[18F]FMDAA1106 and [18F]FEDAA1106: two positron-Emitter labeled ligands for peripheral benzodiazepine receptor (PBR)

Zhang, Ming Rong; Maeda, Jun; Furutsuka, Kenji; Yoshida, Yuichiro; Ogawa, Michio; Suhara, Tetsuya; Suzuki, Kazutoshi

doi:10.1016/s0960-894x(02)00886-7

Cited by 92 publications

(60 citation statements)

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“…Since 18 F has advantages over 11 C, with a longer half-life (110 min vs. 20 min) and a lower positron energy (650 keV vs 960 keV), an 18 F-labeled ligand gives higher quality images with a higher spatial resolution in PET measurements. Moreover, 18 30 Preliminary studies revealed that analogues 4 and 5 have similar or higher inhibitory activity (IC 50 ) for PBR in the rat brain than 2. 30 The ex vivo autoradiograms of [ 18 F]4 and [ 18 F]5 binding sites in rat brain revealed significantly high radioactivity in the olfactory bulb and cerebellum, the richer regions of PBR compared with other brain regions.…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, 18 30 Preliminary studies revealed that analogues 4 and 5 have similar or higher inhibitory activity (IC 50 ) for PBR in the rat brain than 2. 30 The ex vivo autoradiograms of [ 18 F]4 and [ 18 F]5 binding sites in rat brain revealed significantly high radioactivity in the olfactory bulb and cerebellum, the richer regions of PBR compared with other brain regions. 30 In this study, we synthesized four analogues (4-7, Scheme 2) including two novel compounds: (N-(5-fluoro-2-phenoxyphenyl)-N-(2-iodomethyl-5-methoxybenzyl)acetamide (6) and N-(5-fluoro-2-phenoxyphenyl)-N-(5-methoxy-2-tosyloxyethylbenzyl)acetamide (7).…”

Section: Introductionmentioning

confidence: 99%

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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

Zhang¹,

Maeda²,

Ogawa³

et al. 2004

J. Med. Chem.

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140

104

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To develop a positron emission tomography (PET) ligand for imaging the 'peripheral benzodiazepine receptor' (PBR) in brain and elucidating the relationship between PBR and brain diseases, four analogues (4-7) of N-(2,5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamide (2) were synthesized and evaluated as ligands for PBR. Of these compounds, fluoromethyl (4) and fluoroethyl (5) analogues had similar or higher affinities for PBR than the parent compound 2 (K(i) = 0.16 nM for PBR in rat brain sections). Iodomethyl analogue 6 displayed a moderate affinity, whereas tosyloxyethyl analogue 7 had weak affinity. Radiolabeling was performed for the fluoroalkyl analogues 4 and 5 using fluorine-18 ((18)F, beta(+); 96.7%, T(1/2) = 109.8 min). Ligands [(18)F]4 and [(18)F]5 were respectively synthesized by the alkylation of desmethyl precursor 3 with [(18)F]fluoromethyl iodide ([(18)F]8) and 2-[(18)F]fluoroethyl bromide ([(18)F]9). The distribution patterns of [(18)F]4 and [(18)F]5 in mice were consistent with the known distribution of PBR. However, compared with [(18)F]5, [(18)F]4 displayed a high uptake in the bone of mice. The PET image of [(18)F]4 for monkey brain also showed significant radioactivity in the bone, suggesting that this ligand was unstable for in vivo defluorination and was not a useful PET ligand. Ligand [(18)F]5 displayed a high uptake in monkey brain especially in the occipital cortex, a region with richer PBR than the other regions in the brain. The radioactivity level of [(18)F]5 in monkey brain was 1.5 times higher than that of [(11)C]2, and 6 times higher than that of (R)-(1-(2-chlorophenyl)-N-[(11)C]methyl,N-(1-methylpropyl)isoquinoline ([(11)C]1). Moreover, the in vivo binding of [(18)F]5 was significantly inhibited by PBR-selective 2 or 1, indicating that the binding of [(18)F]5 in the monkey brain was mainly due to PBR. Metabolite analysis revealed that [(18)F]4 was rapidly metabolized by defluorination to [(18)F]F(-) in the plasma and brain of mice, whereas [(18)F]5 was metabolized by debenzylation to a polar product [(18)F]13 only in the plasma. No radioactive metabolite of [(18)F]5 was detected in the mouse brain. The biological data indicate that [(18)F]5 is a useful PET ligand for PBR and is currently used for imaging PBR in human brain.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Zhang¹,

Maeda²,

Ogawa³

et al. 2004

J. Med. Chem.

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140

104

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“…In conjunction with other work, the preparation [ 18 5,8,10,11 (3, X ¼ I), had been reported as reagents for introduction of the [ 18 F]fluoromethyl group. These reagents suffer from relatively low reactivity and are somewhat inconvenient to prepare.…”

Section: Introductionmentioning

confidence: 99%

Improved synthesis of [¹⁸F]fluoromethyl tosylate, a convenient reagent for radiofluoromethylations

Neal¹,

Apana²,

Berridge

2005

Labelled Comp Radiopharmac

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“…11 C-(R)-PK11195 has long been considered the standard for TSPO imaging; however, its poor signal-to-noise ratio and low brain permeability limit its accuracy and usefulness (19). Several new TSPO-specific ligands, namely, 11 C-DAA1106, 18 F-FEDAA1106, and 11 C-PBR28, have been described and reported to display good in vivo properties in rodent brains (20,21). 11 C-DAA1106 and 18 F-FEDAA1106 have also been shown to display highly specific in vivo uptake in primate brains (22); 18 F-FE-DAA1106 was recently evaluated in human PET studies (23).…”

mentioning

confidence: 99%

DPA-714, a New Translocator Protein–Specific Ligand: Synthesis, Radiofluorination, and Pharmacologic Characterization

James

Fulton²,

Vercouillie³

et al. 2008

J Nucl Med

249

251

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The translocator protein (18 kDa) (TSPO), formerly known as the peripheral benzodiazepine receptor, is dramatically upregulated under pathologic conditions. Activated microglia are the main cell type expressing the TSPO at sites of central nervous system pathology. Radioligands for the TSPO can therefore measure active disease in the brain. This article details the synthesis, radiofluorination, and pharmacologic evaluation of a new TSPOspecific pyrazolopyrimidine, DPA-714. Methods: The affinity of DPA-714 for the TSPO was measured in rat kidney membranes with 3 H-PK11195. The in vitro functional activity of DPA-714 was measured in a steroidogenic assay in which the ability of DPA-714 to increase pregnenolone synthesis was measured with rat C6 glioma cells. The radiofluorination of DPA-714 was achieved by nucleophilic 18 F-fluoride displacement of the tosylate precursor. 18 F-DPA-714 was assessed in rats harboring unilateral quinolinic acid (QA) lesions. In addition, pretreatment experiments were performed with PK11195 (5 mg/kg), DPA-714 (1 mg/kg), and DPA-713 (1 mg/kg). The in vivo binding and biodistribution of 18 F-DPA-714 were determined in a baboon with PET. Experiments involving presaturation with PK11195 (1.5 mg/kg) and displacement with DPA-714 (1 mg/kg) were conducted to evaluate the specificity of radioligand binding. Results: In vitro binding studies revealed that DPA-714 displayed a high affinity for the TSPO (dissociation constant, 7.0 nM). DPA-714 stimulated pregnenolone synthesis at levels 80% above the baseline. 18 F-DPA-714 was prepared at a 16% radiochemical yield and a specific activity of 270 GBq/mmol. In rats harboring unilateral QA lesions, an 8-fold-higher level of uptake of 18 F-DPA-714 was observed in the ipsilateral striatum than in the contralateral striatum. Uptake in the ipsilateral striatum was shown to be selective because it was inhibited to the level in the contralateral striatum in the presence of PK11195, nonlabeled . PET studies demonstrated rapid penetration and good retention of 18 F-DPA-714 in the baboon brain. Pretreatment with PK11195 effectively inhibited the uptake of 18 F-DPA-714 in the whole brain, indicating its selective binding to the TSPO. The injection of nonlabeled DPA-714 20 min after the injection of 18 F-DPA-714 resulted in radioligand washout, demonstrating the reversibility of 18 F-DPA-714 binding. Conclusion: 18 F-DPA-714 is a specific radioligand for the TSPO, displaying promising in vivo properties and thus warranting further investigation.

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[18F]FMDAA1106 and [18F]FEDAA1106: two positron-Emitter labeled ligands for peripheral benzodiazepine receptor (PBR)

Cited by 92 publications

References 14 publications

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

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

Improved synthesis of [¹⁸F]fluoromethyl tosylate, a convenient reagent for radiofluoromethylations

DPA-714, a New Translocator Protein–Specific Ligand: Synthesis, Radiofluorination, and Pharmacologic Characterization

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[18F]FMDAA1106 and [18F]FEDAA1106: two positron-Emitter labeled ligands for peripheral benzodiazepine receptor (PBR)

Cited by 92 publications

References 14 publications

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

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

Improved synthesis of [18F]fluoromethyl tosylate, a convenient reagent for radiofluoromethylations

DPA-714, a New Translocator Protein–Specific Ligand: Synthesis, Radiofluorination, and Pharmacologic Characterization

Contact Info

Product

Resources

About

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

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

Improved synthesis of [¹⁸F]fluoromethyl tosylate, a convenient reagent for radiofluoromethylations