Obaidur Rahman1, Akihiro Takano2, Nahid Amini2, Kenneth Dahl2, Naoki Kanegawa2, Bengt Långström3, Lars Farde2, Christer Halldin4. 1. Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska University Hospital, R5:U1, 17176 Stockholm, Sweden; Bencar AB, Dag Hammarskjöldsväg 34B, 75183 Uppsala, Sweden; Department of Chemistry-BMC, Uppsala University, Husargatan 3, 75237 Uppsala, Sweden. 2. Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska University Hospital, R5:U1, 17176 Stockholm, Sweden. 3. Bencar AB, Dag Hammarskjöldsväg 34B, 75183 Uppsala, Sweden; Department of Chemistry-BMC, Uppsala University, Husargatan 3, 75237 Uppsala, Sweden. 4. Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska University Hospital, R5:U1, 17176 Stockholm, Sweden; Department of Chemistry-BMC, Uppsala University, Husargatan 3, 75237 Uppsala, Sweden.
Abstract
INTRODUCTION: The selective dopamine D2 receptor antagonist raclopride is usually labeled with carbon-11 using [(11)C]methyl iodide or [(11)C]methyl triflate for use in the quantification of dopamine D2 receptors in human brain. The aim of this work was to label raclopride at the carbonyl position using [(11)C]carbon monoxide chemistry and to compare ([(11)C]carbonyl)raclopride with ([(11)C]methyl)raclopride in non-human primate (NHP) using PET with regard to quantitative outcome measurement, metabolism of the labeled tracers and protein binding. METHODS: Palladium-mediated carbonylation using [(11)C]carbon monoxide, 4,6-dichloro-2-iodo-3-methoxyphenol and (S)-(-)-2-aminomethyl-1-ethylpyrrolidine was applied in the synthesis of ([(11)C]carbonyl)raclopride. The reaction was performed at atmospheric pressure using xantphos as supporting phosphine ligand and palladium (π-cinnamyl) chloride dimer as the palladium source. ([(11)C]Methyl)raclopride was prepared by a previously published method. In the PET study, two female cynomolgus monkeys were used under gas anesthesia of sevoflurane. A dynamic PET measurement was performed for 63 min with an HRRT PET camera after intravenous injection of ([(11)C]carbonyl)raclopride and ([(11)C]methyl)raclopride, respectively, during the same day. The order of injection of the two PET radioligands was changed between the two monkeys. The venous blood sample for measurement of protein binding was taken 3 min prior to the PET scan. Binding potential (BPND) of the putamen and caudate was calculated with SRTM using the cerebellum as a reference region. RESULTS: The target compound ([(11)C]carbonyl)raclopride was obtained with 50 ± 5% decay corrected radiochemical yield and 95% radiochemical purity. The trapping efficiency (TE) of [(11)C]carbon monoxide was 65 ± 5% and the specific radioactivity of the final product was 34 ± 1 GBq/μmol after a 50 min of synthesis time. The radiochemical yield of ([(11)C]methyl)raclopride was in the same range as published previously i. e. 50-60% and specific radioactivity of those two batches which were used in the present PET study were 192 GBq/μmol and 638 GBq/μmol respectively after a synthesis time of 32 min. In monkey PET studies, the percentage difference of BPND in putamen was <3% and that in caudate was <9% for the two radioligands. The plasma protein binding was 86.2 ± 0.3% and 85.7 ± 0.6% for ([(11)C]carbonyl)raclopride and ([(11)C]methyl)raclopride, respectively. The radiometabolite pattern was similar for both radioligands. CONCLUSION: Raclopride was (11)C-labeled at the carbonyl position using a palladium-mediated [(11)C]carbonylation reaction. A comparison between ([(11)C]carbonyl)raclopride and ([(11)C]methyl)raclopride with regard to quantitative PET outcome measurements, metabolism of radioligands and protein binding in monkey was performed. The monkey PET study with ([(11)C]carbonyl)raclopride showed similar results as for ([(11)C]methyl)raclopride. The PET studies were performed on 2 subjects.
INTRODUCTION: The selective dopamine D2 receptor antagonist raclopride is usually labeled with carbon-11 using [(11)C]methyl iodide or [(11)C]methyl triflate for use in the quantification of dopamine D2 receptors in human brain. The aim of this work was to label raclopride at the carbonyl position using [(11)C]carbon monoxide chemistry and to compare ([(11)C]carbonyl)raclopride with ([(11)C]methyl)raclopride in non-human primate (NHP) using PET with regard to quantitative outcome measurement, metabolism of the labeled tracers and protein binding. METHODS:Palladium-mediated carbonylation using [(11)C]carbon monoxide, 4,6-dichloro-2-iodo-3-methoxyphenol and (S)-(-)-2-aminomethyl-1-ethylpyrrolidine was applied in the synthesis of ([(11)C]carbonyl)raclopride. The reaction was performed at atmospheric pressure using xantphos as supporting phosphine ligand and palladium (π-cinnamyl) chloride dimer as the palladium source. ([(11)C]Methyl)raclopride was prepared by a previously published method. In the PET study, two female cynomolgus monkeys were used under gas anesthesia of sevoflurane. A dynamic PET measurement was performed for 63 min with an HRRT PET camera after intravenous injection of ([(11)C]carbonyl)raclopride and ([(11)C]methyl)raclopride, respectively, during the same day. The order of injection of the two PET radioligands was changed between the two monkeys. The venous blood sample for measurement of protein binding was taken 3 min prior to the PET scan. Binding potential (BPND) of the putamen and caudate was calculated with SRTM using the cerebellum as a reference region. RESULTS: The target compound ([(11)C]carbonyl)raclopride was obtained with 50 ± 5% decay corrected radiochemical yield and 95% radiochemical purity. The trapping efficiency (TE) of [(11)C]carbon monoxide was 65 ± 5% and the specific radioactivity of the final product was 34 ± 1 GBq/μmol after a 50 min of synthesis time. The radiochemical yield of ([(11)C]methyl)raclopride was in the same range as published previously i. e. 50-60% and specific radioactivity of those two batches which were used in the present PET study were 192 GBq/μmol and 638 GBq/μmol respectively after a synthesis time of 32 min. In monkey PET studies, the percentage difference of BPND in putamen was <3% and that in caudate was <9% for the two radioligands. The plasma protein binding was 86.2 ± 0.3% and 85.7 ± 0.6% for ([(11)C]carbonyl)raclopride and ([(11)C]methyl)raclopride, respectively. The radiometabolite pattern was similar for both radioligands. CONCLUSION:Raclopride was (11)C-labeled at the carbonyl position using a palladium-mediated [(11)C]carbonylation reaction. A comparison between ([(11)C]carbonyl)raclopride and ([(11)C]methyl)raclopride with regard to quantitative PET outcome measurements, metabolism of radioligands and protein binding in monkey was performed. The monkey PET study with ([(11)C]carbonyl)raclopride showed similar results as for ([(11)C]methyl)raclopride. The PET studies were performed on 2 subjects.
Authors: Benjamin H Rotstein; Steven H Liang; Michael S Placzek; Jacob M Hooker; Antony D Gee; Frédéric Dollé; Alan A Wilson; Neil Vasdev Journal: Chem Soc Rev Date: 2016-08-22 Impact factor: 54.564