Imaging of I2-imidazoline receptors by small-animal PET using 2-(3-fluoro-[4-11C]tolyl)-4,5-dihydro-1H-imidazole ([11C]FTIMD).
BACKGROUND
Imidazoline receptors (IRs) have been established as distinct receptors, and have been categorized into at least two subtypes (I(1)R and I(2)R). I(2)Rs are associated with depression, Alzheimer's disease, Huntington's disease and Parkinson's disease. A few positron emission tomography (PET) probes for I(2)Rs have been synthesized, but a selective PET probe has not been evaluated for the imaging of I(2)Rs by PET. We labeled a selective I(2)R ligand 2-(3-fluoro-4-tolyl)-4,5-dihydro-1H-imidazole (FTIMD) with (11)C and performed the first imaging of I(2)Rs by PET using 2-(3-fluoro-[4-(11)C]tolyl)-4,5-dihydro-1H-imidazole ([(11)C]FTIMD).


METHODS
[(11)C]FTIMD was prepared by a palladium-promoted cross-coupling reaction of the tributylstannyl precursor and [(11)C]methyl iodide in the presence of tris(dibenzylideneacetone)dipalladium(0) and tri(o-tol)phosphine. Biodistribution was investigated in rats by tissue dissection. [(11)C]FTIMD metabolites were measured in brain tissues and plasma. Dynamic PET scans were acquired in rats, and the kinetic parameters estimated.


RESULTS
[(11)C]FTIMD was successfully synthesized with a suitable radioactivity for the injection. Co-injection with 0.1 mg/kg of cold FTIMD and BU224 induced a significant reduction in the brain-to-blood ratio 15 and 30 min after the injection. In metabolite analysis, unchanged [(11)C]FTIMD in the brain was high (98%) 30 min after the injection. In PET studies, high radioactivity levels were observed in regions with a high density of I(2)R. The radioactivity levels and V(T) values in the brain regions were prominently reduced by 1.0 mg/kg of BU224 pretreatment as compared with control.


CONCLUSIONS
[(11)C]FTIMD showed specific binding to I(2)Rs in rat brains with a high density of I(2)R.
Kawamura
Kazunori
K
Department of Molecular Probes, Molecular Imaging Center, National Institute of Radiological Sciences, Chiba 263-8555, Japan. kawamur@nirs.go.jp
Naganawa
Mika
M
Konno
Fujiko
F
Yui
Joji
J
Wakizaka
Hidekatsu
H
Yamasaki
Tomoteru
T
Yanamoto
Kazuhiko
K
Hatori
Akiko
A
Takei
Makoto
M
Yoshida
Yuichiro
Y
Sakaguchi
Kazuya
K
Fukumura
Toshimitsu
T
Kimura
Yuichi
Y
Zhang
Ming-Rong
MR
D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging / Q000378:metabolism; D007093:Imidazoles / Q000097:blood / Q000378:metabolism* / Q000493:pharmacokinetics; D054755:Imidazoline Receptors / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008954:Models, Biological; D049268:Positron-Emission Tomography / Q000379:methods*; D051381:Rats; D017207:Rats, Sprague-Dawley
C552745:2-(3-fluorotolyl)-4,5-dihydro-1H-imidazole; D007093:Imidazoles; D054755:Imidazoline Receptors; C487767:imidazoline receptor 2