Design, synthesis, and pharmacological characterization of (+)-2-aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (LY354740): a potent, selective, and orally active group 2 metabotropic glutamate receptor agonist possessing anticonvulsant and anxiolytic properties.

2-Aminobicyclo[3.1.0]hexane-2,6-dicarboxylic acid (9) was designed as a conformationally constrained analog of glutamic acid. For 9, the key torsion angles (tau 1 and tau 2) which determine the relative positions of the alpha-amino acid and distal carboxyl functionalities are constrained where tau 1 = 166.9 degrees or 202 degrees and tau 2 = 156 degrees, respectively. We hypothesized that 9 would closely approximate the proposed bioactive conformation of glutamate when acting at group 2 metabotropic glutamate receptors (mGluRs). The racemic target molecule (+/-)-9, its C2-diastereomer (+/-)-16, and its enantiomers (+)-9 (LY354740) and (-)-9 (LY366563) were prepared by an efficient, stereocontrolled, and high-yielding synthesis from 2-cyclopentenone. Our hypothesis that 9 could interact with high affinity and specificity at group 2 mGluRs has been supported by the observation that (+/-)-9 (EC50 = 0.086 +/- 0.025 microM) and its enantiomer (+)-9 (EC50 = 0.055 +/- 0.017 microM) are highly potent agonists for group 2 mGluRs in the rat cerebral cortical slice preparation (suppression of forskolin-stimulated cAMP formation) possessing no activity at other glutamate receptor sites (iGluR or group 1 mGluR) at concentrations up to 100 microM. Importantly, the mGluR agonist effects of (+)-9 are evident following oral administration in mice in both the elevated plus maze model of anxiety (ED50 = 0.5 mg/kg) and in the ACPD-induced limbic seizure model (ED50 = 45.6 mg/kg). Thus, (+)-9 is the first orally active group 2 mGluR agonist described thus far and is an important tool for studying the effects of compounds of this class in humans.

Synthesis of [11C]dapoxetine.HCl, a serotonin re-uptake inhibitor: biodistribution in rat and preliminary PET imaging in the monkey.

[11C]Dapoxetine.HCl, S-(+)-N,N-dimethyl-a-[2-(naphthalenyloxy)ethyl] benzenemethanamine hydrochloride, a potent serotonin re-uptake inhibitor was prepared from its mono-methyl precursor, S-(+)-N-methyl-a-[2-(naphthalenyloxy)ethyl]benzene methanamine hydrochloride. Biodistribution was determined in rats at 5, 30 and 60 min after injection and preliminary PET studies were performed in a Rhesus monkey. 11CH3I was bubbled into a solution of S-(+)-N-methyl-alpha-[2-(naphthalenyloxy)ethyl]benzene methanamine hydrochloride (3.0 mg in DMSO) and the mixture was heated at 110 degrees C for 8 min. [11C]Dapoxetine.HCl was purified by HPLC on a C18 cartridge eluted with MeOH:phosphate buffer, pH 7,2 (75:25) with a 10% yield (end of synthesis). The time required for the synthesis was 40 min, from the end of bombardment. Radiochemical purity of the final product was > 99% and specific activity was routinely > 400 mCi/mumol [EOS]. In the biodistribution studies the highest concentration (%ID/g +/- SEM) of dapoxetine.HCl was detected in lung: 4.56 +/- 0.27 (5 min), 1.28 +/- 0.18 (30 min) and 0.67 +/- 0.04 (60 min). Brain accumulation was 0.76 +/- 0.02 (5 min), 0.46 +/- 0.04 (30 min) and 0.27 +/- 0.01 (60 min). Preliminary PET studies demonstrated significant displaceable binding in the cerebral cortex and subcortical grey matter. These results demonstrate that [11C]dapoxetine.HCl can be prepared in high purity and may be useful for the in vivo evaluation of serotonin re-uptake mechanisms.