Development of a new radiotracer (11C-MPTB) for imaging of metabotropic glutamate receptor subtype 5 in brain

Objectives Metabotropic glutamate receptor 5 (mGluR5) is characterized as a G protein coupled receptor and is known as one of regulators for excitatory neurotransmission, which is involved in central nervous system (CNS) disorders, such as fragile X syndrome, Parkinson’s disease, and depression. Therefore, mGluR5 is an important target for development of new pharmaceuticals against these CNS disorders. The most widely used PET radiotracer for mGluR5 was (E)-11C-ABP688 containing alkyne moiety. However, some test-retest PET studies with this radiotracer indicated low reliability for quantification of mGluR5 density. Here, we describe the synthesis of a new radiotracer 11C-MPTB not containing alkyne moiety and evaluation for PET imaging of mGluR5 in brain.

Methods MPTB and its arylstannyl precursor for radiolabeling were synthesized using commercially available compounds. 11C-MPTB was synthesized via C-11C-methylation of the precursor with 11C-methyl iodide. In vitro binding of 11C-MPTB to mGluR5 was characterized by homogenate assay and autoradiography using rat brain. Further, in vivo brain regional distribution and test-retest reliability of 11C-MPTB were determined by small-animal PET assessments.

Results 11C-MPTB was synthesized with 25 ± 14% (n = 11) radiochemical yield at 32 min after end of bombardment and 52-190 GBq/µmol specific activity at the end of synthesis. MPTB showed high in vitro binding affinity (Ki = 9.4 nM) for mGluR5. In vitro autoradiography with 11C-MPTB exhibited heterogeneous distribution pattern of radioactivity in the rat brain sections, which corresponded with the biological localization of mGluR5. These radioactive accumulations were totally diminished by co-incubation with mGluR5-selective antagonist MPEP. In the PET study, the time-activity curves of 11C-MPTB immediately reached maximum levels after the injection and then quickly decreased. The uptake ratio of each region against cerebellum, a reference region for mGluR5, under the equilibrium state was 3.0 ± 0.1 in the striatum, the richest brain region with mGluR5. By treatment with MPEP, the ratio decreased to 1.3. The parametric PET images scaled with binding potential visualized regional differences in specific binding to mGluR5, indicating that PET with 11C-MPTB could provide significant signal for mGluR5 in brain regions. Moreover, test-retest PET studies with this tracer exhibited high reliability for quantification of mGluR5 density.

Conclusions 11C-MPTB is a useful PET radiotracer for the imaging and quantitative analysis of mGluR5 in brain and may merit further evaluation in humans.

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