Synthesis and evaluation of dopamine D-3 receptor antagonist C-11-GR218231 as PET tracer for P-glycoprotein

While searching for a PET method to determine the density and occupancy of the dopamine D-3 receptor, we found evidence that suggested that the dopamine D-3 antagonist GR218231 could be a substrate of the P-glycoprotein efflux pump. P-glycoprotein protects the brain against toxic substances and xenobiotics, but it also hampers the delivery of various drugs into the brain. In this study, we aimed to explore whether radiolabeled GR218231 could be applied as a PET tracer for monitoring P-glycoprotein activity in the blood-brain barrier. Such an imaging technique could be useful for the development of new drugs and novel strategies to deliver drugs to the brain and for identification of undesirable drug-drug interactions. Methods: As a potential PET tracer, GR218231 was labeled with C-11 by reaction of the newly synthesized desmethyl precursor with C-11-methyl triflate. The biodistribution of C-11-GR218231 was determined in rats. To assess specific binding to the dopamine D3 receptor, blocking experiments with unlabeled GR218231 (0.2 and 2.5 mg/kg) were performed. To demonstrate the influence of P-glycoprotein on cerebral uptake of C-11-GR218231, the efflux pump was modulated with 50 mg/kg cyclosporine A. The sensitivity of C-11-GR218231 for P-glycoprotein modulation was assessed in dose-response studies, using escalating cyclosporine A dosages. Results: C-11-GR218231 was prepared in 53% +/- 8% decay-corrected radiochemical yield and had a specific activity of 15 +/- 10 GBq/mu mol (mean +/- SD). Biodistribution studies in rats revealed a low and homogeneous uptake in the brain. Pretreatment of the animals with unlabeled GR218231 did not demonstrate any specific binding. Modulation of P-glycoprotein with cyclosporine A caused a 12-fold higher C-11-GR218231 uptake in the brain, indicating that the low cerebral tracer uptake was caused by the P-glycoprotein efflux pump in the blood-brain barrier. Cyclosporine A close-escalation studies showed a dose-dependent sigmoidal increase in C-11-GR218231 uptake in brain and spleen (median effective dose [ED50], 23.3 +/- 0.6 and 38.4 +/- 2.4 mg/kg, respectively), whereas a dose-dependent decrease was observed in the pancreas (ED50, 36.0 +/- 4.4 mg/kg). Conclusion: Although C-11-GR218231 is unsuited for dopamine D3 receptor imaging with PET, it appears to be an attractive PET tracer for visualization and quantification of P-glycoprotein activity in the blood-brain barrier

Dopaminergic and serotonergic agents : synthesis and pharmacological evaluation of 2-aminotetralins and related tricyclic compounds

The main interest of our research group is the medicinal chemisq of agonists and antagonists of the neurotransmitters dopamine (DA) and serotonine (5-HT) and their modes of pharmacological interaction with dopaminergic and serotonergic neurotransmitter systems in the brain. The group is currently interested in the rational design, synthesis and pharmacological evaluation of new dopaminergic and serotonergic agents with clinical potential. Dopamine is an important neurotransmitter in the brain and is known to play an important role in Parkinson's disease, schizophrenia, and possibly depression. Serotonine is thought to be involved in various functions such as anxiety, aggression, depression, stress, sexual behaviour, and body temperature.

Conformational study of cinchona and ephedra alkaloids

Chirality and Natun an closely associated. Living organisms use chiral catalysts (enzymes) to synthesize many of their chemical constituents. Over millions of years the complex compositions of enzymes have developed into efficient and specific catalysts for the synthesis (and breakdown) of chiral organic compounds. Because of the complexity of mynatic reactha, it is difficult to study the details of their reaction mechanisms directly from experiments. Recently several breakthroughs in the design and the synthesis of organic catalysts have taken place. With these catalysts it is possible to control the stereoselectivity of some reactions with efficiencies rivalling those of enzymes. In many casts th-e chiral organic catalysts am, like cnzymea, natclral products or their derivatives. However, such catalysts are much smaller than enzymes and are thus better suited to mechanistic studies. A recent example is given by lnouel . With the dipeptide cyclo-phcnyldaninc-histidinea s chiral caEatyst in a reaction between beaualdehyde