TY - JOUR T1 - Use of [11C]ABP688 and PET to measure drug occupancy at the metabotropic glutamate subtype 5 receptor JF - Journal of Nuclear Medicine JO - J Nucl Med SP - 214 LP - 214 VL - 51 IS - supplement 2 AU - William Mathews AU - Hiroto Kuwabara AU - Kirstie Stansfield AU - Heather Valentine AU - Mohab Alexander AU - Anil Kumar AU - Babar Hussain AU - Fabrizio Gasparini AU - Dean Wong Y1 - 2010/05/01 UR - http://jnm.snmjournals.org/content/51/supplement_2/214.abstract N2 - 214 Objectives Metabotropic glutamate subtype 5 receptors (mGluR5) are suggested to be involved in various neuropsychiatric diseases. Thus, therapeutic antagonist drugs such as Fenobam targeting mGluR5 are under development. We evaluated whether [11C]ABP688, an antagonist radioligand, is appropriate for drug occupancy estimation. Methods Baboons (n=4) were studied with PET following a bolus injection of [11C]ABP688 with and without Fenobam pre-treatment (Doses: 0.2, 0.67, 0.9 and 1.33 mg/kg). Total distribution volume (VT) was obtained by plasma reference graphical analysis (Logan et al., 1990) for 11 brain regions. Non-displaceable distribution volume (VND) and overall occupancy for each subject were obtained as x-intercept and slope, respectively, of the regression line (R2: 0.77-0.99) of plot of VT(baseline)-VT(pre-Tx) (=y) versus VT(baseline) (=x). Regional occupancies were given as VT(baseline) - VT(preTx) over VT(baseline) - VND. The Langmuir equation was used to fit occupancy dose plots in regions with maximal occupancy set at 100%. Results Regional VT patterns agreed with published ones (e.g., Ametamey et al., 2007), with cingulate, putamen, and caudate nucleus showing high VT. Overall occupancy estimates were 12.0, 65.4, 75.5, and 91.3% for the 4 dose levels of Fenobam. Fifty percent occupancy (IC50) estimates ranged from 0.3 to 0.5 mg/kg among brain regions. On visual inspection, the Langmuir equation described occupancy dose plots appropriately, as exemplified for putamen in supplemental material. Conclusions This study indicated that [11C]ABP688 is appropriate for imaging mGluR5 with PET and for evaluation of occupancies of drugs targeting mGluR5. The estimate of VND obtained from scatter plot of VT(baseline) minus VT(pre-Tx) versus VT(baseline) may be useful for occupancy calculation in systems without receptor free regions. Research Support This work was supported by NIH grants R33 DA016182 and K24 DA000412 ER -