Translocator Protein (18 kDa) Polymorphism (rs6971) Explains <i>in-vivo</i> Brain Binding Affinity of the PET Radioligand [<sup>18</sup>F]-FEPPA

Mizrahi, Romina; Rusjan, Pablo; Kennedy, James L.; Pollock, Bruce G.; Mulsant, Benoit H.; Suridjan, Ivonne; Luca, Vincenzo De; Wilson, Alan A.; Houle, Sylvain

doi:10.1038/jcbfm.2012.46

Cited by 130 publications

(137 citation statements)

References 20 publications

(30 reference statements)

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“…The frequencies of this polymorphism vary across ethnic groups, with Caucasians having the highest frequency for LABs (HAB:MAB:LAB 5 49:42:9) compared with African Americans (56:38:6) and Han Chinese and Japanese (94:6:0.001). Our hypothesis that the rs6971 polymorphism explained the large betweensubject variability seen with second-generation TSPO PET ligands was consistent with early imaging data from our group (14) and with data showing differences between HAB and MAB binding for TSPO ligands, 18 F-FEPPA, and 11 C-PBR28 (9,15).…”

supporting

confidence: 76%

“…In the past 5 y, a substantial number (.50) of second-generation TSPO ligands have been proposed, including 18 F-PBR111, 11 C-PBR28, 18 F-FEPPA ( 18 F-N-2-(2-fluoroethoxy)benzyl)-N-(4-phenoxypyridin-3-yl)acetamide), and 11 C-DPA713 ( 11 C-N,N-diethyl-2-[2-(4-methoxyphenyl)-5,7-dimethyl-pyrazolo [1,5-a]pyrimidin-3-yl]-acetamide) (7)(8)(9)(10). Although these ligands were claimed to have increased delivery across the blood-brain barrier or a higher signal-to-noise ratio than 11 C-(R)-PK11195, initial human studies have demonstrated considerable variability in their binding across subjects, including the presence of the so-called nonbinders, healthy subjects who demonstrated very little if any binding of 11 C-PBR28 (8).…”

mentioning

confidence: 99%

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

et al. 2013

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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.

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supporting

confidence: 76%

mentioning

confidence: 99%

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

et al. 2013

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“…In the HABs, V T showed high variability that could be related to K 1 higher variability in that group, compared with MABs (Table 1). Such variability in HABs has already been reported for other tracers, namely 18 F-PBR111 (5) and 18 F-FEPPA (22). As described in Guo et al (5), we checked here if age or injected mass could influence the binding of radiotracers to TSPO but we found no correlation between those variables and ligand binding.…”

Section: Discussionmentioning

confidence: 55%

Optimized Quantification of Translocator Protein Radioligand ¹⁸F-DPA-714 Uptake in the Brain of Genotyped Healthy Volunteers

et al. 2015

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Translocator protein (TSPO) is expressed at a low level in healthy brain and is upregulated during inflammatory processes that may occur in neurodegenerative diseases. Thus, TSPO may be a suitable in vivo indicator of neurodegeneration. Here, we quantified the 18 F-DPA-714 radioligand in healthy TSPO-genotyped volunteers and developed a method to eliminate the need for invasive arterial blood sampling. Methods: Ten controls (7 high-affinity binders [HABs] and 3 mixed-affinity binders [MABs]) underwent 18 F-DPA-714 PET with arterial and venous sampling. 18 F-DPA-714 binding was quantified with a metabolite-corrected arterial plasma input function, using the 1-and 2-tissue-compartment models (TCMs) as well as the Logan analysis to estimate total volume distribution (V T ) in the regions of interest. Alternative quantification methods were tested, including tissue-to-plasma ratio or population-based input function approaches normalized by late time points of arterial or venous samples. Results: The distribution pattern of 18 F-DPA-714 was consistent with the known distribution of TSPO in humans, with the thalamus displaying the highest binding and the cerebellum the lowest. The 2-TCM best described the regional kinetics of 18 F-DPA-714 in the brain, with good identifiability (percentage coefficient of variation , 5%). For each region of interest, V T was 47.6% ± 6.3% higher in HABs than in MABs, and estimates from the 2-TCM and the Logan analyses were highly correlated. Equilibrium was reached at 60 min after injection. V T calculated with alternative methods using arterial samples was strongly and significantly correlated with that calculated by the 2-TCM. Replacement of arterial with venous sampling in these methods led to a significant but lower correlation. Conclusion: Genotyping of subjects is a prerequisite for a reliable quantification of 18 F-DPA-714 PET images. The 2-TCM and the Logan analyses are accurate methods to estimate 18 F-DPA-714 V T in the human brain of both HAB and MAB individuals. Population-based input function and tissue-to-plasma ratio with a single arterial sample are promising alternatives to classic arterial plasma input function. Substitution with venous samples is promising but still requires methodologic improvements.

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“…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).…”

Section: Complications In the Application Of Certain Tspo Pet Ligandsmentioning

confidence: 99%

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

Gatliff

Campanella

2016

Biochemical Journal

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The 18-kDa translocator protein (TSPO) localizes in the outer mitochondrial membrane (OMM) of cells and is readily up-regulated under various pathological conditions such as cancer, inflammation, mechanical lesions and neurological diseases. Able to bind with high affinity synthetic and endogenous ligands, its core biochemical function resides in the translocation of cholesterol into the mitochondria influencing the subsequent steps of (neuro-)steroid synthesis and systemic endocrine regulation. Over the years, however, TSPO has also been linked to core cellular processes such as apoptosis and autophagy. It interacts and forms complexes with other mitochondrial proteins such as the voltage-dependent anion channel (VDAC) via which signalling and regulatory transduction of these core cellular events may be influenced. Despite nearly 40 years of study, the precise functional role of TSPO beyond cholesterol trafficking remains elusive even though the recent breakthroughs on its high-resolution crystal structure and contribution to quality-control signalling of mitochondria. All this along with a captivating pharmacological profile provides novel opportunities to investigate and understand the significance of this highly conserved protein as well as contribute the development of specific therapeutics as presented and discussed in the present review.

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Translocator Protein (18 kDa) Polymorphism (rs6971) Explains in-vivo Brain Binding Affinity of the PET Radioligand [¹⁸F]-FEPPA

Cited by 130 publications

References 20 publications

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

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

Optimized Quantification of Translocator Protein Radioligand ¹⁸F-DPA-714 Uptake in the Brain of Genotyped Healthy Volunteers

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

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Translocator Protein (18 kDa) Polymorphism (rs6971) Explains in-vivo Brain Binding Affinity of the PET Radioligand [18F]-FEPPA

Cited by 130 publications

References 20 publications

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

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

Optimized Quantification of Translocator Protein Radioligand 18F-DPA-714 Uptake in the Brain of Genotyped Healthy Volunteers

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

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Product

Resources

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Translocator Protein (18 kDa) Polymorphism (rs6971) Explains in-vivo Brain Binding Affinity of the PET Radioligand [¹⁸F]-FEPPA

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

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

Optimized Quantification of Translocator Protein Radioligand ¹⁸F-DPA-714 Uptake in the Brain of Genotyped Healthy Volunteers