Synthesis of ([(11)C]carbonyl)raclopride and a comparison with ([(11)C]methyl)raclopride in a monkey PET study.
BACKGROUND
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.


CONCLUSIONS
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.
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.
Obaidur
O
Rahman
Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska University Hospital, R5:U1, 17176 Stockholm, Sweden.
Akihiro
A
Takano
Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska University Hospital, R5:U1, 17176 Stockholm, Sweden.
Nahid
N
Amini
Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska University Hospital, R5:U1, 17176 Stockholm, Sweden.
Kenneth
K
Dahl
Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska University Hospital, R5:U1, 17176 Stockholm, Sweden.
Naoki
N
Kanegawa
Bencar AB, Dag Hammarskjöldsväg 34B, 75183 Uppsala, Sweden; Department of Chemistry-BMC, Uppsala University, Husargatan 3, 75237 Uppsala, Sweden.
Bengt
B
Långström
Karolinska Institutet, Department of Clinical Neuroscience, Centre for Psychiatric Research, Karolinska University Hospital, R5:U1, 17176 Stockholm, Sweden.
Lars
L
Farde
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.
Christer
C
Halldin
D000818:Animals; D001798:Blood Proteins / Q000378:metabolism; D060326:Chemistry Techniques, Synthetic; D005260:Female; D008252:Macaca fascicularis; D049268:Positron-Emission Tomography / Q000379:methods*; D020891:Raclopride / Q000138:chemical synthesis* / Q000737:chemistry / Q000378:metabolism; D011854:Radiochemistry
D001798:Blood Proteins; D020891:Raclopride
(11)CO; ([(11)C]carbonyl)raclopride; NHP; PET; [(11)C]aminocarbonylation; radiometabolites