Yigong Gao

[11C]β-CIT, a cocaine analogue. Preparation, autoradiography and preliminary PET investigations

beta-CIT (2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane) is a cocaine analogue with a high affinity for the dopamine transporter. [11C] beta-CIT was prepared by N-methylation of nor-beta-CIT with [11C]methyl iodide. The total radiochemical yield of [11C] beta-CIT was 40-50% with an overall synthesis time of 35-40 min. The radiochemical purity was > 99% and the specific radioactivity at the time of injection was about 1000 Ci/mmol (37 GBq/mumol). Autoradiographic examination of [11C] beta-CIT binding in human brains post-mortem demonstrated a high level of specific binding in the striatum. PET examination of [11C] beta-CIT in a Cynomolgus monkey showed a marked accumulation of radioactivity in the striatum. The ratio of radioactivity in the striatum-to-cerebellum approached 5 after 87 min. In a displacement experiment, radioactivity in the striatum but not in the cerebellum, was markedly reduced after injection of unlabelled cocaine. [11C] beta-CIT has a potential as ligand for PET examination of cocaine effects in man.

R(−)2-fluoro-n-n-propylnorapomorphine: A very potent and D2-selective dopamine agonist

A series of 2-substituted N-n-propylnorapomorphine (NPA) derivatives were synthesized and compared with other DA agonists for affinity to D1 and D2 dopamine (DA) receptors in rat brain corpus striatum tissue. The 2-substituents tested reduced D1 affinity similarly, but enhanced D2 affinity in the rank order: F greater than OH greater than Br greater than OCH3 greater than H greater than or equal to NH2. The extraordinarily high D2 affinity (Ki = 12 pM) and D2 vs. D1 selectivity (57,500) of 2-F-NPA far-exceeded that of all other DA agonists tested, and it was about 10-times more potent than NPA in vivo.

An efficient synthesis of m-hydroxycocaine and m-hydroxybenzoylecgonine, two metabolites of cocaine

Abstract An efficient pathway for the preparation of m -hydroxycocaine ( 6 ) and m -hydroxybenzoylecgonine ( 7 ) is described.

N-phthalimidoalkyl derivatives of 2β-carbomethoxy-3β-(4'-iodophenyl)tropane (β-CIT) : Brain monoamine transporter affinity

Abstract A series of novel N-phthalimidoalkyl analogs of the stable phenyltropane β-CIT were synthesized and evaluated by selective radioligand binding assays for affinity to transporters for dopamine (DA), serotonin (5-HT) and norepinephrine (NE) in corpus striatum tissue from rat forebrain. β-CIT and novel compounds with the phthalimido moiety separated by ≥4 methylene groups from the nitrogen atom of the tropane ring (6–8) showed similarly greater affinity at 5-HT than DA transporters; this affinity was lost with only 2 or 3 carbon atoms (4 and 5). These results are consistent with interference at a critical binding site for the tropane nitrogen on the transporter proteins and indicate that the tropane nitrogen atom can be substituted with large substituted alkyl moieties without loss of affinity or selectivity for amine transporters.