Quantification of the Specific Translocator Protein Signal of ¹⁸F-PBR111 in Healthy Humans: A Genetic Polymorphism Effect on In Vivo Binding

Abstract

PET is used to image active inflammatory processes by targeting the translocator protein (TSPO). In vitro, second-generation TSPO radioligands, such as PBR111, have been shown to bind to human tissue samples with either high affinity (high-affinity binders, HABs), low affinity (low-affinity binders, LABs), or an intermediate, mixed affinity (mixed-affinity binders, MABs). We previously explained these differences in affinity in human tissue via the rs6971 polymorphism in the TSPO gene and predicted that the specific signal from PET ligands in vivo would vary accordingly. In silico modeling predicted that 18 F-PBR111 would have a moderate to high specificto-nonspecific ratio in the normal human brain. To test these predictions, we present here the analysis and modeling of 18 F-PBR111 data in healthy humans. Methods: Twenty-one subjects (9 HABs, 8 MABs, and 4 LABs), 28-62 y old, genotyped for the rs6971 polymorphism, underwent 120-min PET scans with arterial sampling after a bolus injection of 18 F-PBR111. Compartmental models and Logan graphical methods enabled estimation of the total volume of distribution (V T ) in regions of interest (ROIs). To evaluate the specific signal, we developed 2 methods to estimate the nondisplaceable volume of distribution (V ND ): the first assumed that the in vitro affinity ratio of 18 F-PBR111 in HABs relative to LABs (4-fold) is preserved in vivo; the second modeled the difference in the HAB and MAB signals in the context of an occupancy plot. Results: A 2-tissue-compartment model described the data well, and a significant difference was found between the V T of HABs, MABs, and LABs across all ROIs examined (P , 0.05). We also found a significant correlation between V T and age for both HABs and MABs in most ROIs. The average V ND estimated by the 2 methods was 1.18 6 0.35 (method I: V ND 5 0.93, method II: V ND 5 1.42), implying that the 18 F-PBR111 BP ND was 2.78 6 0.46 in HABs, 1.48 6 0.28 in MABs, and 0.51 6 0.17 in LABs and that the in vivo affinity ratio was similar to that measured in vitro. Conclusion: 18 F-PBR111 shows a high specific signal in the healthy human brain in vivo. A large component of the variability in the signal across subjects is explained by genetic variation and age, indicating that 18 F-PBR111 can be used for the quantitative assessment of TSPO expression.

Determination of [11C]PBR28 Binding Potential in vivo: A First Human TSPO Blocking Study

“…The procedure used to generate the metabolite corrected plasma input function has been described previously. 10 In brief, the total plasma curve was generated by multiplying the whole blood curve by plasma-over-blood ratio, and the parent fraction data were fitted to a sigmoid model:…”

In Vivo Assessment of Brain White Matter Inflammation in Multiple Sclerosis with18F-PBR111 PET

“…A 2-tissue-compartment kinetic model with a metabolite-corrected plasma input function was applied to the dynamic PET data using a fixed blood volume correction of 5% (19). For each VOI examined, the total volume of distribution (V T ) was estimated from the rate constants as described previously (22).…”

“…A recent study showed increased 18 F-PBR111 uptake corresponding specifically to activated microglia in experimental autoimmune encephalomyelitis (18). We have developed a robust approach for quantitative in vivo assessment of specific 18 F-PBR111 binding to TSPO (19).…”

TSPO: kaleidoscopic 18-kDa amid biochemical pharmacology, control and targeting of mitochondria

“…and [(18)F]-FEPPA for imaging brain inflammation have been linked to this polymorphism (88,(93)(94)(95)(96). However, structural analyses have shown that A147T TSPO is able to retain the same structural profile as the wild-type protein, and binds the first generation TSPO ligand, PK 11195, with comparable affinity (97).…”

“…Future follow on studies could therefore focus to assessing susceptibility in standard stress models of diseases where TSPO has already been linked to, for example, LPS-induced inflammation, ischemia-reperfusion injury, radiation/chemical-induced cancers, overfeeding or bacterial/viral infection. Nonetheless, age-related studies should also be recommended based on the brain-imaging evidences lately produced (96).…”