A genetic polymorphism based kinetic analysis of [11C]DPA-713 dynamic PET for precision imaging of brain injury in National Football League players (2018)

498 Objectives: [11C]DPA-713 is one of a number of radioligands that targets the translocator protein 18 kDa (TSPO) for PET imaging of glial cell activation [1]. As with most agents that target TSPO, it is challenging to estimate [11C]DPA-713 specific binding due to lack of a true reference tissue. Three genotypes of TSPO, CC (Ala147/Ala147), CT (Ala147/Thr147), and TT (Thr147/Thr147), are identified to have high, intermediate or mixed, and low [11C]DPA-713 binding affinity, respectively. A polymorphism plot was proposed to estimate population-wise nonspecific TSPO binding [2-3]. The objective of this study is to evaluate a constrained compartmental modeling approach for estimation of [11C]DPA-713 TSPO specific binding (BPND) and nonspecific binding at individual levels for National Football League (NFL) players and healthy controls (HCs) [4].
 Methods: [11C]DPA-713 PET data from 62 historical subjects with known TSPO genotype were studied. These participants included 37 HCs (23 CC and 14 CT), 19 NFL players (9 CC, 10 CT), and 6 subjects (3 HCs, 1 NFL player, 2 patients with schizophrenia) of TT genotype were included in the study. Each subject had one ninety min dynamic brain PET study with metabolite-corrected plasma input function. Regions of interest (ROIs) were defined on co-registered structural MRIs. Mean ROI time-activity curves (TACs) and plasma inputs calculated from the TT group were used as reference ROI TACs and plasma inputs for all subjects. A standard two-tissue compartment model for reversible receptor binding was used to quantify [11C]DPA-713 nonspecific and specific binding. A constrained fitting algorithm was used to fit the model to each subject’s all ROI TACs and all the reference ROI TACs simultaneously with coupled free-plus-nonspecific distribution volume (VND). For comparison, the population VND was estimated with a polymorphism plot that used each mean regional VT estimate from CC or CT subjects and the mean regional VT estimates from the TT group, where the VT estimateswere obtained by Logan plot.
 Results: Estimates of [11C]DPA-713 VND are 0.48 (± 0.04, 0.23-0.59), and 0.42 mL/cc for compartmental modeling and the polymorphism plot, respectively. The results are close to the previous estimates of 0.44 (0.34-0.53) mL/cc obtained by a blocking study [3]. As compared to the HCs, the regional BPND estimates in NFL playerswere 26.4 (± 4.2)% and 39 (± 1.4)% higher for CC (P < 0.05 for all ROIs except cerebellum, caudate, and occipital) and CT (P < 0.001 for all ROIs) subjects (Figure), respectively.Conclusion: The constrained compartmental modeling approach is suggested to estimate [11C]DPA-713 nonspecific and specific binding. Results from the study demonstrate the TSPO genotype effects on the higher regional BPND estimates inNFL subjects. The full kinetics of specific and nonspecific components obtained from the compartmental modeling analysis will be used to simplify data acquisition and quantification of [11C]DPA-713 PET.
References
[1] Fujita et al., EJNMMI Res. 2017;16:7(1):84.
[2] Guo et al., J Nucl Med. 2013; 54:1915-1923.
[3] Kobayashi et al., J Cereb Blood Flow Metab. 2017; Online.
[4] Coughlin et al., JAMA Neurol. 2017; 74(1):67-74.