Synthesis and preliminary biological evaluation of 3‐[¹⁸F]fluoro‐5‐(2‐pyridinylethynyl)benzonitrile as a PET radiotracer for imaging metabotropic glutamate receptor subtype 5

Abstract

The metabotropic glutamate receptor subtype 5 (mGluR5) has been reported to be implicated in various neurological disorders in the central nervous system. To investigate physiological and pathological functions of mGluR5, noninvasive imaging in a living body with PET technology and an mGluR5-specific radiotracer is urgently needed. Here, we report the synthesis of 3-[(18)F]fluoro-5-(2-pyridinylethynyl)benzonitrile ([(18)F]FPEB) through a convenient thermal reaction as a highly specific PET radiotracer for mGluR5. The precursor and standard compounds were prepared by a coupling reaction catalyzed by palladium. Radiosynthesis of [(18)F]FPEB was performed using nitro as a leaving group replaced by [(18)F]fluoride under conventional heating condition. Biodistribution, metabolite, and microPET studies were performed using Sprague-Dawley rats. Upto 30 mCi of [(18)F]FPEB was obtained with a radiochemical yield of 5% and a specific activity of 1900 +/- 200 mCi/mumol at the end of syntheses. Biodistribution showed rapid clearance from the blood pool and fast and steady accumulation of radioactivity into the brain. Metabolite studies indicated that only 22% of [(18)F]FPEB remained in the blood system 10 min after administration, and that a metabolite existed which was much more polar than the parent tracer. MicroPET studies demonstrated that [(18)F]FPEB accumulated specifically in mGluR5-rich regions of the brain such as striatum and hippocampus, and that blockade with 2-methyl-6-(2-phenylethynyl)pyridine (MPEP) and 3-[(2-methyl-1,3-thiazol-4-yl)ethynyl]pyridine (MTEP) substantially reduced the activity uptake in these regions. Selectivity was investigated by blockage with 6-amino-N-cyclohexyl-N,3-dimethylthiazolo[3,2-a]benzimidazole-2-caroxamide (YM-298198), a specific antagonist for mGluR1. [(18)F]FPEB was prepared conveniently and showed high specificity and selectivity toward mGluR5. It possesses the potential to be used in human studies to evaluate mGluR5 functions in various neurological disorders.

Enhanced binding of metabotropic glutamate receptor type 5 (mGluR5) PET tracers in the brain of parkinsonian primates

“…The synthesis and labeling of these tracers has been described by us (Brownell et al, 2003;Pellegrino et al, 2007;Wang et al, 2007). Regions of interest (ROIs) were delineated based on MRI high resolution anatomical images acquired on a Siemens 3T Trio system, as previously reported by our group (Jenkins et al, 2004;Sanchez-Pernaute et al, 2007) and anatomical atlas (Fig.…”

“…1e) as we have previously described in this model (Jenkins et al, 2004). To confirm that the change in [ 11 C]MPEPy binding reflected changes in mGluR5, we examined in 2 other primates, the distribution of the novel compound [ 18 F]FPEB (Hamill et al, 2005;Wang et al, 2007), which has exceptionally high affinity to mGluR5. The reported in vitro Bmax/Kd value based on the saturation binding studies in rhesus caudate-putamen tissue is 210 (Patel et al, 2007) and in vivo studies have shown that it is subgroup specific .…”

“…While the role of mGluR5 in cocaine addiction has been firmly established (Chiamulera et al, 2001) using mGluR5 knockout mice, data from Parkinson models are equivocal (Armentero et al, 2006;Breysse et al, 2003;Mela et al, 2007;Oueslati et al, 2005;Samadi et al, 2007) except for a likely involvement in the pathophysiology of dyskinesias (Mela et al, 2007), a frequent complication of long-term L-DOPA replacement therapy. Taking advantage of novel PET tracers Wang et al, 2007) we examined the distribution of mGluR5 in the primate brain and the effect of DA denervation in MPTP-lesioned parkinsonian primates to determine whether mGluR5 drugs may be therapeutically relevant for PD. …”

“…In two animals imaging studies of mGluR5 and DAT were done in different session to avoid background activity, since [ 18 F] FPEB has long retention time. After administration of [ 18 F]FPEB (3-[ 18 F]fluoro-5-(2-pyridinylethynyl)benzonitrile) (0.8-1.2 mCi i.v., specific activity 1900 mCi/µmol) dynamic volumetric data were acquired for 120min followed by transmission imaging and data reconstruction as above.The synthesis and labeling of these tracers has been described by us (Brownell et al, 2003;Pellegrino et al, 2007;Wang et al, 2007). Regions of interest (ROIs) were delineated based on MRI high resolution anatomical images acquired on a Siemens 3T Trio system, as previously reported by our group (Jenkins et al, 2004;Sanchez-Pernaute et al, 2007) and anatomical atlas (Fig.…”

Kinetic Analysis of the Metabotropic Glutamate Subtype 5 Tracer [18F]FPEB in Bolus and Bolus-Plus-Constant-Infusion Studies in Humans

“…13 [ 18 F]FPEB was the most successful among the three mGluR5 tracers characterized in rhesus monkeys by Hamill et al 15 In preclinical studies, [ 18 F]FPEB displayed high specificity and affinity for mGluR5 as well as a regional uptake pattern consistent with the known distribution of mGluR5 in the brain. [16][17][18] Hence, [ 18 F]FPEB may have the potential to be used in humans to assess mGluR5 function in a variety of psychiatric and neurological disorders.…”