Initial evaluation in healthy humans of [18F]DPA-714, a potential PET biomarker for neuroinflammation

Arlicot, Nicolas; Vercouillie, Johnny; Ribeiro, Monica; Tauber, Clovis; Venel, Y.; Baulieu, Jean-Louis; Maïa, S.; Corcia, Philippe; Stabin, Michael G.; Reynolds, Aaron; Kassiou, Michael; Guilloteau, Denis

doi:10.1016/j.nucmedbio.2011.10.012

Cited by 112 publications

(125 citation statements)

References 49 publications

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“…Therefore, the referencebased quantitative method (simplified reference tissue model) with the cerebellum as a reference region may be an easier alternative method for data analysis (10,12). Although Golla et al found a good correlation between the binding potential (BP nd ) estimated in the simplified reference tissue model and the associated V T-2TCM values, here we could not always reliably estimate the BP nd parameter using same method.…”

Section: Discussionmentioning

confidence: 65%

“…Recent preclinical studies (7-9) have identified 18 F-DPA-714 as a promising TSPO ligand for in vivo imaging, and 18 F-DPA-714 has been used to quantify TSPOs in healthy subjects (10) and in amyotrophic lateral sclerosis, Alzheimer, or stroke patients (11)(12)(13). In most studies, quantification was performed without arterial samples or metabolite analysis and was based either on a simplified compartmental model (the cerebellum as a reference region (10,12)) or on a cluster analysis (10,11,13).…”

mentioning

confidence: 99%

“…In most studies, quantification was performed without arterial samples or metabolite analysis and was based either on a simplified compartmental model (the cerebellum as a reference region (10,12)) or on a cluster analysis (10,11,13).…”

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confidence: 99%

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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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confidence: 65%

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confidence: 99%

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

et al. 2015

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“…In addition, [ 18 F]DPA-714 was studied in the healthy primate and displayed marked uptake in TSPOrich organs and specific binding in the brain as demonstrated using PK11195 . [ 18 F]DPA-714 has been studied recently in healthy human subjects (Arlicot et al, 2012) and is currently evaluated in phase I-II clinical trials in Alzheimer's disease and amyotrophic lateral sclerosis patients (Clinical Trials NCT01009359 and NCT00563537).…”

Section: Discussionmentioning

confidence: 99%

Reactive Astrocytes Overexpress TSPO and Are Detected by TSPO Positron Emission Tomography Imaging

Lavisse¹,

Guillermier²,

Hérard³

et al. 2012

J. Neurosci.

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Astrocytes and microglia become reactive under most brain pathological conditions, making this neuroinflammation process a surrogate marker of neuronal dysfunction. Neuroinflammation is associated with increased levels of translocator protein 18 kDa (TSPO) and binding sites for TSPO ligands. Positron emission tomography (PET) imaging of TSPO is thus commonly used to monitor neuroinflammation in preclinical and clinical studies. It is widely considered that TSPO PET signal reveals reactive microglia, although a few studies suggested a potential contribution of reactive astrocytes. Because astrocytes and microglia play very different roles, it is crucial to determine whether reactive astrocytes can also overexpress TSPO and yield to a detectable TSPO PET signal in vivo. We used a model of selective astrocyte activation through lentiviral gene transfer of the cytokine ciliary neurotrophic factor (CNTF) into the rat striatum, in the absence of neurodegeneration. CNTF induced an extensive activation of astrocytes, which overexpressed GFAP and become hypertrophic, whereas microglia displayed minimal increaseinreactivemarkers.TwoTSPOradioligands,[ TSPO mRNA levels were significantly increased, and TSPO protein was overexpressed by CNTF-activated astrocytes. We show that reactive astrocytes overexpress TSPO, yielding to a significant and selective binding of TSPO radioligands. Therefore, caution must be used when interpreting TSPO PET imaging in animals or patients because reactive astrocytes can contribute to the signal in addition to reactive microglia.

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“…In a recent study of several animal models of brain inflammation in our institution, [ 18 (Chauveau et al, 2009 F]DPA-714, N,N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl) 5,7 dimethylpyrazolo[1,5a]pyrimidin-3-yl)acetamide; G6P, glucose 6-phosphate; G6PDH, glucose-6-phosphate dehydrogenase; HPLC, high-performance liquid chromatography; LC-MS, liquid chromatography-mass spectrometry; LC-MS/MS, liquid chromatography-tandem mass spectrometry; NADP, nicotinamide adenine dinucleotide phosphate; NADPH, nicotinamide adenine dinucleotide phosphate reduced form; PET, positron emission tomography; SPE, solid-phase extraction; TSPO, 18-kDa translocator protein; VOI, volume of interest; PK11195: N-methyl-N-(1-methylpropyl)-1-(2-chlorophenyl)isoquinoline-3-carboxamide; pyrimidin-3-yl]-acetamide; PBR102: 2-(6-chloro-2-(4-(3-fluoroethoxy)phenyl)imidazo[1,2-a]pyridin-3-yl)-N,N-diethylacetamide; PBR111:2-(6-chloro-2-(4-(3-fluoropropoxy)phenyl)imidazo[1,2-a] pyridin-3-yl)-N,N-diethylacetamide. (Arlicot et al, 2012;Boellaard et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Metabolism and Quantification of [¹⁸F]DPA-714, a New TSPO Positron Emission Tomography Radioligand

et al. 2012

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]DPA-714 were investigated in rats, baboons, and humans. Whole-body PET experiments showed a high uptake of radioactivity in the kidneys, heart, liver, and gallbladder. The liver was a major route of elimination of [ 18 F]DPA-714, and urine was a route of excretion for radiometabolites. In rat and baboon plasma, high-performance liquid chromatography (HPLC) metabolic profiles showed three major radiometabolites accounting for 85% and 89% of total radioactivity at 120 minutes after injection, respectively. Rat microsomal incubations and analyses by liquid chromatography-mass spectrometry (LC-MS) identified seven metabolites, characterized as O-deethyl, hydroxyl, and N-deethyl derivatives of nonradioactive DPA-714, two of them having the same retention times than those detected in rat and baboon plasma. The third plasma radiometabolite was suggested to be a carboxylic acid compound that accounted for 15% of the rat brain radioactivity.

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Initial evaluation in healthy humans of [18F]DPA-714, a potential PET biomarker for neuroinflammation

Cited by 112 publications

References 49 publications

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

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

Reactive Astrocytes Overexpress TSPO and Are Detected by TSPO Positron Emission Tomography Imaging

Metabolism and Quantification of [¹⁸F]DPA-714, a New TSPO Positron Emission Tomography Radioligand

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Initial evaluation in healthy humans of [18F]DPA-714, a potential PET biomarker for neuroinflammation

Cited by 112 publications

References 49 publications

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

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

Reactive Astrocytes Overexpress TSPO and Are Detected by TSPO Positron Emission Tomography Imaging

Metabolism and Quantification of [18F]DPA-714, a New TSPO Positron Emission Tomography Radioligand

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Product

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

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

Metabolism and Quantification of [¹⁸F]DPA-714, a New TSPO Positron Emission Tomography Radioligand