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Synthesis and Evaluation of Dopamine D₃ Receptor Antagonist ¹¹C-GR218231 as PET Tracer for P-Glycoprotein

¹ PET Center, University Medical Center Groningen, Groningen, The Netherlands
² Department of Neurology, University Medical Center Groningen, Groningen, The Netherlands
³ Department of Anatomy, University of Groningen, Groningen, The Netherlands
⁴ Department of Medicinal Chemistry, University of Groningen, Groningen, The Netherlands

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.

Key Words: PET • dopamine D₃ receptor • GR218231 • P-glycoprotein • blood–brain barrier

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