Abstract
Dopamine D2 receptors (D2-R) in extrastriatal brain regions are of high interest for research in a wide range of psychiatric and neurologic disorders. Pharmacological competition studies and test–retest experiments have shown high validity and reliability of the positron emission tomography (PET) radioligand [11C]FLB 457 for D2-R quantification in extrastriatal brain regions. However, this radioligand is not available at most research centers. Instead, the medium affinity radioligand [11C]raclopride, which has been extensively validated for quantification of D2-R in the high-density region striatum, has been applied also in studies on extrastriatal D2-R. Recently, the validity of this approach has been questioned by observations of low occupancy of [11C]raclopride in extrastriatal regions in a pharmacological competition study with quetiapine. Here, we utilise a data set of 16 healthy control subjects examined with both [11C]raclopride and [11C]FLB 457 to assess the correlation in binding potential (BPND) in extrastriatal brain regions. BPND was quantified using the simplified reference tissue model with cerebellum as reference region. The rank order of mean regional BPND values were similar for both radioligands, and corresponded to previously reported data, both post-mortem and using PET. Nevertheless, weak to moderate within-subject correlations were observed between [11C]raclopride and [11C]FLB 457 BPND extrastriatally (Pearson's R: 0.30–0.56), in contrast to very strong correlations between repeated [11C]FLB 457 measurements (Pearson's R: 0.82–0.98). In comparison, correlations between repeated [11C]raclopride measurements were low to moderate (Pearson's R: 0.28–0.75). These results are likely related to low signal to noise ratio of [11C]raclopride in extrastriatal brain regions, and further strengthen the recommendation that extrastriatal D2-R measures obtained with [11C]raclopride should be interpreted with caution.
Highlights
Of the dopamine receptor subtypes, the dopamine D2-receptor (D2R) has been of central interest in research on many neurological and psychiatric disorders
For additional test–retest metrics for [11C]raclopride and [11C]FLB 457 see supplementary material (Supplementary Tables 1 and 2). To our knowledge this is the first study to report on within-subject correlations of binding in extrastriatal regions of interest (ROIs) between [11C]raclopride and a very high affinity D2 receptors (D2-R) radioligand
Given that multiple competition and test–retest studies have demonstrated that [11C]FLB 457 is a well suited radioligand to index extrastriatal D2-R binding (Farde et al, 1997; Halldin et al, 1995; Narendran et al, 2013, 2011a, 2011b; Sudo et al, 2001; Suhara et al, 1999; Vilkman et al, 2000), the results imply that the low correlation to [11C]raclopride binding is due to low precision of [11C]raclopride for extrastriatal D2-R quantification
Summary
Of the dopamine receptor subtypes, the dopamine D2-receptor (D2R) has been of central interest in research on many neurological and psychiatric disorders. To quantify D2-R binding in low-density extrastriatal regions, a series of radioligands with high affinity have been developed for both autoradiography and molecular imaging use (de Paulis, 2003). One of those is [11C]FLB 457 with the very high affinity of Kd = 0.02 nM (Halldin et al, 1995). A limitation of high affinity radioligands such as [11C]FLB 457 and [18F]fallypride (Kd = 0.2 nM) (Slifstein et al, 2004) is that accurate quantification of D2-R in the high-density region striatum is rendered either impossible or very impractical: [11C]FLB does not reach equilibrium within feasible scanning durations for carbon-11, and [18F]fallypride requires 3–4 h of measurement.
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