Brain imaging of¹⁸F‐fallypride in normal volunteers: Blood analysis, distribution, test‐retest studies, and preliminary assessment of sensitivity to aging effects on dopamine D‐2/D‐3 receptors

Abstract

Human studies of dopamine D2/D3 receptors using 18F-fallypride-PET in normal volunteers were performed to evaluate brain distribution in striatal and extrastriatal regions, evaluate metabolites in blood plasma, establish PET imaging protocol for this new radiotracer, evaluate graphical methods of analysis to quantitate D2/D3 receptors, and assess the ability of 18F-fallypride to measure changes in D2/D3 receptors with aging as a model. Subjects (6; 21-63 years) had a PET scan on a Siemens HR+ scanner with 18F-fallypride and a T1-weighted MRI scan on a 1.5T GE scanner for purposes of anatomical coregistration with PET. A 3-h PET scan with 18F-fallypride (0.07 mCi/Kg) was carried out on each subject and repeated in 4-6 weeks. Arterial or arterialized venous blood was obtained in all subjects in order to evaluate blood activity levels and analyze metabolites in the plasma. Brain regions-of-interest were identified and drawn using PET and PET-MR coregistered images. PET data was analyzed using graphical methods in which cerebellum was used as the reference region providing distribution volume ratios (DVR) from which binding potential (BP) was derived and used as a measure of concentration of receptors. Distribution of 18F-fallypride was consistent in all subjects studied and the rank order of receptor concentration was putamen > caudate > thalamus = pituitary > amygdala > colliculi > substantia nigra > hippocampus = temporal cortex > parietal cortex = occipital cortex = orbitofrontal cortex. For younger subjects, BP ranged from 37 for the putamen to 0.4 for orbitofrontal cortex, with a test-retest error of about 10%. Both hydrophilic and lipophilic metabolites were observed in arterial blood plasma and analyses showed approx. 30-40% of plasma radioactivity at 3 h was 18F-fallypride. With aging, all brain regions exhibited a significant decrease (>10% per decade) in binding of 18F-fallypride. PET studies with 18F-fallypride are thus suitable to study changes in D2/D3 receptors in striatal and extrastriatal brain regions.

The Striatal and Extrastriatal D2/D3 Receptor-Binding Profile of Clozapine in Patients with Schizophrenia

“…However, the low D 2 receptor density in the cortex in conjunction with the use of a normal control group for the baseline condition contributes to the comparatively high variability in our data for these regions. Nevertheless, Mukherjee et al (2002) found a test-retest variability of less than 10% both for striatal and temporal cortical regions, supporting the view that D 2 receptors can be reliably quantified with [ 18 F]fallypride even in brain regions with a low D 2 density (Mukherjee et al, 2002).…”

“…It has been consistently demonstrated in human studies that a dynamic scan of 180 min duration allows for establishment of a transient equilibrium both in extrastriatal and striatal brain regions (Mukherjee et al, 2002;Siessmeier et al, 2005). Furthermore, Mukherjee et al (2002) have shown that the test-retest variability in all brain regions is below 10%.…”

“…It has been consistently demonstrated in human studies that a dynamic scan of 180 min duration allows for establishment of a transient equilibrium both in extrastriatal and striatal brain regions (Mukherjee et al, 2002;Siessmeier et al, 2005). Furthermore, Mukherjee et al (2002) have shown that the test-retest variability in all brain regions is below 10%. Thus, the purpose of this [ 18 F]fallypride PET study was to determine the striatal and extrastriatal D 2 /D 3 receptor-binding characteristics of the prototypic 'atypical' antipsychotic clozapine in patients with schizophrenia.…”

Long-Term Test–Retest Reliability of Striatal and Extrastriatal Dopamine D2/3 Receptor Binding: Study with [11C]Raclopride and High-Resolution PET

“…[12][13][14] Moreover, a recent study using diffusion-weighted magnetic resonance imaging and PET found that connectivity-based subdivision of human striatum improved the evaluation of regional differences in DA transmission, supporting an association between striatal DA release and cortical connectivity. 35 36,37 In the current study, cortical VAR and ICC values were good to moderate, ranging from 6.1%, 0.79 (temporal cortex) to 13.1%, 0.67 (superior frontal gyrus). This is clearly superior to previous results by Stokes et al 11 and comparable to test-retest parameters obtained with high-affinity ligands.…”

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

“…One striking observation of our study was the conspicuously high level of [ 11 C]-( + )-PHNO binding in GP, a region that does not stand out as having a particularly high D 2 -receptor density in vitro and that has been scarcely studied using PET or SPECT. (Farde et al, 1997;Fujita et al, 1999;Mukherjee et al, 2002) but did not report on the visualization of GP in vivo. Only one PET study, using [ 11 C]FLB457 in human, clearly identified GP as a region with high D 2/3 binding, with a binding only slightly less than that measured in caudate-putamen (Okubo et al, 1999).…”