Quantitative Analysis of Peripheral Benzodiazepine Receptor in the Human Brain Using PET with <sup>11</sup>C-AC-5216

Miyoshi, Michie; Ito, Hiroshi; Arakawa, Ryosuke; Takahashi, Hidehiko; Takano, Harumasa; Higuchi, Makoto; Okumura, Masaki; Otsuka, Tatsui; Kodaka, Fumitoshi; Sekine, Mizuho; Sasaki, Takeshi; Fujie, Saori; Seki, Chie; Maeda, Jun; Nakao, Ryuji; Zhang, Ming Rong; Fukumura, Toshimitsu; Matsumoto, Masayasu; Suhara, Tetsuya

doi:10.2967/jnumed.109.062554

Cited by 26 publications

(19 citation statements)

References 31 publications

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“…5). PET images showed that the distribution patterns of both 18 F-ligands were consistent with that of 11 C-AC-5216 in the monkey brain and were also similar to those of 11 C-AC-5216 in the human brain, reported previously (26). This result, in addition to the structural similarity of the 3 radioligands, confirmed that the uptake of both 18 F-ligands reflected the distribution of TSPO in the monkey brain.…”

Section: Discussionsupporting

confidence: 85%

“…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%

“…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). Thus, PET studies with ligands such as 11 C-AC-5216 create complications in the quantitative analysis of the measurement of TSPO expression and function in health and disease.…”

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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: Discussionsupporting

confidence: 85%

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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“…As the kinetics of [ 11 C]AC-5216 has been characterized in normal human subjects (Miyoshi et al, 2009), a side-by-side comparison would be enabled between courses of neuroinflammatory insults in humans and experimental models, toward the establishment of immunotherapeutic interventions in the disease pathogenesis and creation of better genetically engineered animals recapitulating the amyloidosis-gliosis intercontinuum in human diseases.…”

Section: Discussionmentioning

confidence: 99%

In VivoPositron Emission Tomographic Imaging of Glial Responses to Amyloid-β and Tau Pathologies in Mouse Models of Alzheimer's Disease and Related Disorders

Maeda¹,

Zhang²,

Okauchi³

et al. 2011

J. Neurosci.

128

134

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Core pathologies of Alzheimer's disease (AD) are aggregated amyloid-β peptides (Aβ) and tau, and the latter is also characteristic of diverse neurodegenerative tauopathies. These amyloid lesions provoke microglial activation, and recent neuroimaging technologies have enabled visualization of this response in living brains using radioligands for the peripheral benzodiazepine receptor also known as the 18-kDa translocator protein (TSPO). Here we elucidated contributions of Aβ and tau deposits to in vivo TSPO signals in pursuit of mechanistic and diagnostic significance of TSPO imaging in AD and other tauopathies. A new antibody to human TSPO revealed induction of TSPO-positive microgliosis by tau fibrils in tauopathy brains. Emergence of TSPO signals prior to occurrence of brain atrophy and thioflavin-S-positive tau amyloidosis was also demonstrated in living mice transgenic for mutant tau by positron emission tomography (PET) with two classes of TSPO radioligands, [11C]AC-5216 and [18F]fluoroethoxy-DAA1106. Meanwhile, only modest TSPO elevation was observed in aged mice modeling Aβ plaque deposition, despite the notably enhanced in vivo binding of amyloid radiotracer, [11C]Pittsburgh Compound-B, to plaques. In these animals, [11C]AC-5216 yielded better TSPO contrasts than [18F]fluoroethoxy-DAA1106, supporting the possibility of capturing early neurotoxicity with high-performance TSPO probes. Furthermore, an additional line of mice modeling intraneuronal Aβ accumulation displayed elevated TSPO signals following noticeable neuronal loss, unlike TSPO upregulation heralding massive neuronal death in tauopathy model mice. Our data corroborate the utility of TSPO-PET imaging as a biomarker for tau-triggered toxicity, and as a complement to amyloid scans for diagnostic assessment of tauopathies with and without Aβ pathologies.

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“…[159,160] families. Three of these ligands have so far been applied to human subjects [161][162][163], and a comparative PET analysis of nondemented elderly and AD cases was conducted with [ 11 C]DAA1106 [164]. The [24,158].…”

Section: Accepted Manuscriptmentioning

confidence: 99%

In-vivo visualization of key molecular processes involved in Alzheimer's disease pathogenesis: Insights from neuroimaging research in humans and rodent models

Higuchi¹,

Maeda²,

Ji³

et al. 2010

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Diverse age-associated neurodegenerative disorders are featured at a molecular level by depositions of self-aggregating molecules, as represented by amyloid beta peptides (Abeta) and tau proteins in Alzheimer's disease, and cascade-type chain reactions are supposedly commenced with biochemical aberrancies of these amyloidogenic components. Mutagenesis and multiplication of the genes encoding Abeta, tau and other pathogenic initiators may accelerate the incipient process at the cascade top, rationalizing generations of transgenic and knock-in animal models of these illnesses. Meanwhile, these genetic manipulations do not necessarily compress the timelines of crucial intermediate events linking amyloidogenesis and neuronal lethality, resulting in an incomplete recapitulation of the diseases. Requirements for modeling the entire cascade can be illustrated by a side-by-side comparison of humans and animal models with the aid of imaging-based biomarkers commonly applicable to different species. Notably, key components in a highly reactive state are assayable by probe-assisted neuroimaging techniques exemplified by positron emission tomography (PET), providing critical information on the in-vivo accessibility of these target molecules. In fact, multispecies PET studies in conjunction with biochemical, electrophysiological and neuropathological tests have revealed putative neurotoxic subspecies of Abeta assemblies, translocator proteins accumulating in aggressive but not neuroprotective microglia, and functionally active neuroreceptors available to endogenous neurotransmitters and exogenous agonistic ligands. Bidirectional translational studies between human cases and model strains based on this experimental paradigm are presently aimed at clarifying the tau pathogenesis, and would be expanded to analyses of disrupted calcium homeostasis and mitochondrial impairments. Since reciprocal causalities among the key processes have indicated an architectural interchangeability between cascade and network connections as an etiological representation, longitudinal imaging assays with manifold probes covering the cascade from top to bottom virtually delineate the network dynamics continuously altering in the course of the disease and its treatment, and therefore expedite the evaluation and optimization of therapeutic strategies intended for suppressing the neurodegenerative pathway over its full length.

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Quantitative Analysis of Peripheral Benzodiazepine Receptor in the Human Brain Using PET with ¹¹C-AC-5216

Cited by 26 publications

References 31 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

In VivoPositron Emission Tomographic Imaging of Glial Responses to Amyloid-β and Tau Pathologies in Mouse Models of Alzheimer's Disease and Related Disorders

In-vivo visualization of key molecular processes involved in Alzheimer's disease pathogenesis: Insights from neuroimaging research in humans and rodent models

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Quantitative Analysis of Peripheral Benzodiazepine Receptor in the Human Brain Using PET with 11C-AC-5216

Cited by 26 publications

References 31 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

In VivoPositron Emission Tomographic Imaging of Glial Responses to Amyloid-β and Tau Pathologies in Mouse Models of Alzheimer's Disease and Related Disorders

In-vivo visualization of key molecular processes involved in Alzheimer's disease pathogenesis: Insights from neuroimaging research in humans and rodent models

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Product

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Quantitative Analysis of Peripheral Benzodiazepine Receptor in the Human Brain Using PET with ¹¹C-AC-5216

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