Faculty Bibliography

Several studies have examined the link between the cannabinoid CB1 receptor and several neuropsychiatric illnesses, including schizophrenia. As such, there is a need for in vivo imaging tracers so that the relationship between CB1 and schizophrenia (SZ) can be further studied. In this paper, we present our first human studies in both healthy control patients and patients with schizophrenia using the novel PET tracer, [(11)C]OMAR (JHU75528), we have shown its utility as a tracer for imaging human CB1 receptors and to investigate normal aging and the differences in the cannabinoid system of healthy controls versus patients with schizophrenia. A total of ten healthy controls and nine patients with schizophrenia were included and studied with high specific activity [(11)C]OMAR. The CB1 binding (expressed as the distribution volume; V(T)) was highest in the globus pallidus and the cortex in both controls and patients with schizophrenia. Controls showed a correlation with the known distribution of CB1 and decline of [(11)C]OMAR binding with age, most significantly in the globus pallidus. Overall, we observed elevated mean binding in patients with schizophrenia across all regions studied, and this increase was statistically significant in the pons (p<0.05), by the Students t-test. When we ran a regression of the control subjects V(T) values with age and then compared the patient data to 95% prediction limits of the linear regression, three patients fell completely outside for the globus pallidus, and in all other regions there were at least 1-3 patients outside of the prediction intervals. There was no statistically significant correlations between PET measures and the individual Brief Psychiatry Rating Score (BPRS) subscores (r=0.49), but there was a significant correlation between V(T) and the ratio of the BPRS psychosis to withdrawal score in the frontal lobe (r=0.60), and middle and posterior cingulate regions (r=0.71 and r=0.79 respectively). In conclusion, we found that [(11)C] OMAR can image human CB1 receptors in normal aging and schizophrenia. In addition, our initial data in subjects with schizophrenia seem to suggest an association of elevated binding specific brain regions and symptoms of the disease.

In quantitative dynamic PET studies, graphical analysis methods including the Gjedde-Patlak plot, the Logan plot, and the relative equilibrium-based graphical plot (RE plot) (Zhou Y., Ye W., Brasic J.R., Crabb A.H., Hilton J., Wong D.F. 2009b. A consistent and efficient graphical analysis method to improve the quantification of reversible tracer binding in radioligand receptor dynamic PET studies. Neuroimage 44(3):661-670) are based on the theory of a compartmental model with assumptions on tissue tracer kinetics. If those assumptions are violated, then the resulting estimates may be biased. In this study, a multi-graphical analysis method was developed to characterize the non-relative equilibrium effects on the estimates of total distribution volume (DV(T)) from the RE plot. A novel bi-graphical analysis method using the RE plot with the Gjedde-Patlak plot (RE-GP plots) was proposed to estimate DV(T) for the quantification of reversible tracer kinetics that may not be at relative equilibrium states during PET study period. The RE-GP plots and the Logan plot were evaluated by 19 [(11)C]WIN35,428 and 10 [(11)C]MDL100,907 normal human dynamic PET studies with brain tissue tracer kinetics measured at both region of interest (ROI) and pixel levels. A 2-tissue compartment model (2TCM) was used to fit ROI time activity curves (TACs). By applying multi-graphical plots to the 2TCM fitted ROI TACs which were considered as the noise-free tracer kinetics, the estimates of DV(T) from the RE-GP plots, the Logan plot, and the 2TCM fitting were equal to each other. For the measured ROI TACs, there was no significant difference between the estimates of the DV(T) from the RE-GP plots and those from 2TCM fitting (p=0.77), but the estimates of the DV(T) from the Logan plot were significantly (p<0.001) lower, 2.3% on average, than those from 2TCM fitting. There was a highly linear correlation between the ROI DV(T) from the parametric images (Y) and those from the ROI kinetics (X) by using the RE-GP plots (Y=1.01X+0.23, R(2)=0.99). For the Logan plot, the ROI estimates from the parametric images were 13% to 83% lower than those from ROI kinetics. The computational time for generating parametric images was reduced by 69% on average by the RE-GP plots in contrast to the Logan plot. In conclusion, the bi-graphical analysis method using the RE-GP plots was a reliable, robust and computationally efficient kinetic modeling approach to improve the quantification of dynamic PET.