci/mmol). In addition to providing syntheses for labeled forms of the drug which are useful in drug disposition and receptor binding studies, this approach also provides a convenient synthesis for the unlabeled form of drug

Application of In-Line Liquid Chromatography-Accurate Radioisotope Counting-Mass Spectrometry (LC-ARC-MS) to Evaluate Metabolic Profile of [3H]-Mefenamic Acid in Rat Plasma

Profiling of rat plasma using a highly sensitive LC-ARC-MS technique showed that [(3)H] mefenamic acid was metabolized to several products, including a sulfate conjugate and a hydroxylated analogue as major metabolites. This technique of detecting low levels of radioactivity in plasma was superior to previously used methods, such as beta-RAM detectors.

An improved method for preparing tritium labeled fluoxetine

Palladium-on-charcoal catalyzed reduction of N-methyl-3-(3-bromo)phenyl-3-(4-trifluoromethyl)phenoxypropylamine (1) with tritium gas produces a mixture of the debrominated product [ 3 H]fluoxetine (2) and N-methyl-3-[3- 3 H]phenylpropylamine(3), which results from cleavage of the benzylic carbon-oxygen bond. Carrying out this reaction in the presence of pyridine eliminates hydrogenolysis and produces [ 3 H]fluoxetine as the sole product.

Synthesis of isotopically labeled CIS-(3aR)-(-)-2,3,3a,4,5,9b-hexahydro-3-(N-propyl)-1H-benz[e]indole-9-carboxamide, a 5-HT1A receptor agonist

The title compound is a potent and selective 5-HT 1A receptor agonist with clinical potentials for treating anxiety and depression. It has been labeled with stable and radioactive isotopes to support ADME studies in animals and human subjects. Its carboxamide group was labeled with C-14, C-13, or C-13, N-15, and O-18. To provide a radioligand for investigating the receptor binding characteristics of the compound, we also labeled it with tritium in the N-propyl group to obtain the high specific activity of 86.7 Ci/mmol.