RRC ID 16019
Author Fujinaga M, Yamasaki T, Yui J, Hatori A, Xie L, Kawamura K, Asagawa C, Kumata K, Yoshida Y, Ogawa M, Nengaki N, Fukumura T, Zhang MR.
Title Synthesis and evaluation of novel radioligands for positron emission tomography imaging of metabotropic glutamate receptor subtype 1 (mGluR1) in rodent brain.
Journal J. Med. Chem.
Abstract 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.
Volume 55(5)
Pages 2342-52
Published 2012-3-8
DOI 10.1021/jm201590g
PMID 22316010
MeSH Animals Autoradiography Benzamides / chemical synthesis* Benzamides / chemistry Benzamides / pharmacokinetics Brain / diagnostic imaging* Brain / metabolism Fluorine Radioisotopes In Vitro Techniques Isotope Labeling Ligands Magnetic Resonance Imaging Male Mice Mice, Inbred C57BL Mice, Knockout Molecular Imaging Positron-Emission Tomography Radiopharmaceuticals / chemical synthesis* Radiopharmaceuticals / chemistry Radiopharmaceuticals / pharmacokinetics Rats Rats, Sprague-Dawley Receptors, Metabotropic Glutamate / genetics Receptors, Metabotropic Glutamate / metabolism* Structure-Activity Relationship Thiazoles / chemical synthesis* Thiazoles / chemistry Thiazoles / pharmacokinetics Tissue Distribution
IF 6.253
Times Cited 24
Mice mGluR1 KO