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...licot et al. / Nuclear Medicine and Biology xx (2011) xxx–xxxdiazepam and has been demonstrated to be functionally and structurally different from the classical central benzodiazepine receptor. This protein was initially found in peripheral organs including kidneys, nasal epithelium, adrenal glands, lungs and heart. TSPO is also minimally expressed in intact brain, where it is primarily localized in glial cells, including astrocytes and microglia [3]. Its basal expression rises in several acute and neurodegenerative disorders, including stroke [4], Alzheimer's disease [5], Parkinson's disease [6], multiple sclerosis [7], Huntington's disease [8] and amyotrophic lateral sclerosis [9], reflecting microglial activation and neuroinflammation [10]. Accordingly, TSPO is a potential target to explore in vivo neuroinflammatory changes in a variety of neurological disorders by molecular imaging [11]. Thus, the development and validation of a noninvasive TSPO biomarker would be a major advance to improve diagnosis and follow-up of therapeutic interventions. [11C]- (R)-PK11195 was the first TSPO radioligand to be developed and evaluated [12,13]. However, it presented several limitations, includi...

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...edicine and Biology xx (2011) xxx–xxxdiazepam and has been demonstrated to be functionally and structurally different from the classical central benzodiazepine receptor. This protein was initially found in peripheral organs including kidneys, nasal epithelium, adrenal glands, lungs and heart. TSPO is also minimally expressed in intact brain, where it is primarily localized in glial cells, including astrocytes and microglia [3]. Its basal expression rises in several acute and neurodegenerative disorders, including stroke [4], Alzheimer's disease [5], Parkinson's disease [6], multiple sclerosis [7], Huntington's disease [8] and amyotrophic lateral sclerosis [9], reflecting microglial activation and neuroinflammation [10]. Accordingly, TSPO is a potential target to explore in vivo neuroinflammatory changes in a variety of neurological disorders by molecular imaging [11]. Thus, the development and validation of a noninvasive TSPO biomarker would be a major advance to improve diagnosis and follow-up of therapeutic interventions. [11C]- (R)-PK11195 was the first TSPO radioligand to be developed and evaluated [12,13]. However, it presented several limitations, including a relatively low bioa...

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...ty, and allow distribution of the radioligands to distant nuclear medicine centers, as routinely done for [18F]FDG, whereas carbon-11 half-life (20.4 min) restricts its use exclusively to centers equipped with a cyclotron. The in vivo biodistribution and dosimetry of [18F]DPA714 have been performed in mice. [18F]DPA-714 rapidly accumulated in TSPO-rich tissues such as the heart, kidneys and adrenals, and at a lower level in the brain, which was further confirmed by PET human whole-body images. It was in agreement with previous findings on TSPO localization in the peripheral systems of rodents [33,34], with high density in endocrine tissues such as the adrenal glands [3], and in peripheral organs such as the kidney [35] and heart [36]. Uptake in the heart may be related to calcium metabolism since TSPO is coupled to calcium channels in this organ [37]. Moreover, the decreasing kinetic of heart activity included a blood flow part of the [18F]DPA-714 distribution. Conversely, the activity increased over time in gallbladder, suggesting a gastrointestinal elimination of the compound. The uptake of [18F]DPA-714 was also in accordance with the distribution of [11C]-(R)-PK11195 in mouse [38]. The...

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...to the bladder data; feces and large intestine contents were also collected, and their activity was measured too. All radioactivity measurements were corrected for decay. 2.7. Extrapolation to human radiation dosimetry Biodistribution data described above were extrapolated to a reference 70-kg adult male phantom using the % kg/g mass-based extrapolation method [29] and entered into the OLINDA/EXM software. The absorbed dose in 25 target organs of the adult male phantom was estimated from the residence times of source organs by implementing the RADAR (RAdiation Dose Assessment Resource) method [30] using the OLINDA/EXM [31]. The effective dose was also calculated by OLINDA/EXM using the methodology described in Publication 60 of the International Commission on Radiological Protection [32].ig. 1. Plasma metabolites concentration for [18F]DPA-714 in human ubjects. Plasma metabolites fraction (A) and radiometabolite-corrected lasma radioactivity (B) obtained after [18F]DPA-714 injection (mean±S.D., =2). Fig. 2. Brain radioactivity distribution after bolus injection of [18F]DPA-714 in healthy volunteer (injected dose: 304 MBq). (A) Integrated image from 0 to 10 min p.i.; (B) average from 30...

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..., lungs and heart. TSPO is also minimally expressed in intact brain, where it is primarily localized in glial cells, including astrocytes and microglia [3]. Its basal expression rises in several acute and neurodegenerative disorders, including stroke [4], Alzheimer's disease [5], Parkinson's disease [6], multiple sclerosis [7], Huntington's disease [8] and amyotrophic lateral sclerosis [9], reflecting microglial activation and neuroinflammation [10]. Accordingly, TSPO is a potential target to explore in vivo neuroinflammatory changes in a variety of neurological disorders by molecular imaging [11]. Thus, the development and validation of a noninvasive TSPO biomarker would be a major advance to improve diagnosis and follow-up of therapeutic interventions. [11C]- (R)-PK11195 was the first TSPO radioligand to be developed and evaluated [12,13]. However, it presented several limitations, including a relatively low bioavailability, a poor signal-to-noise ratio and high lipophilicity. Therefore, a strong impetus to produce new selective positron emission tomography (PET) TSPO radioligands occurred, and other compounds were then evaluated, including [11C]DAA1106, [18F]FEDAA1106, [11C]PBR28 an...

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...troke [4], Alzheimer's disease [5], Parkinson's disease [6], multiple sclerosis [7], Huntington's disease [8] and amyotrophic lateral sclerosis [9], reflecting microglial activation and neuroinflammation [10]. Accordingly, TSPO is a potential target to explore in vivo neuroinflammatory changes in a variety of neurological disorders by molecular imaging [11]. Thus, the development and validation of a noninvasive TSPO biomarker would be a major advance to improve diagnosis and follow-up of therapeutic interventions. [11C]- (R)-PK11195 was the first TSPO radioligand to be developed and evaluated [12,13]. However, it presented several limitations, including a relatively low bioavailability, a poor signal-to-noise ratio and high lipophilicity. Therefore, a strong impetus to produce new selective positron emission tomography (PET) TSPO radioligands occurred, and other compounds were then evaluated, including [11C]DAA1106, [18F]FEDAA1106, [11C]PBR28 and [18F]PBR06 [14–17]. Recently, a putative antagonist of TSPO, [11C]-N,N-diethyl2[2-(4-methoxyphenyl)-5,7-dimethyl-pyrazolol[1,5-α]pyrimidin-3-yl]-acetamide ([11C]DPA-713), has been described [18,19]. Concurrently, the fluoro-ethoxy derivative DPA7...

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...tory epithelium. These results are in accordance with autoradiographic studies performed with either of the selective TSPO tritium-labeled ligands Ro5-4864 or PK11195 [2,33]. Moreover, the accumulation of activity in gallbladder suggests an at least partial elimination of [18F] DPA-714 by the hepatobiliary system. Finally, we observed [18F]DPA-714 vertebral uptake in the spinal cord, whereas bone had relatively little uptake, suggesting negligible defluorination in vivo. This accumulation of activity in bones with high marrow content has already been described with [11C]-(R)-PK11195 in animal [53] as well as human [41] studies. A recent publication demonstrated the existence of different binder populations for the [11C]PBR28, for which about 10% of the population appeared to be nonbinders [54]. Owen and colleagues [55] evidenced three types of binding pattern: high-affinity binders (∼50%), low-affinity binders (∼20%) and mixed-affinity binders (∼30%), and extended this finding to other PET TSPO radioligands, including the carbon 11-radiolabeled derivative of [18F]DPA-714, namely, DPA-713. Although we have not directly identified a subject with low affinity for TSPO in the present study...

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...troke [4], Alzheimer's disease [5], Parkinson's disease [6], multiple sclerosis [7], Huntington's disease [8] and amyotrophic lateral sclerosis [9], reflecting microglial activation and neuroinflammation [10]. Accordingly, TSPO is a potential target to explore in vivo neuroinflammatory changes in a variety of neurological disorders by molecular imaging [11]. Thus, the development and validation of a noninvasive TSPO biomarker would be a major advance to improve diagnosis and follow-up of therapeutic interventions. [11C]- (R)-PK11195 was the first TSPO radioligand to be developed and evaluated [12,13]. However, it presented several limitations, including a relatively low bioavailability, a poor signal-to-noise ratio and high lipophilicity. Therefore, a strong impetus to produce new selective positron emission tomography (PET) TSPO radioligands occurred, and other compounds were then evaluated, including [11C]DAA1106, [18F]FEDAA1106, [11C]PBR28 and [18F]PBR06 [14–17]. Recently, a putative antagonist of TSPO, [11C]-N,N-diethyl2[2-(4-methoxyphenyl)-5,7-dimethyl-pyrazolol[1,5-α]pyrimidin-3-yl]-acetamide ([11C]DPA-713), has been described [18,19]. Concurrently, the fluoro-ethoxy derivative DPA7...

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...11C]DPA-713 has excellent brain uptake and provided a higher brain signal than [11C]-(R)-PK11195. The biodistribution of [18F]DPA-714 was also in good agreement with previous reports of fluorine-18-radiolabeled tracers in human brain. Thus, intravenous injection of [18F]PBR06 showed radioactivity to peak in the brain at 3 min, followed by a 50% decrease of the peak 1 h p.i. [40,43]. As expected from the known distribution of TSPO in the human brain, the activity biodistribution was widespread and relatively identical in the different cerebral cortical regions, cerebellum and deep brain nuclei [44]. However, the activity concentration in the pons always remained higher than that in the other cerebral regions throughout the PET study. This is in accordance with the known distribution of TSPO in the central nervous system and particularly in the pons [45,46] as confirmed by other PET studies showing high TSPO binding in this brain area [19,46,47]. A limitation of our study may be the use of cerebellum as a reference tissue [44]. However, several authors have compared cerebellum and plasma radioactivity concentration as input function and Logan graphical analysis for quantification of the ...

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...carbon-11 half-life (20.4 min) restricts its use exclusively to centers equipped with a cyclotron. The in vivo biodistribution and dosimetry of [18F]DPA714 have been performed in mice. [18F]DPA-714 rapidly accumulated in TSPO-rich tissues such as the heart, kidneys and adrenals, and at a lower level in the brain, which was further confirmed by PET human whole-body images. It was in agreement with previous findings on TSPO localization in the peripheral systems of rodents [33,34], with high density in endocrine tissues such as the adrenal glands [3], and in peripheral organs such as the kidney [35] and heart [36]. Uptake in the heart may be related to calcium metabolism since TSPO is coupled to calcium channels in this organ [37]. Moreover, the decreasing kinetic of heart activity included a blood flow part of the [18F]DPA-714 distribution. Conversely, the activity increased over time in gallbladder, suggesting a gastrointestinal elimination of the compound. The uptake of [18F]DPA-714 was also in accordance with the distribution of [11C]-(R)-PK11195 in mouse [38]. The effective dose of [18F]DPA-714, extrapolated from the animal biodistribution results, was 17.2 μSv/MBq. This dose level ...

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...life (20.4 min) restricts its use exclusively to centers equipped with a cyclotron. The in vivo biodistribution and dosimetry of [18F]DPA714 have been performed in mice. [18F]DPA-714 rapidly accumulated in TSPO-rich tissues such as the heart, kidneys and adrenals, and at a lower level in the brain, which was further confirmed by PET human whole-body images. It was in agreement with previous findings on TSPO localization in the peripheral systems of rodents [33,34], with high density in endocrine tissues such as the adrenal glands [3], and in peripheral organs such as the kidney [35] and heart [36]. Uptake in the heart may be related to calcium metabolism since TSPO is coupled to calcium channels in this organ [37]. Moreover, the decreasing kinetic of heart activity included a blood flow part of the [18F]DPA-714 distribution. Conversely, the activity increased over time in gallbladder, suggesting a gastrointestinal elimination of the compound. The uptake of [18F]DPA-714 was also in accordance with the distribution of [11C]-(R)-PK11195 in mouse [38]. The effective dose of [18F]DPA-714, extrapolated from the animal biodistribution results, was 17.2 μSv/MBq. This dose level for [18F]DPA-71...

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...on of [18F]PBR06 showed radioactivity to peak in the brain at 3 min, followed by a 50% decrease of the peak 1 h p.i. [40,43]. As expected from the known distribution of TSPO in the human brain, the activity biodistribution was widespread and relatively identical in the different cerebral cortical regions, cerebellum and deep brain nuclei [44]. However, the activity concentration in the pons always remained higher than that in the other cerebral regions throughout the PET study. This is in accordance with the known distribution of TSPO in the central nervous system and particularly in the pons [45,46] as confirmed by other PET studies showing high TSPO binding in this brain area [19,46,47]. A limitation of our study may be the use of cerebellum as a reference tissue [44]. However, several authors have compared cerebellum and plasma radioactivity concentration as input function and Logan graphical analysis for quantification of the binding of otherTSPO radioligands, including [11C]-(R)-PK11195 [47–50]. They compared cerebellum and cluster analysis and have shown that potential binding values were reasonably well correlated [48–50]. Our results showed that DVR values, using cerebellum as ref...

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...d the percentage injected dose per gram of wet tissue(% ID/g) was calculated by comparison to a diluted standard solution derived from the initial injected solution. Radioactivity of urine absorbed on filter paper was measured and added to the bladder data; feces and large intestine contents were also collected, and their activity was measured too. All radioactivity measurements were corrected for decay. 2.7. Extrapolation to human radiation dosimetry Biodistribution data described above were extrapolated to a reference 70-kg adult male phantom using the % kg/g mass-based extrapolation method [29] and entered into the OLINDA/EXM software. The absorbed dose in 25 target organs of the adult male phantom was estimated from the residence times of source organs by implementing the RADAR (RAdiation Dose Assessment Resource) method [30] using the OLINDA/EXM [31]. The effective dose was also calculated by OLINDA/EXM using the methodology described in Publication 60 of the International Commission on Radiological Protection [32].ig. 1. Plasma metabolites concentration for [18F]DPA-714 in human ubjects. Plasma metabolites fraction (A) and radiometabolite-corrected lasma radioactivity (B) obtaine...

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...s [33,34], with high density in endocrine tissues such as the adrenal glands [3], and in peripheral organs such as the kidney [35] and heart [36]. Uptake in the heart may be related to calcium metabolism since TSPO is coupled to calcium channels in this organ [37]. Moreover, the decreasing kinetic of heart activity included a blood flow part of the [18F]DPA-714 distribution. Conversely, the activity increased over time in gallbladder, suggesting a gastrointestinal elimination of the compound. The uptake of [18F]DPA-714 was also in accordance with the distribution of [11C]-(R)-PK11195 in mouse [38]. The effective dose of [18F]DPA-714, extrapolated from the animal biodistribution results, was 17.2 μSv/MBq. This dose level for [18F]DPA-714 was half of that recently estimated in human for FEDAA1106 (36 μSv/MBq) [39], but similar to that measured in human for PBR06 (18.5 μSv/ 7N. Arlicot et al. / Nuclear Medicine and Biology xx (2011) xxx–xxxMBq) [40], two other TSPO [18F]-labeled radioligands, whereas it was about three times more than the one established for PK11195 and PBR28, both radiolabeled with carbon-11, for which effective dose was estimated between 4 and 7 μSv/MBq [41,42]. This co...

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...oupled to calcium channels in this organ [37]. Moreover, the decreasing kinetic of heart activity included a blood flow part of the [18F]DPA-714 distribution. Conversely, the activity increased over time in gallbladder, suggesting a gastrointestinal elimination of the compound. The uptake of [18F]DPA-714 was also in accordance with the distribution of [11C]-(R)-PK11195 in mouse [38]. The effective dose of [18F]DPA-714, extrapolated from the animal biodistribution results, was 17.2 μSv/MBq. This dose level for [18F]DPA-714 was half of that recently estimated in human for FEDAA1106 (36 μSv/MBq) [39], but similar to that measured in human for PBR06 (18.5 μSv/ 7N. Arlicot et al. / Nuclear Medicine and Biology xx (2011) xxx–xxxMBq) [40], two other TSPO [18F]-labeled radioligands, whereas it was about three times more than the one established for PK11195 and PBR28, both radiolabeled with carbon-11, for which effective dose was estimated between 4 and 7 μSv/MBq [41,42]. This concordance may be related to the fact that the majority of dosimetric studies of tracers labeled with fluorine-18 showed that residence times and the effective dose depend more on the physical half-life than biological h...