Validation of the reference tissue model for estimation of dopaminergic D2-like receptor binding with [18F](N-methyl)benperidol in humans

Abstract

PET measurements of dopaminergic D 2 -like receptors may provide important insights into disorders such as Parkinson's disease, schizophrenia, dystonia and Tourette's syndrome. The PET radioligand [ 18 F] (N-Methyl)Benperidol ([ 18 F]-NMB) has high affinity and selectivity for D 2 -like receptors and is not displaced by endogenous dopamine. The goal of this study is to evaluate use of a graphical method utilizing a reference tissue region for ([ 18 F]-NMB PET analysis by comparisons to an explicit three-compartment tracer kinetic model and graphical method that use arterial blood measurements. We estimated binding potential (BP) in the caudate and putamen using all three methods in 16 humans and found that the three-compartment tracer kinetic method provided the highest BP estimates while the graphical method using a reference region yielded the lowest estimates (p<0.0001 by repeated measures ANOVA). However, the three methods yielded highly correlated BP estimates for the two regions of interest. We conclude that the graphical method using a reference region still provides a useful estimate of BP comparable to methods using arterial blood sampling, especially since the reference region method is less invasive and computationally more straightforward; thereby simplifying these measurements.

Characterization of extrastriatal D2 in vivo specific binding of [18F](N‐methyl)benperidol using PET

“…[ 18 F]NMB BP ND 's for each ROI for each subject were calculated from the PET data using the Logan graphical method with cerebellum as reference region (Logan et al, 1996) as previously described (Antenor-Dorsey et al, 2008). Only regions with BP ND 's greater than 0.1 were included in the analysis.…”

“…Four extrastriatal regions that represent high and low BP ND were selected for comparison among the three methods in 8 unique human subjects (4 male, 4 female, aged 31-71 years) who were included in a similar comparison of striatal BP ND estimation methods (Antenor-Dorsey et al, 2008). These extrastriatal regions included thalamus, amygdala, rostral anterior cingulate cortex, and medial orbitofrontal cortex.…”

“…Data from 60-120min post-injection was used as the standard interval for the linear regression. Otherwise, the comparison among the three methods was carried out as described in Antenor-Dorsey et al (2008). Importantly, for the 3-compartment model, we calculated the BP ND by the ratio of the combined forward rate ( k 3 ) constant to the dissociation rate constant ( k 4 ) and did not use a brain reference region.…”

“…Thus, [ 18 F]NMB is an excellent candidate radioligand for unambiguous PET quantification of the D2R subtype in brain. Previous research demonstrated [ 18 F]NMB's ability to specifically bind to D2R in striatum (Antenor-Dorsey et al, 2008; Karimi et al, 2011). However, PET measures of extrastriatal D2R specific binding with [ 18 F]NMB has not yet been quantified.…”

Preliminary evidence that negative symptom severity relates to multilocus genetic profile for dopamine signaling capacity and D2 receptor binding in healthy controls and in schizophrenia

“…Decay-corrected tissue activity curves were obtained from the dynamic PET data. D2R non-displaceable binding potentials (BP ND s ) were obtained for each ROI using the Logan graphical method with whole cerebellum as a reference region (Antenor-Dorsey et al, 2008). D2R BP ND s for each ROI were averaged across left and right hemispheres to reduce the number of comparisons for primary analyses.…”