Evaluation of dopamine D_2/3specific binding in the cerebellum for the positron emission tomography radiotracer [¹¹C]FLB 457: Implications for measuring cortical dopamine release

Abstract

In a recent PET study we demonstrated the ability to measure amphetamine-induced DA release in the human cortex with the dopamine D 2/3 radioligand [ 11 C]FLB 457. As previous studies in animals have shown that a relatively high fraction of the [ 11 C]FLB 457 signal in the cerebellum represents specific binding to D 2/3 receptors, there was concern that the use of the cerebellum as a measure of nonspecific binding (i.e., reference region) to derive [ 11 C]FLB 457 binding potential (BP ND ) would bias cortical dopamine release measurements. Thus, we evaluated the fractional contribution of specific binding to D 2/3 receptors in the human cerebellum for [ 11 C]FLB 457.Six healthy human subjects (5M/1F) were studied twice with [ 11 C]FLB 457, once at baseline and again following a single oral dose of 15 mg of aripiprazole, a D 2/3 partial agonist. [ 11 C]FLB 457 distribution volume (V T ) was estimated using kinetic analysis in the cortical regions of interest and potential reference regions. The change in [ 11 C]FLB 457 V T following aripiprazole ranged from −33 to −42% in the cortical regions of interest (ROIs). The aripiprazole-induced change in [ 11 C]FLB 457 V T in three potential reference regions suggests significant specific binding the cerebellum (CER, −17 ± 12%), but not pons (PON, −10 ± 10%) and centrum semiovale (CESVL, −3 ± 12%). Nevertheless, a re-analysis of the published [ 11 C]FLB 457 test-retest and amphetamine studies suggests that the use of the PON V T and CESVL V T as an estimate of nonspecific binding to derive [ 11 C]FLB 457 BP ND in dopamine release studies is unlikely to be successful because it leads to less reproducible outcome measures, which in turn diminishes the ability to measure dopamine release in the cortex. D 2/3 blocking studies with aripiprazole and [ 11 C]FLB 457 suggest specific binding to D 2/3 receptors in the cerebellum. These data also suggest that the contribution of specific binding to D 2/3 receptors in the cerebellum is lower than that in the cortical ROIs and that CER V T is mostly representative of nonspecific binding. Nevertheless, caution is advised when using reference tissue methods that rely solely on the cerebellum signal as an input function to quantify [ 11 C]FLB 457

Reference Region Modeling Approaches for Amphetamine Challenge Studies with [11C]FLB 457 and PET

“…[10][11][12] A more recent [ 11 C]FLB 457 blocking study with aripiprazole (D2/D3 partial agonist) was performed to evaluate the fractional contribution to specific D2/D3 binding in the cerebellum, in addition to the pons and centrum semiovale (CESVL), to assess potential reference regions. 13 The change in V T before and after aripiprazole was lower in the CESVL (−3%) and the pons (−10%), compared with the cerebellum (−17%). However, a reevaluation of previous data yielded lower variability with testretest and amphetamine-induced changes in BP ND and greater sensitivity to detect amphetamine-induced DA release across regions when V T (CER) was used to estimate the nondisplaceable distribution volume, V ND , compared with V T (PONS) and V T (CESVL).…”

“…Using the cerebellum as a reference in 2TC to compute BP ND in amphetamine challenge studies induces a bias in the estimation of %ΔBP ND . For example, if we assume that 17% of the cerebellum V T correspond to specific binding, 13 then %ΔBP ND would be overestimated bỹ 25% (i.e., a true 16% decrease in the true BP ND would lead to a % ΔBP ND estimate of − 20%) in a region which true BP ND is 1. This bias decreases in regions with larger true BP ND (it would be~11% in a region which true BP ND is 2).…”

Measuring Cigarette Smoking-Induced Cortical Dopamine Release: A [11C]FLB-457 PET Study

“…A third potential limitation of this study is the use of the cerebellum as a reference region and possible carryover mass across scans due to remaining radiotracer. Although some investigators use similar methods, there is evidence for specific binding in this region (Narendran et al, 2011a) and others use an arterial input function to model [ 11 C]-FLB-457 BP ND ; this remains a subject of debate in the field. Nevertheless, [ 11 C]-FLB-457 has been shown to have acceptable test-retest variability (p15%) and low carryover mass effects if scans are done more than 195 min apart (Narendran et al, 2014;Narendran et al, 2011b;Sudo et al, 2001).…”

“…Despite some studies reporting detectable D2/3-receptor-specific [ 11 C]-FLB-457 binding in the cerebellum (Asselin et al, 2007;Delforge et al, 1999), the tissue time activity curve (TAC) of the cerebellar cortex (excluding vermis) was used as the reference region, because it has been deemed suitable for the calculation of [ 11 C]-FLB-457 BP ND in several studies Narendran et al, 2011a;Olsson et al, 2004;Vilkman et al, 2000). This approach yielded maps of [ 11 C]-FLB-457 BP ND for the abstinent and smoking conditions, which were registered to each individual's MRI, transformed into standardized stereotaxic space (the ICBM 305 template), and spatially smoothed with a 6-mm FWHM kernel.…”

Extrastriatal dopamine D2-receptor availability in social anxiety disorder

“…In addition, a grey-matter MR mask was obtained from the MR segmentation and used on the cerebellar regions in order to produce a grey-matter-specific reference region. Previous studies have shown low levels of specific [ 11 C]FLB457 binding in the cerebellum (Olsson et al, 2004;Asselin et al, 2007;Narendran et al, 2011). For this reason we tested for group differences in reference region uptake, by extracting cerebellum standardized uptake values (SUV) curves (radioactivity concentration normalized by injected radioactivity and subject's weight).…”