TY - JOUR
T1 - Methoxyphenylethynyl, methoxypyridylethynyl and phenylethynyl derivatives of pyridine
T2 - Synthesis, radiolabeling and evaluation of new PET ligands for metabotropic glutamate subtype 5 receptors
AU - Yu, Meixiang
AU - Tueckmantel, Werner
AU - Wang, Xukui
AU - Zhu, Aijun
AU - Kozikowski, Alan P.
AU - Brownell, Anna Liisa
N1 - Funding Information:
We wish to acknowledge cyclotron operators William Buckelewicz and Davis Lee. This work was supported by NIH/NIBIB grant EB01850 to A-LB.
PY - 2005/8
Y1 - 2005/8
N2 - We have synthesized three different PET ligands to investigate the physiological function of metabotropic glutamate subtype 5 receptors (mGluR5) in vivo: 2-[11C]methyl-6-(2-phenylethynyl)pyridine ([ 11C]MPEP), 2-(2-(3-[11C]methoxyphenyl)ethynyl)pyridine ([11C]M-MPEP) and 2-(2-(5-[11C]methoxypyridin-3-yl) ethynyl)pyridine ([11C]M-PEPy). [11C]Methyl iodide was used to label the compounds under basic conditions, and a Pd(0) catalyst was applied to label [11C]MPEP in a Stille coupling reaction. In vivo microPET imaging studies of the functional accumulation of radiolabeled ligands were conducted in 35 rats (Sprague-Dawley, 8 weeks old male, weight of 300 g). Specific binding was tested using pre-administration of unlabeled mGluR5 antagonist 2-methyl-6-(2-phenylethynyl)pyridine (MPEP) (10 mg/kg iv 5 min before radioactivity injection). In the radiolabeling of [11C]MPEP, [ 11C]M-MPEP and [11C]M-PEPy, a specific radioactivity of 700-1200 mCi/μmol and over 97% radiochemical purity were obtained. The microPET studies showed these three radiolabeled mGluR5 antagonists having the highest binding in the olfactory bulb followed by striatum, hippocampus and cortex. Pre-administration of the mGluR5 antagonist MPEP induced a 45.1% decrease in [11C]MPEP binding, a 59.7% decrease in [ 11C]M-MPEP binding and an 84.6% decrease in [11C]M-PEPy binding in the olfactory bulb at 5 min. The feasibility of synthesizing high-affinity and high-selectivity ligands for mGluR5 receptors and their suitability as PET imaging ligands for mGluR5 receptors in vivo are demonstrated.
AB - We have synthesized three different PET ligands to investigate the physiological function of metabotropic glutamate subtype 5 receptors (mGluR5) in vivo: 2-[11C]methyl-6-(2-phenylethynyl)pyridine ([ 11C]MPEP), 2-(2-(3-[11C]methoxyphenyl)ethynyl)pyridine ([11C]M-MPEP) and 2-(2-(5-[11C]methoxypyridin-3-yl) ethynyl)pyridine ([11C]M-PEPy). [11C]Methyl iodide was used to label the compounds under basic conditions, and a Pd(0) catalyst was applied to label [11C]MPEP in a Stille coupling reaction. In vivo microPET imaging studies of the functional accumulation of radiolabeled ligands were conducted in 35 rats (Sprague-Dawley, 8 weeks old male, weight of 300 g). Specific binding was tested using pre-administration of unlabeled mGluR5 antagonist 2-methyl-6-(2-phenylethynyl)pyridine (MPEP) (10 mg/kg iv 5 min before radioactivity injection). In the radiolabeling of [11C]MPEP, [ 11C]M-MPEP and [11C]M-PEPy, a specific radioactivity of 700-1200 mCi/μmol and over 97% radiochemical purity were obtained. The microPET studies showed these three radiolabeled mGluR5 antagonists having the highest binding in the olfactory bulb followed by striatum, hippocampus and cortex. Pre-administration of the mGluR5 antagonist MPEP induced a 45.1% decrease in [11C]MPEP binding, a 59.7% decrease in [ 11C]M-MPEP binding and an 84.6% decrease in [11C]M-PEPy binding in the olfactory bulb at 5 min. The feasibility of synthesizing high-affinity and high-selectivity ligands for mGluR5 receptors and their suitability as PET imaging ligands for mGluR5 receptors in vivo are demonstrated.
KW - Carbon-11
KW - M-MPEP
KW - M-PEPy
KW - MgluR5
KW - MPEP
KW - PET
UR - http://www.scopus.com/inward/record.url?scp=22144488055&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=22144488055&partnerID=8YFLogxK
U2 - 10.1016/j.nucmedbio.2005.05.004
DO - 10.1016/j.nucmedbio.2005.05.004
M3 - Article
C2 - 16026710
AN - SCOPUS:22144488055
SN - 0969-8051
VL - 32
SP - 631
EP - 640
JO - Nuclear Medicine and Biology
JF - Nuclear Medicine and Biology
IS - 6
ER -