Synthesis and evaluation of novel radioligands for positron emission tomography imaging of metabotropic glutamate receptor subtype 1 (mGluR1) in rodent brain.
We designed three novel positron emission tomography ligands, N-(4-(6-(isopropylamino)pyrimidin-4-yl)-1,3-thiazol-2-yl)-4-[(11)C]methoxy-N-methylbenzamide ([(11)C]6), 4-[(18)F]fluoroethoxy-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide ([(18)F]7), and 4-[(18)F]fluoropropoxy-N-[4-[6-(isopropylamino)pyrimidin-4-yl]-1,3-thiazol-2-yl]-N-methylbenzamide ([(18)F]8), for imaging metabotropic glutamate receptor type 1 (mGluR1) in rodent brain. Unlabeled compound 6 was synthesized by benzoylation of 4-pyrimidinyl-2-methylaminothiazole 10, followed by reaction with isopropylamine. Removal of the methyl group in 6 gave phenol precursor 12 for radiosynthesis. Two fluoroalkoxy analogues 7 and 8 were prepared by reacting 12 with tosylates 13 and 14. Radioligands [(11)C]6, [(18)F]7, and [(18)F]8 were synthesized by O-[(11)C]methylation or [(18)F]fluoroalkylation of 12. Compound 6 showed high in vitro binding affinity for mGluR1, whereas 7 and 8 had weak affinity. Autoradiography using rat brain sections showed that [(11)C]6 binding is aligned with the reported distribution of mGluR1 with high specific binding in the cerebellum and thalamus. PET study with [(11)C]6 in rats showed high brain uptake and a similar distribution pattern to that in autoradiography, indicating the usefulness of [(11)C]6 for imaging brain mGluR1.
Molecular Imaging Center, National Institute of Radiological Sciences, 4-9-1 Anagawa, Inage-ku, Chiba 263-8555, Japan.
Masayuki
M
Fujinaga
Tomoteru
T
Yamasaki
Joji
J
Yui
Akiko
A
Hatori
Lin
L
Xie
Kazunori
K
Kawamura
Chiharu
C
Asagawa
Katsushi
K
Kumata
Yuichiro
Y
Yoshida
Masanao
M
Ogawa
Nobuki
N
Nengaki
Toshimitsu
T
Fukumura
Ming-Rong
MR
Zhang
D000818:Animals; D001345:Autoradiography; D001549:Benzamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D005462:Fluorine Radioisotopes; D066298:In Vitro Techniques; D007553:Isotope Labeling; D008024:Ligands; D008279:Magnetic Resonance Imaging; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D057054:Molecular Imaging; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D018094:Receptors, Metabotropic Glutamate / Q000235:genetics / Q000378:metabolism*; D013329:Structure-Activity Relationship; D013844:Thiazoles / Q000138:chemical synthesis* / Q000737:chemistry / Q000493:pharmacokinetics; D014018:Tissue Distribution
C573293:4-fluoroethoxy-N-(4-(6-(isopropylamino)pyrimidin-4-yl)-1,3-thiazol-2-yl)-N-methylbenzamide; C573294:4-fluoropropoxy-N-(4-(6-(isopropylamino)pyrimidin-4-yl)-1,3-thiazol-2-yl)-N-methylbenzamide; D001549:Benzamides; D005462:Fluorine Radioisotopes; D008024:Ligands; C573292:N-(4-(6-(isopropylamino)pyrimidin-4-yl)-1,3-thiazol-2-yl)-4-methoxy-N-methylbenzamide; D019275:Radiopharmaceuticals; D018094:Receptors, Metabotropic Glutamate; D013844:Thiazoles; C104077:metabotropic glutamate receptor type 1