Evaluation of the Metabotropic Glutamate Receptor Subtype 5 Using PET and 11C-ABP688: Assessment of Methods

Abstract

11 C-ABP688 is a new PET ligand to assess the subtype 5 metabotropic glutamate receptor (mGlu 5 ). The purpose of this study was to evaluate different methods for the analysis of human 11 C-ABP688 data acquired from 6 healthy, young volunteers. Methods: The methods were a 1-tissue-compartment model (K 1 , k 2 $), a 2-tissue-compartment model (K1-k4), and the noncompartmental method developed by Logan. Parameters related to receptor density were the total distribution volume (DV), DV$ (5 K 1 /k 2 $, 1 tissue compartment); specific DV, DV C2 (5 K 1 /k 2 9 · k 3 9/k 4 , 2 tissue compartments); and DV tot for the noncompartmental method. Results: The 1-tissue-compartment model was too simple to adequately fit the data. DV C2 calculated with the 2-tissue-compartment model ranged from 5.45 6 1.47 (anterior cingulate) to 1.91 6 0.32 (cerebellum). The corresponding values for DV tot , calculated with the 2-tissue-compartment model and the Logan method (in parentheses), were 6.57 6 1.45 (6.35 6 1.32) and 2.93 6 0.53 (2.48 6 0.40). There was no clear evidence of a region devoid of mGlu 5 receptors. The first-pass extraction fraction exceeded 95%. The minimal scan duration to obtain stable results was estimated to be 45 min. Conclusion: 11 C-ABP688 displays favorable kinetics for assessing mGlu 5 receptors. For tracer kinetic modeling, 2-tissue-compartment models are clearly superior to models with only 1 tissue compartment. In comparison to the compartmental models, the Logan method is equally useful if only DV tot values are required and fast pixelwise parametric maps are desired. The lack of regions devoid of receptors limits the use of reference region methods that do not require arterial blood sampling. Another advantage of the tracer is the fast kinetics that allow for relatively short acquisitions.

Kinetic Analysis of the Metabotropic Glutamate Subtype 5 Tracer [18F]FPEB in Bolus and Bolus-Plus-Constant-Infusion Studies in Humans

“…10,11 The regional time activity curves (TACs) were well fitted by the two-tissue compartment (2TC) model and Logan graphical approach. 11 However, a [ 11 C]ABP688 test-retest study in humans showed a significant increase in binding parameters in the second scan, which is currently unexplained. 12 [ 18 F]SP203 also displayed regional uptake consistent with the known distribution of mGluR5.…”

Smoking but not cocaine use is associated with lower cerebral metabotropic glutamate receptor 5 density in humans

“…47 Figure 3). Moreover, age of onset of smoking correlated positively with mGluR5 availability in the frontal VOI (r=.41, p<.05) and thalamus (r=.45, p<.05), but this result also did not survive correction for age (p>.31).…”

“…Before the PET acquisition, a catheter was placed in the left antecubital vein for tracer injection and a low-dose CT was conducted for attenuation correction. In order to avoid inconvenient arterial blood sampling, we relied on a previously evaluated equilibrium paradigm 46,47 based on the premise that a steady-state between tracer concentration in tissue and blood can be obtained. 48 To verify that steady-state of receptor binding was reached after 45min (frames 17 to 19), timeactivity curves were generated for high (ACC, putamen), medium (thalamus), and low receptor density regions (cerebellum) in both hemispheres for all participants.…”

Comparative Assessment of Parametric Neuroreceptor Mapping Approaches Based on the Simplified Reference Tissue Model Using [11C]ABP688 PET

“…[18][19][20][21] [ 11 C]ABP688 shows fast kinetics and its binding can be reliably quantified using the NLS-SRTM as shown in previous PET studies in both animals [22][23][24] and humans, 25 where the results of NLS-SRTM showed a high correlation (r ⩾ 0.97) with those of a two-tissue compartment model despite small bias (see section Reference Region for [ 11 C]ABP688). Although its uptake pattern is consistent with mGluR5 distribution in the human brain, 19,26 a relatively moderate uptake in the brain due to lower affinity of [ 11 C]ABP688 to mGluR5 compared with others, 20,27,28 and the short half-life of [ 11 C] usually yield noisy dynamic PET data. Such noise properties of [ 11 C]ABP688, in addition to the wide distribution of the binding sites in the brain, should well allow differences to be seen at high noise levels among the parametric imaging approaches.…”

“…In previous human studies using [ 11 C]ABP688 PET, 19,26,38 the ROI TACs for various brain regions including the cerebellum or its gray matter were best fitted by a two-tissue compartment model. The violation of the single-tissue compartment assumption for the reference region (and also tissue) would introduce biases to the gold standard.…”