Positron Emission Tomography Quantification of [11C]-(+)-PHNO Binding in the Human Brain

Abstract

The kinetic modeling of [11C]-(+)-PHNO binding to the dopamine D2/3 receptors in six human volunteers using positron emission tomography (PET) is described. [11C]-(+)-PHNO is the first agonist radioligand for the D2/3 in humans and as expected showed high uptake in caudate, putamen, globus pallidus (GP) and ventral striatum, and low uptake in cerebellum. A two-tissue compartment model (2CM) with four parameters was necessary to adequately fit time—activity data in all regions. Although a 2CM provided an excellent estimation of total distribution volumes, which were highly correlated with those obtained with the invasive Logan approach, it provided a poor identification of the k3/ k4 ratios. Coupling K1/ k2 between brain regions (Method C) or fixing K1/ k2 to the value obtained in cerebellum (Method D) enabled more stable estimates of k3/ k4 as compared with an unconstrained 2CM. The k3/ k4 obtained with Method D ranged from 0.12 ± 0.03 in cerebellum to 3.93 ± 0.77 in GP and were similar to those obtained when coupling K1/ k2. Binding potentials (BPs) obtained using the simplified reference tissue model ( BPSRTM) ranged from 2.08 ± 0.34 in caudate to 3.55 ± 0.78 in GP and were highly correlated with k3/ k4 estimates obtained with Method D ( r = 0.98). However, BPSRTM were 11% ± 5% lower than values obtained with Method D. BPs derived using the noninvasive Logan approach were slightly lower but not significantly different than BPSRTM. This study demonstrates that [11C]-(+)-PHNO can be used for the quantitative measurement of D2/3 densities and should enable further studies of potential D2/3 dysregulation in several important psychiatric and neurologic illnesses.