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Radiolabeling and efficient synthesis of tritiated 2‐chloro‐ N 6 ‐(3‐iodobenzyl)adenosine‐5′‐ N ‐methyluron‐amide, a potent, selective A 3 adenosine receptor agonist
Author(s) -
Kim H.O.,
Hawes C.,
Towers P.,
Jacobson K.A.
Publication year - 1996
Publication title -
journal of labelled compounds and radiopharmaceuticals
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.432
H-Index - 47
eISSN - 1099-1344
pISSN - 0362-4803
DOI - 10.1002/(sici)1099-1344(199606)38:6<547::aid-jlcr870>3.0.co;2-y
Subject(s) - chemistry , adenosine receptor , methylamine , agonist , adenosine , receptor , nucleoside , tritium , stereochemistry , selectivity , amide , biochemistry , physics , nuclear physics , catalysis
We recently reported that 2‐substitution of N 6 ‐benzyladenosine‐5′‐uronamides greatly enhances selectivity of agonists for rat A 3 adenosine receptors ( J. Med. Chem. 1994, 37, 3614–3621). Specifically, 2‐Chloro‐ N 6 ‐(3‐iodobenzyl)adenosine‐5′‐ N ‐methyluronamide (2‐CI‐IB‐MECA), which displayed a K i value of 0.33 nM, is the most selective for A 3 receptors yet reported with selectivity versus A 1 and A 2a receptors of 2500‐ and 1400‐fold, respectively. In order to obtain pharmacological tools for the study of A 3 adenosine receptors, two routes for radiolabeling of 2‐CI‐IB‐MECA through incorporation of tritium at the 5′‐methylamido group were compared. One route formed a 2′,3′‐protected nucleoside 5′‐carboxylic acid ( 9 ), which was condensed with methylamine and deprotected. The more efficient synthesis started from D‐ribose and provided 2‐CI‐IB‐MECA ( 12 ) in six steps with an overall yield of 5.6%. Tritium was introduced in the penultimate step by heating N 6 ‐(3‐iodobenzyl)‐2‐chloro‐2′,3′‐di‐ O ‐acetyl‐5′‐(methoxycarbonyl)adenosine ( 17 ) with [ 3 H]methylamine in methanol at 60°C for 2 h. The specific activity of [ 3 H]2‐CI‐IB‐MECA was 29 Ci/mmol with a radiochemical purity of 99%.