Measurement of striatal and extrastriatal dopamine D1 receptor binding potential with [11C]NNC 112 in humans:: Validation and reproducibility

To evaluate the postulated role of extrastriatal D(1) receptors in human cognition and psychopathology requires an accurate and reliable method for quantification of these receptors in the living human brain. [(11)C]NNC 112 is a promising novel radiotracer for positron emission tomography imaging of the D(1) receptor. The goal of this study was to develop and evaluate methods to derive D(1) receptor parameters in striatal and extrastriatal regions of the human brain with [(11)C]NNC 112. Six healthy volunteers were studied twice. Two methods of analysis (kinetic and graphical) were applied to 12 regions (neocortical, limbic, and subcortical regions) to derive four outcome measures: total distribution volume, distribution volume ratio, binding potential (BP), and specific-to-nonspecific equilibrium partition coefficient (k(3)/k(4)). Both kinetic and graphic analyses provided BP and k(3)/k(4) values in good agreement with the known distribution of D(1) receptors (striatum > limbic regions = neocortical regions > thalamus). The identifiability of outcome measures derived by kinetic analysis was excellent. Time-stability analysis indicated that 90 minutes of data collection generated stable outcome measures. Derivation of BP and k(3)/k(4) by kinetic analysis was highly reliable, with intraclass correlation coefficients (ICCs) of 0.90 +/- 0.06 (mean +/- SD of 12 regions) and 0.84 +/- 0.11, respectively. The reliability of these parameters derived by graphical analysis was lower, with ICCs of 0.72 +/- 0.17 and 0.58 +/- 0.21, respectively. Noise analysis revealed a noise-dependent bias in the graphical but not the kinetic analysis. In conclusion, kinetic analysis of [(11)C]NNC 112 uptake provides an appropriate method with which to derive D(1) receptor parameters in regions with both high (striatal) and low (extrastriatal) D(1) receptor density.