TY - JOUR T1 - Synthesis and Evaluation of Dopamine D<sub>3</sub> Receptor Antagonist <sup>11</sup>C-GR218231 as PET Tracer for P-Glycoprotein JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 1384 LP - 1392 VL - 46 IS - 8 AU - Erik F.J. de Vries AU - Rudie Kortekaas AU - Aren van Waarde AU - Durk Dijkstra AU - Philip H. Elsinga AU - Willem Vaalburg Y1 - 2005/08/01 UR - http://jnm.snmjournals.org/content/46/8/1384.abstract N2 - While searching for a PET method to determine the density and occupancy of the dopamine D3 receptor, we found evidence that suggested that the dopamine D3 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 11C by reaction of the newly synthesized desmethyl precursor with 11C-methyl triflate. The biodistribution of 11C-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 11C-GR218231, the efflux pump was modulated with 50 mg/kg cyclosporine A. The sensitivity of 11C-GR218231 for P-glycoprotein modulation was assessed in dose–response studies, using escalating cyclosporine A dosages. Results: 11C-GR218231 was prepared in 53% ± 8% decay-corrected radiochemical yield and had a specific activity of 15 ± 10 GBq/μmol (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 11C-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 dose-escalation studies showed a dose-dependent sigmoidal increase in 11C-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 11C-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. ER -