Quantification of [¹¹C]FLB 457 Binding to Extrastriatal Dopamine Receptors in the Human Brain

Abstract

Positron emission tomography (PET) has hitherto been used to examine D2 dopamine receptor binding in the striatum, a region with a high density of receptors. Research has been hampered by the lack of suitable radioligands for detection of the low-density D2 dopamine receptor populations in the limbic and cortical dopamine systems that are implicated in the pathophysiology of schizophrenia. [11C]FLB 457 is a new radioligand with the very high affinity of 20 pmol/L (K(i)) for the D2 and D3 dopamine receptor subtypes. This study in eight healthy subjects was designed to evaluate the suitability of [11C]FLB 457 for quantification of extrastriatal D2/D3 dopamine receptors. PET-data were acquired in the three-dimensional mode and the arterial input function was corrected for labeled metabolites. The standard three-compartment model and four derived approaches were applied to calculate and compare the binding potentials. Besides the striatum, conspicuous radioactivity was found in extrastriatal regions such as the thalamus, the anterior cinguli, and the temporal and frontal cortices. The time activity curves could be described by the three compartment model. The different approaches gave similar binding potential values and the rank order between regions was consistent with that found in vitro. The short time of a PET measurement using [11C]FLB 457 (63 minutes) seemed not to be sufficient for reliable determination of the high binding potential in the striatum. These results are of principal importance because they show the potential for PET quantification of minute receptor populations in the human brain.

Extrastriatal dopaminergic abnormalities of DA homeostasis in Parkinson's patients with medication-induced pathological gambling: A [11C] FLB-457 and PET study

“…Here were report the results of our PET and [11C] FLB-457 study, a radiotracer with high affinity for DA D2/3 receptors, and therefore sensitivity to extrastriatal, but not striatal D2/3 receptors (Olsson et al, 1999), showing midbrain and PFC dopaminergic differences in PD patients with and without PG.…”

Striatal Vs Extrastriatal Dopamine D2 Receptors in Antipsychotic Response—A Double-Blind PET Study in Schizophrenia

“…The method shows a scan-rescan SD of 6% and has been standardized in our lab with a high intra-and inter-rater reliability (intra-class correlation coefficients: r40.95) (Kapur et al, 1998). Extrastriatal D 2 receptor BP was calculated from the TACs generated from the [ 11 C]-FLB457 scans using the SRTM, using the cerebellum as the reference region and the frontal cortex, temporal cortex, and thalamus as the ROIs (Lammertsma and Hume, 1996;Olsson et al, 1999).…”

The Neural Circuitry of Executive Functions in Healthy Subjects and Parkinson's Disease

“…For instance, during the performance of working memory tasks, DA release increases in the PFC (Aalto et al, 2005a;Sawamoto et al, 2008), and anterior cingulate cortex (ACC) DA receptor density has been shown to be significantly correlated with performance level on the WCST in normal control subjects (Lumme et al, 2007). Recently, Ko et al (2009) (Figure 6) addressed the role of prefrontal DA during set-shifting tasks in healthy subjects by using [ 11 C]FLB 457, a chemical compound with a greater affinity (Kd ¼ 20 nM) for D2 receptors, which allows evaluation of extrastriatal DA release (Aalto et al, 2005a;Olsson et al, 1999;Sudo et al, 2001). Olsson et al (2004) had previously shown that [ 11 C]FLB 457 BP calculated by simplified reference tissue model (Gunn et al, 1997;Lammertsma and Hume, 1996;Sudo et al, 2001) may provide a reasonable estimate of receptor densities in different extrastriatal areas (for example, in cingulate cortex, frontal cortex, thalamus, and temporal cortex), consistent with postmortem studies using [ 125 I]epidepride (Kessler et al, 1993).…”