[11C]cyclopropyl-FLB 457: a PET radioligand for low densities of dopamine D2 receptors.
(S)-5-bromo-N-[(1-cyclopropylmethyl-2-pyrrolidinyl)methyl]-2,3-dimethoxybenzamide (4) has pico-molar in vitro binding affinity to D(2) receptor (K(i) (D(2))=0.003 nM) with lower affinity to D(3) receptor (K(i) (D(3))=0.22 nM). In this study, we describe radiosynthesis of [(11)C]4 and evaluation of its binding characteristics in post-mortem human brain autoradiography and with PET in cynomolgus monkeys. The (11)C labelled 4 was synthesized by using [(11)C]methyltriflate in a methylation reaction with its phenolic precursor with good incorporation yield (64+/-11%, DCY) and high specific radioactivity >370 GBq/micromol (>10,000 Ci/mmol). In post-mortem human brain autoradiography [(11)C]4 exhibited high specific binding in brain regions enriched with dopamine D(2)/D(3) receptors and low level of non-specific binding. In cynomolgus monkeys [(11)C]4 exhibited high brain uptake reaching 4.4% ID at 7.5 min. The binding in the extrastriatal low density D(2)-receptor regions; thalamus and frontal, parietal, temporal, and occipital cortex, was clearly visible. Pre-treatment with raclopride (1 mg/kg as tartrate) caused high reduction of binding in extrastriatal regions, including cerebellum. [(11)C]4 is a promising radioligand for imaging D(2) receptors in low density regions in brain.
Karolinska Institutet, Department of Clinical Neuroscience, Psychiatry Section, Karolinska Hospital, S-17176 Stockholm, Sweden. anu.airaksinen@helsinki.fi
Anu J
AJ
Airaksinen
Sangram
S
Nag
Sjoerd J
SJ
Finnema
Jogeshwar
J
Mukherjee
Sankha
S
Chattopadhyay
Balázs
B
Gulyás
Lars
L
Farde
Christer
C
Halldin
D000818:Animals; D002247:Carbon Isotopes; D002851:Chromatography, High Pressure Liquid; D000882:Haplorhini; D006801:Humans; D008024:Ligands; D015394:Molecular Structure; D049268:Positron-Emission Tomography; D011759:Pyrrolidines / Q000737:chemistry* / Q000378:metabolism*; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D012457:Salicylamides / Q000737:chemistry* / Q000378:metabolism*
D002247:Carbon Isotopes; D008024:Ligands; D011759:Pyrrolidines; D017448:Receptors, Dopamine D2; D012457:Salicylamides; C065065:FLB 457