Richard S. P. Hsi

Preparation of [14c]colestipol hydrochloride and its disposition in the human, dog and rat

Colestipol hydrochloride, a polymeric, ion-exchange type, hypocholesterolemic agent, acting by sequestering bile acids, was labeled with carbon-14. The disposition of the labeled material was studied in the human, dog and rat. The extent of absorption from the gastrointestinal tract, as judged by urinary excretion of radioactivity, was very small and correlated well with the contents of water-soluble and dialyzable materials in the colestipol hydrochloride. Results were consistent with the dialyzable material in the drug being the absorbable species.

Dopamine D2 receptor binding properties of [3H]U-86170, a dopamine receptor agonist

U-86170F, an imidazoguinolinone, is a potent dopamine D2 agonist, binding with high affinity to the dopamine D2 receptor. A Kd of 0.99 nM was determined in membranes from Chinese hamster ovarian (CHO) cells transfected with the D2 receptor and a Kd of 1.72 nM was obtained in rat striatal homogenates. GTP sensitivity was demonstrated when its addition (300 microM) reduced [3H]U-86170 binding by 60%. This agonist ligand is especially effective in identifying agonists and partial agonists, as well as antagonists, and affords a more precise evaluation of their affinity for the dopamine D2 receptor, without the use of multiple site analysis, than does an antagonist [3H]-ligand.

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

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.