Quantitative evaluation of 11C-ABP688 as PET ligand for the measurement of the metabotropic glutamate receptor subtype 5 using autoradiographic studies and a beta-scintillator

In this study we assessed the new glutamatergic ligand C-11-ABP688 with regard to the following characteristics: (A) brain distribution, (B) first pass extraction fraction, (C) suitable model to describe tracer kinetics and (D) specificity for the mGlu5 receptor. These parameters were assessed using autoradiography and a beta-scintillator positioned in the striatum. The study included 13 male rats. In 2 animals cerebral blood flow was measured using (H2O)-O-15. The C-11-ABP688 data were analyzed using compartmental modeling. A two-tissue compartment model turned out to fit the data more adequately (parameters: K-1, k(2)', k(3)', k(4), total distribution volume DVtot=K-1/k(2)' (1 + k(3)'/k(4)) than a one-tissue compartment model. The autoradiographic studies revealed high uptake in hippocampus, striatum and cortex and low accumulation in thalamus and cerebellum. The uptake was markedly reduced following blockade with the mGlu5 antagonist M-MPEP. The first pass extraction fraction exceeded 85%. Baseline DVtot was 15.16 +/- 2.67 ml plasma/ml tissue and decreased by 56, 67 and 72% following blockade with 1, 2 and 6 mg/kg M-MPEP, respectively. These results show that C-11-ABP688 is a promising PET ligand for the quantification of mGlu5 receptors in humans and animals. It readily crosses the blood-brain barrier and binds with high specificity to the mGlu5 receptor. The study furthermore demonstrates the usefulness of a beta-scintillator, if necessary in connection with autoradiography, to evaluate new receptor tracers. (C) 2007 Elsevier Inc. All rights reserved.