Evaluation of four pyridine analogs to characterize 6-OHDA-induced modulation of mGluR5 function in rat brain using microPET studies

Micro-positron emission tomography imaging studies were conducted to characterize modulation of metabotropic glutamate subtype-5 receptor (mGluR5) function in a 6-hydroxydopamine (6-OHDA)-induced rat model of Parkinson's disease using four analogical PET ligands: 2-[¹¹C]methyl-6-(2- phenylethynyl) pyridine ([¹¹C]MPEP), 2-(2-(3-[¹¹C] methoxyphenyl)ethynyl)pyridine ([¹¹C]M-MPEP), 2-(2-(5-[ ¹¹C]methoxypyridin-3-yl)ethynyl)pyridine ([¹¹C]M-PEPy), and 3-[(2-[¹⁸F]methyl-1,3-thiazol-4-yl)ethynyl]pyridine ([ ¹⁸F]M-TEP). A total of 45 positron emission tomography (PET) imaging studies were conducted on nine male Sprague-Dawley rats within 4 to 6 weeks after unilateral 6-OHDA lesioning into the right medial forebrain bundle. The severity of the lesion was determined with [¹¹C]CFT ([ ¹¹C]2-β-carbomethoxy-3-β-(4-fluorophenyl)tropane), a specific and sensitive ligand for imaging dopamine transporter function. The binding potential (BP) images were processed on pixel-by-pixel basis by using a method of the distribution volume ratio with cerebellum as a reference tissue. The values for BP were determined on striatum, hippocampus, and cortex. [ ¹¹C]CFT binding was decreased on the lesioned (right) striatum by 35.4%±13.4% compared with the intact left striatum, indicating corresponding loss of presynaptic dopamine terminals. On the same areas of the lesioned striatum, three of the four tested mGluR5 ligands showed enhanced binding characteristics. The average differences between the right and left striatum were 4.4%±6.5% (P<0.05) with [¹¹C]MPEP, -0.1%±1.7% (P>0.05) with [¹¹C]M-MPEP, 3.9%±4.6% (P<0.05) with [¹¹C]M-PEPy, and 6.6%±2.7% (P>0.05) with [¹⁸F]M-TEP. The enhanced binding was also observed in the right hippocampus and cortex. These studies showed that glutamatergic neurotransmission might have a complementary role in dopaminergic degeneration, which can be evaluated by in vivo PET imaging.