[2-11C]Isopropyl-, [1-11C]Ethyl-, and [11C]Methyl-Labeled Phenoxyphenyl Acetamide Derivatives as Positron Emission Tomography Ligands for the Peripheral Benzodiazepine Receptor:  Radiosynthesis, Uptake, and in Vivo Binding in Brain

Ming-Rong Zhang,*†‡ Masanao Ogawa,†‡ Jun Maeda,§ Takehito Ito,†‡ Junko Noguchi,‡§ Katsushi Kumata,† Takashi Okauchi,§ Tetsuya Suhara,§ and Kazutoshi Suzuki†
Department of Medical Imaging, National Institute of Radiological Sciences, 491 Anagawa, Inage-ku, Chiba 263-8555, Japan, Brain Imaging Project, National Institute of Radiological Sciences, 491 Anagawa, Inage-ku, Chiba 263-8555, Japan, SHI Accelerator Service Co. Ltd., 5911 Kitashinagawa, Shinagawa-ku, Tokyo 141-8686, Japan, and WDB Co. Ltd., 262 Ohte, Chiyoda-ku, Tokyo 100-0004, Japan
J. Med. Chem., 2006, 49 (9), pp 2735–2742
DOI: 10.1021/jm060006k
Publication Date (Web): April 12, 2006
Copyright © 2006 American Chemical Society
*

 Corresponding author. Tel:  81-43-206-4041. Fax:  81-43-206-3261. E-mail:  zhang@nirs.go.jp.

,
†

 Department of Medical Imaging, National Institute of Radiological Sciences.

,
‡

 SHI Accelerator Service Co. Ltd.

,
§

 Brain Imaging Project, National Institute of Radiological Sciences.

,

 WDB Co. Ltd.

Abstract

Abstract Image

The peripheral benzodiazepine receptor (PBR) is widely expressed in peripheral tissues, blood cells, and in glia cells in the brain. We have previously developed two positron emission tomography (PET) ligands, N-(2-[11C],5-dimethoxybenzyl)-N-(5-fluoro-2-phenoxyphenyl)acetamide ([11C]2) and its [18F]fluoroethyl analogue ([18F]6), for the current investigation of PBR in the human brain. The aim of this study was to label the potent PBR agonist N-(4-chloro-2-phenoxyphenyl)-N-(isopropoxybenzyl)acetamide (3) and its ethyl (7) and methyl (8) homologues with 11C and to evaluate them as PET ligands for PBR with mice, rats, and monkeys. Ligands [11C]3, [11C]7, and [11C]8 were synthesized by alkylation of phenol precursor 9 with 2-[2-11C]iodopropane ([11C]10), [1-11C]iodoethane ([11C]11), and [11C]iodomethane ([11C]12), respectively. The alkylating agent [11C]10 or [11C]11 was prepared by reacting CH3MgBr with [11C]CO2, followed by reduction with LiAlH4 and iodination with HI. In vitro quantitative autoradiography determined that 3, 7, and 8 had potent binding affinities (Ki = 0.07−0.19 nM) for PBR in the rat brain. These [11C]ligands could pass across the blood−brain barrier and enter the rat brain (0.17−0.32% of injected dose per gram wet tissue). Ex vivo autoradiography showed that the [11C]ligands preferably distributed in the olfactory bulb and cerebellum, two regions with richer PBR density in the rat brain. The co-injection of PBR-selective 2 reduced the [11C]ligand binding in the two regions, suggesting that binding in the rat brain was specific to PBR. PET study determined that the [11C]ligands preferably accumulate in the occipital cortex of the monkey brain, a region with a high density of PBR in the primate brain. Moreover, in vivo binding of the methyl homologue [11C]8 in the monkey brain could be inhibited by PBR-selective 2 or 1, indicating that some of the [11C]8 binding was due to PBR. Metabolite analysis demonstrated that these [11C]ligands were metabolized by debenzylation to polar products mainly in the plasma.

View: Full Text HTML | Hi-Res PDF

Tools

History

  • Published In Issue May 04, 2006
  • Received January 4, 2006

Recommend & Share

Related Content

Other ACS content by these authors: