Synthesis and Radiolabeling of (S)-4-Amino-5-iodo-2-methoxy-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide, the Active Enantiomer of [^<125>I]Iodozacopride, and Re-evaluation of Its 5-HT_3 Receptor Affinity

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概要

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• We report an improved synthesis of unlabeled (S)-iodozacopride, the radiolabeling of (S)-[^<125>I]iodozacopride via deschloro-(S)-zacopride, and a re-evaluation of its affinity for the 5-HT_3 receptor. Unlabeled (S)-iodozacopride was prepared in seven steps from 4-aminosalicylic acid via alkaline hydrolysis of its 4-acetamide derivative. Catalytic hydrogenation of (S)-iodozacopride gave deschloro-(S)-zacopride, identical to the obtained from (S)-3-amino-quinuclidine and 4-amino-2-methoxybenzoic acid via its corresponding 1-imidazole derivative. Radioiodination to produce (S)-[^<125>I]idozacopride was accomplished by treatment of deschloro-(S)-zacopride with 5 mCi sodium ^<125>iodide and chloramine-T in hydrochloric acid. Purification of the reaction products using an HPLC system capable of detecting chlorinated side-products revealed a mixture of 2.1 mCi (1.3 nmol) (S)-[^<125>I]idozacopride and (S)-zacopride (1.5 nmol). Saturation analysis of the binding of the purified (S)-[^<125>I]iodozacopride to whole rat brain homogenates gave an estimated K_D of 1.10±0.07 nM. As anticipated, this is approximately half the K_D reported for binding of racemic [^<125>I]iodozacopride, and differs from the previosuly reported values by an order of magnitude. Analysis of the apparent binding affinity of a 1 : 1 mixture of (S)-[^<125>I]iodozacopride and (S)-zacopride suggests that the previous result may have been confounded by contamination of the product with unlabeled (S)-zacopride. Competition analysis of the displacement of the displacement of (S)-[^<125>I]iodozacopride binding by unlabeled (S)-iodozacopride and (S)-zacopride gave K_i values of 0.95 and 0.21 nM, respectively.

• 公益社団法人日本薬学会の論文
• 1997-12-15

著者

• Ebert Michael

  Departments Of Psychiatry Vanderbilt University School Of Medicine

• Zhang Zhang-jin

  Departments Of Psychiatry Vanderbilt University School Of Medicine

• Trivedi Bakula

  Departments Of Psychiatry Vanderbilt University School Of Medicine

• HEWLETT William

  Departments of Psychiatry Vanderbilt University School of Medicine

• PAULIS Tomas

  Departments of Psychiatry Vanderbilt University School of Medicine, Radiology, Vanderbilt University

• MASON N.

  Radiology, Vanderbilt University School of Medicine

• SCHMIDT Dennis

  Departments of Psychiatry Vanderbilt University School of Medicine

• Paulis Tomas

  Departments Of Psychiatry Vanderbilt University School Of Medicine Radiology Vanderbilt University S

• De Paulis

  Departments Of Psychiatry Vanderbilt University School Of Medicine

• Zhang Zhang-jin

  Department Of Psychiatry Uniformed Services University Of The Health Sciences

• Mason N.

  Radiology Vanderbilt University School Of Medicine

• Mason N.Scott

  Radiology, Vanderbilt University School of Medicine

関連論文

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• Synthesis and Radiolabeling of (S)-4-Amino-5-iodo-2-methoxy-N-(1-azabicyclo[2.2.2]oct-3-yl)benzamide, the Active Enantiomer of [^I]Iodozacopride, and Re-evaluation of Its 5-HT_3 Receptor Affinity

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