Development of a New Radioligand, N-(5-Fluoro-2-phenoxyphenyl)-N-(2-[18F]fluoroethyl-5-methoxybenzyl)acetamide, for PET Imaging of Peripheral Benzodiazepine Receptor in Primate Brain

Zhang, Ming‐Rong; Maeda, Jun; Ogawa, Michio; Noguchi, Junko; Ito, Takehito; Yoshida, Yuichiro; Okauchi, Takashi; Obayashi, Shigeru; Suhara, Tetsuya; Suzuki, Kazutoshi

doi:10.1021/jm0304919

Cited by 138 publications

(111 citation statements)

References 33 publications

(104 reference statements)

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“…Recently, several other compounds have been evaluated: [ 11 65 Maeda et al, 66 Zhang et al, 67,68 and Fujimara et al 69 have extensively described [ 11 C]DAA1106 and fluorinated derivatives in ex vivo binding experiments on rat brain sections and biodistribution studies in mice. PET imaging has also been performed in normal monkeys or healthy patients, but so far no published data from in vivo experiments using DAA1106 and derivatives in disease states have been published.…”

Section: New Pbr Ligands For Pet Studies Of Microglial Activationmentioning

confidence: 99%

Positron Emission Tomography Imaging of Neuroinflammation

et al. 2007

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In the diseased brain, upon activation microglia express binding sites for synthetic ligands designed to recognize the 18-kDa translocator protein TP-18, which is part of the so-called peripheral benzodiazepine receptor complex. PK11195 [1-(2-chlorophenyl)-N-methyl-N-(1-methylpropyl)-3-isoquinoline carboxamide], the prototype synthetic ligand, has been widely used for the functional characterization of TP-18. Its cellular source in activated microglia has been established using high-resolution, single-cell autoradiography with the R-enantiomer [3H](R)-PK11195. Radiolabeled [11C](R)-PK11195 has been used to image active brain disease with positron emission tomography. Consistent with experimental and postmortem observations of a characteristically distributed pattern of microglia activation in areas of focal pathology, as well as in anterograde and retrograde projection areas, the in vivo regional [11C](R)-PK11195 signal is found in active focal lesions and over time also along the affected neural tracts and their respective cortical and subcortical projection areas. Thus, a profile of active disease emerges that matches some of the typical distribution patterns known from structural neuroimaging techniques, but additionally shows involvement of brain regions linked through neural pathways. In the context of cell-based in vivo neuropathology, the image data are thus best interpreted in the context of the emerging cellular understanding of brain disease or damage, rather than the definitions of clinical diagnosis. One important observation, borne out by experiment, is the long latency with which activated microglia or increased PK11195 retention appear to gradually emerge and remain in distal areas secondarily affected by disease, supporting speculations that the presence of activated microglia is an important corollary of brain plasticity

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Section: New Pbr Ligands For Pet Studies Of Microglial Activationmentioning

confidence: 99%

Positron Emission Tomography Imaging of Neuroinflammation

et al. 2007

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“…These radioligands have 4 to 18 times greater affinity for PBRs than PK 11195 and have higher levels of brain uptake (Zhang et al, 2003). Among this class of ligands, [ 11 C]DAA1106 and [ 18 F] FEDAA1106 have been studied in monkeys and demonstrate high brain uptake and high ratios of specific to nonspecific binding Zhang et al, 2004). Studies in human with these ligands show high brain uptake, but displacement studies have not been performed to measure definitively the percentage of specific binding in human brain (Fujimura et al, 2006;Ikoma et al, 2007).…”

Section: Introductionmentioning

confidence: 99%

Kinetic analysis in healthy humans of a novel positron emission tomography radioligand to image the peripheral benzodiazepine receptor, a potential biomarker for inflammation

et al. 2008

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The peripheral benzodiazepine receptor (PBR) is upregulated on activated microglia and macrophages and thereby is a useful biomarker of inflammation. We developed a novel PET radioligand, [ 11 C]PBR28, that was able to image and quantify PBRs in healthy monkeys and in a rat model of stroke. The objective of this study was to evaluate the ability of [ 11 C]PBR28 to quantify PBRs in brain of healthy human subjects. Twelve subjects had PET scans of 120 to 180 min duration as well as serial sampling of arterial plasma to measure the concentration of unchanged parent radioligand. One-and two-tissue compartmental analyses were performed. To obtain stable estimates of distribution volume, which is a summation of B max /K D and nondisplaceable activity, 90 min of brain imaging was required. Distribution volumes in human were only ∼5% of those in monkey. This comparatively low amount of receptor binding required a two-rather than a one-compartment model, suggesting that nonspecific binding was a sizeable percentage compared to specific binding. The time-activity curves in two of the twelve subjects appeared as if they had no PBR binding -i.e., rapid peak of uptake and fast washout from brain. The cause(s) of these unusual findings are unknown, but both subjects were also found to lack binding to PBRs in peripheral organs such as lung and kidney. In conclusion, with the exception of those subjects who appeared to have no PBR binding, [ 11 C]PBR28 is a promising ligand to quantify PBRs and localize inflammation associated with increased densities of PBRs.

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“…This Letter presents the synthesis of 6-fluoro-PBR28 (15), its radiolabelling with fluorine-18 and its preliminary in vitro and in vivo evaluation as a radiotracer to image the TSPO 18 kDa with PET. The synthesis of non-radioactive 6-fluoro-PBR28 (15), needed as reference compound in radiochemistry and the two radiolabelling precursors (13,14) as well as radiosynthesis of fluorine-18-labelled compound 6-…”

Section: -5mentioning

confidence: 99%

Synthesis of 6-[18F]fluoro-PBR28, a novel radiotracer for imaging the TSPO 18 kDa with PET

Damont

Boisgard

Kühnast

et al. 2011

Bioorganic & Medicinal Chemistry Letters

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a b s t r a c t 6-Fluoro-PBR28 (N-(6-fluoro-4-phenoxypyridin-3-yl)-N-(2-methoxybenzyl)acetamide), a fluorinated analogue of the recently developed TSPO 18 kDa ligand PBR28, was synthesized and labelled with fluorine-18. 6-Fluoro-PBR28 and its 6-chloro/6-bromo counterparts were synthesized in six chemical steps and obtained in 16%, 10% and 19% overall yields, respectively. Labelling with fluorine-18 was performed in one single step (chlorine/bromine-for-fluorine heteroaromatic substitution) using a Zymate-XP robotic system affording HPLC-purified, ready-to-inject, 6-[ 18 F]fluoro-PBR28 (>95% radiochemically pure). Nondecay-corrected overall yields were 9-10% and specific radioactivities ranged from 74 to 148 GBq/lmol.In vitro binding experiments, dynamic lPET studies performed in a rat model of acute neuroinflammation (unilaterally, AMPA-induced, striatum-lesioned rats) and ex vivo autoradiography on the same model demonstrated the potential of 6-[ 18 F]fluoro-PBR28 to image the TSPO 18 kDa using PET.

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Development of a New Radioligand, N-(5-Fluoro-2-phenoxyphenyl)-N-(2-[¹⁸F]fluoroethyl-5-methoxybenzyl)acetamide, for PET Imaging of Peripheral Benzodiazepine Receptor in Primate Brain

Cited by 138 publications

References 33 publications

Positron Emission Tomography Imaging of Neuroinflammation

Positron Emission Tomography Imaging of Neuroinflammation

Kinetic analysis in healthy humans of a novel positron emission tomography radioligand to image the peripheral benzodiazepine receptor, a potential biomarker for inflammation

Synthesis of 6-[18F]fluoro-PBR28, a novel radiotracer for imaging the TSPO 18 kDa with PET

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