11C-AC-5216: A Novel PET Ligand for Peripheral Benzodiazepine Receptors in the Primate Brain

Zhang, Ming‐Rong; Kumata, Katsushi; Maeda, Jun; Yanamoto, Kazuhiko; Hatori, Akiko; Okada, Maki; Higuchi, Makoto; Obayashi, Shigeru; Suhara, Tetsuya; Suzuki, Kazutoshi

doi:10.2967/jnumed.107.043505

Cited by 76 publications

(75 citation statements)

References 25 publications

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“…18 F-FEAC also displayed a slow decrease in the brain after the maximum level had been reached at 5 min. In contrast to both 18 F-ligands, 11 C-AC-5216, like 11 C-DAA1106 and 18 F-FEDAA1106, did not dissociate in any brain regions (23). The kinetics of both 18 F-ligands in the monkey brain may be preferable to those of 11 C-AC-5216 for PET assessment.…”

Section: Discussionmentioning

confidence: 83%

“…Although several dozen PET ligands have been developed for in vivo TSPO imaging (10,11), radioligands such as 11 C-AC-5216, 11 C-DAA1106, and 18 F-FEDAA1106 had little dissociation in the primate brain (23)(24)(25)(26). The slow kinetics of these PET ligands is a significant disadvantage.…”

Section: Discussionmentioning

confidence: 99%

“…Of these ligands, 11 C-labeled N,N-diethyl-2-[2-(4-methoxyphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl]acetamide (DPA-713) and 18 F-labeled N, N-diethyl-2-(2-(4-(2-fluoroethoxy)phenyl)-5,7-dimethylpyrazolo [1,5-a]pyrimidin-3-yl)acetamide (DPA-714) are promising PET ligands with potent binding affinity and suitable kinetics in rodent and primate brains for TSPO imaging (14,15,17,18). We have developed N-(2-11 C,5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl) acetamide ( 11 C-DAA1106), N-(5-fluoro-2-phenoxyphenyl)-N-(2-18 F-fluoroethyl-5-methoxybenzyl)acetamide ( 18 F-FEDAA1106), and N-benzyl-N-ethyl-2-(7-11 C-methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin-9-yl)acetamide ( 11 C-AC-5216) for the clinical investigation of TSPO in our institute (20)(21)(22)(23). However, these PET ligands had little dissociation in the primate brain, which makes the assessment of their brain kinetics difficult (24)(25)(26).…”

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confidence: 99%

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¹⁸F-FEAC and ¹⁸F-FEDAC: PET of the Monkey Brain and Imaging of Translocator Protein (18 kDa) in the Infarcted Rat Brain

Yui¹,

Maeda²,

Kumata³

et al. 2010

J Nucl Med

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We evaluated two F-fluoroethyl)-8-oxo-2-phenyl-9H-purin-9-yl] acetamide ( 18 F-FEAC) and N-benzyl-N-methyl-2-[7,8-dihydro-7-(2-18 F-fluoroethyl)-8-oxo-2-phenyl-9H-purin-9-yl]acetamide ( 18 F-FEDAC), by investigating their kinetics in the monkey brain and by performing in vitro and in vivo imaging of translocator protein (18 kDa) (TSPO) in the infarcted rat brain. Methods: Dissection was used to determine the distribution of 18 F-FEAC and 18 F-FEDAC in mice, whereas PET was used for a monkey. With each 18 F-ligand, in vitro autoradiography and small-animal PET were performed on infarcted rat brains. Results: 18 F-FEAC and 18 F-FEDAC had a high uptake of radioactivity in the heart, lung, and other TSPO-rich organs of mice. In vitro autoradiography showed that the binding of each 18 F-ligand significantly increased on the ipsilateral side of rat brains, compared with the contralateral side. In a smallanimal PET study, PET summation images showed the contrast of radioactivity between ipsilateral and contralateral sides. Pretreatment with TSPO ligands N-benzyl-N-ethyl-2-(7-methyl-8-oxo-2-phenyl-7,8-dihydro-9H-purin-9-yl) acetamide (AC-5216) or (R)-N-methyl-N-(1-methylpropyl)-1-(2-chlorophenyl)isoquinoline-3-carboxamide (PK11195) diminished the difference in uptake between the 2 sides. The PET study showed that each 18 F-ligand had uptake and distribution patterns in the monkey brain similar to those of 11 C-AC-5216. After injection into the monkey during PET, the uptake of each 18 F-ligand in the brain decreased over time whereas 11 C-AC-5216 did not. In the brain homogenate of mice, the percentage of the fraction corresponding to intact 18 F-FEAC and 18 F-FEDAC was 68% and 75% at 30 min after injection. In monkey plasma, each 18 F-ligand was scarcely metabolized until the end of the PET scan. Conclusion: 18 F-FEAC and 18 F-FEDAC produced in vitro and in vivo signals allowing visualization of the increase in TSPO expression in the infarcted rat brain. The kinetics of both 18 F-ligands in the monkey brain and tolerance for in vivo metabolism suggested their usefulness for imaging studies of TSPO in primates.

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Section: Discussionmentioning

confidence: 83%

Section: Discussionmentioning

confidence: 99%

mentioning

confidence: 99%

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¹⁸F-FEAC and ¹⁸F-FEDAC: PET of the Monkey Brain and Imaging of Translocator Protein (18 kDa) in the Infarcted Rat Brain

Yui¹,

Maeda²,

Kumata³

et al. 2010

J Nucl Med

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“…Previously, it has been reported that the TSPO protein is also expressed in the ependymal cells (34) and cells within the choroid plexus (9,35). Additionally, the binding in the olfactory bulbs in rodents has previously been observed (36). The causes for this binding remain unclear, with several reports suggesting that neuronal cells in this brain region express TSPO in neo-natal rats (35) and humans (37).…”

Section: Discussionmentioning

confidence: 99%

Detection of Microglial Activation in an Acute Model of Neuroinflammation Using PET and Radiotracers¹¹C-(R)-PK11195 and¹⁸F-GE-180

Dickens¹,

Vainio²,

Marjamäki³

et al. 2014

J Nucl Med

128

104

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“…The use of 11 C-XBD173 identified high accumulation in the lungs, heart, adrenal glands and other organs rich in TSPO; accumulation observed in the CNS is relatively much lower (Zhang et al 2007). Drug effects in these peripheral tissues/organs that express high levels of TSPO that could be more robust and distinct from nervous system responses are almost always ignored.…”

Section: Da Settimo Et Al (2008) Rat C6 Glioma Cellsmentioning

confidence: 99%

Current status and future perspectives: TSPO in steroid neuroendocrinology

Selvaraj

2016

Journal of Endocrinology

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The mitochondrial translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor (PBR), has received significant attention both as a diagnostic biomarker and as a therapeutic target for different neuronal disease pathologies. Recently, its functional basis believed to be mediating mitochondrial cholesterol import for steroid hormone production has been refuted by studies examining both in vivo and in vitro genetic Tspo-deficient models. As a result, there now exists a fundamental gap in the understanding of TSPO function in the nervous system, and its putative pharmacology in neurosteroid production. In this review, we discuss several recent findings in steroidogenic cells that are in direct contradiction to previous studies, and necessitate a re-examination of the purported role for TSPO in de novo neurosteroid biosynthesis. We critically examine the pharmacological effects of different TSPObinding drugs with particular focus on studies that measure neurosteroid levels. We highlight the basis of key misconceptions regarding TSPO that continue to pervade the literature, and the need for interpretation with caution to avoid negative impacts. We also summarize the emerging perspectives that point to new directions that need to be investigated for understanding the molecular function of TSPO, only after which the true potential of this therapeutic target in medicine may be realized.

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11C-AC-5216: A Novel PET Ligand for Peripheral Benzodiazepine Receptors in the Primate Brain

Cited by 76 publications

References 25 publications

¹⁸F-FEAC and ¹⁸F-FEDAC: PET of the Monkey Brain and Imaging of Translocator Protein (18 kDa) in the Infarcted Rat Brain

¹⁸F-FEAC and ¹⁸F-FEDAC: PET of the Monkey Brain and Imaging of Translocator Protein (18 kDa) in the Infarcted Rat Brain

Detection of Microglial Activation in an Acute Model of Neuroinflammation Using PET and Radiotracers¹¹C-(R)-PK11195 and¹⁸F-GE-180

Current status and future perspectives: TSPO in steroid neuroendocrinology

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11C-AC-5216: A Novel PET Ligand for Peripheral Benzodiazepine Receptors in the Primate Brain

Cited by 76 publications

References 25 publications

18F-FEAC and 18F-FEDAC: PET of the Monkey Brain and Imaging of Translocator Protein (18 kDa) in the Infarcted Rat Brain

18F-FEAC and 18F-FEDAC: PET of the Monkey Brain and Imaging of Translocator Protein (18 kDa) in the Infarcted Rat Brain

Detection of Microglial Activation in an Acute Model of Neuroinflammation Using PET and Radiotracers11C-(R)-PK11195 and18F-GE-180

Current status and future perspectives: TSPO in steroid neuroendocrinology

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¹⁸F-FEAC and ¹⁸F-FEDAC: PET of the Monkey Brain and Imaging of Translocator Protein (18 kDa) in the Infarcted Rat Brain

¹⁸F-FEAC and ¹⁸F-FEDAC: PET of the Monkey Brain and Imaging of Translocator Protein (18 kDa) in the Infarcted Rat Brain

Detection of Microglial Activation in an Acute Model of Neuroinflammation Using PET and Radiotracers¹¹C-(R)-PK11195 and¹⁸F-GE-180