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

Peyronneau, Marie-Anne; Saba, Wadad; Goutal, Sébastien; Damont, Annelaure; Dollé, Frédéric; Kassiou, Michael; Bottlaender, Michel; Valette, Héric

doi:10.1124/dmd.112.046342

Cited by 63 publications

(53 citation statements)

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“…Our analyses showed that equilibrium was attained by 60 min, suggesting that acquisition time can be reduced to 60 min in clinical trials. Moreover, the small increase in V T between 60 and 90 min suggests that radiometabolites potentially entering the brain do not substantially contribute to V T , as previously described (23). Indeed, we recently showed that one 18 F-DPA-714 radiometabolite contributes to about 15% of brain radioactivity after 120 min in rats.…”

Section: Discussionsupporting

confidence: 62%

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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Section: Discussionsupporting

confidence: 62%

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

et al. 2015

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“…While the fluorine-18-labeled tracers, [ 18 F]PBR102, [ 18 F]PBR111, [ 18 F]PBR146, and [ 18 F]DPA-714, have good brain penetration and kinetics, their main pitfall arises from their labeling positions. Metabolism of these tracers results in cleavage of the radioactive label [21, 22] and the formation of non-specifically binding radiometabolites. Despite these shortcomings, the extensive use of these tracers in both preclinical and clinical studies, together with the ongoing development of more metabolically stable analogues [23, 24], further underpins the importance of this motif.…”

Section: Introductionmentioning

confidence: 99%

Radiosynthesis and Preclinical Evaluation of [18F]F-DPA, A Novel Pyrazolo[1,5a]pyrimidine Acetamide TSPO Radioligand, in Healthy Sprague Dawley Rats

et al. 2017

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PurposeMany neurological conditions result in the overexpression of the translocator protein 18 kDa (TSPO), today recognized as a biomarker for microglial activation and neuroinflammation imaging. The pyrazolo[1,5-a]pyrimidine acetamides are a particularly attractive class of TSPO-specific ligands, prompting the development of several positron emission tomography (PET) radiotracers. This includes F-DPA, a recently reported fluorinated ligand (K i = 1.7 nM), wherein the fluorine atom is directly linked to the phenyl moiety without the presence of an alkyl or alkoxy spacer chain. Reported here is the preparation of [18F]F-DPA using [18F]Selectfluor bis(triflate) and the preliminary evaluation of [18F]F-DPA in healthy rats. Its metabolic profile and biodistribution in rats are compared with that of [18F]DPA-714, a closely related structure.Procedures[18F]F-DPA was synthesized by electrophilic fluorination using [18F]Selectfluor bis(triflate), [18F]DPA-714 was synthesized by conventional nucleophilic fluorination. The biodistribution of both radiotracers was compared in Sprague Dawley rats. Radiometabolites of both radiotracers in plasma and brain homogenates were analyzed by radioTLC.ResultsThe radiochemical yield of [18F]F-DPA was 15 ± 3 % and the specific activity was 7.8 ± 0.4 GBq/μmol. The radiochemical purity exceeded 99 %. The in vivo time activity curves of [18F]F-DPA demonstrate rapid entry into the brain and a concentration equilibrium at 20–30 min after injection. The metabolic profiles at 90 min after radiotracer injection in the plasma show that unchanged [18F]F-DPA and [18F]DPA-714 account for 28.3 ± 6.4 and 11.1 ± 2.6 % of the remaining radioactivity, respectively. In the brain, unchanged [18F]F-DPA accounts for 93.5 ± 2.8 % of the radioactivity; whereas for [18F]DPA-714, this value is 53.6 ± 1.6 %.Conclusions[18F]Selectfluor bis(triflate) was successfully used to label F-DPA with fluorine-18. The labeling position on the aromatic moiety imparts a higher stability compared to [18F]DPA-714 with regard to in vivo metabolism. [18F]F-DPA is a promising new radiotracer and warrants further investigation in animal models of disease.Electronic supplementary materialThe online version of this article (doi:10.1007/s11307-016-1040-z) contains supplementary material, which is available to authorized users.

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“…To investigate the metabolism of [ 11 C]PBB3 mediated by cytochrome P450 enzymes (CYPs), we performed an in vitro metabolite analysis of [ 11 C]PBB3 using human or mouse liver microsomes and an NADPH regeneration system as an activator of oxidative reactions by CYPs, as previously described, with minor modifications [10,11]. stopped by the addition of an equal volume of acetonitrile.…”

Section: Human and Mouse Liver Microsomesmentioning

confidence: 99%

Identification of a major radiometabolite of [ 11 C]PBB3

Hashimoto¹,

Kawamura²,

Takei³

et al. 2015

Nuclear Medicine and Biology

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

Cited by 63 publications

References 28 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

Radiosynthesis and Preclinical Evaluation of [18F]F-DPA, A Novel Pyrazolo[1,5a]pyrimidine Acetamide TSPO Radioligand, in Healthy Sprague Dawley Rats

Identification of a major radiometabolite of [ 11 C]PBB3

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

Cited by 63 publications

References 28 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

Radiosynthesis and Preclinical Evaluation of [18F]F-DPA, A Novel Pyrazolo[1,5a]pyrimidine Acetamide TSPO Radioligand, in Healthy Sprague Dawley Rats

Identification of a major radiometabolite of [ 11 C]PBB3

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

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