Iodine-125 labeled 1-(2,5-dimethoxy-4-iodophenyl)-2-aminopropane: an iodinated radioligand that specifically labels the agonist high-affinity state of 5-HT2 serotonin receptors

Journal of Medicinal Chemistry
1988.0

Abstract

Type A and type B hydroxamates show distinct in vivo differences. Type B compounds are resistant to metabolism to inactive carboxylic acids (unlike type A), resulting in longer plasma circulation. For example, 4b (Abbott-63162) has a 2.5-fold longer plasma half-life than 4a (1.1 vs 0.4 h, iv 20 mg/kg) and higher oral plasma concentrations (140 pM vs 15 pM). Type B's major metabolism is glucuronide conjugation. Type B has greater in vivo potency: 4b is 5-fold more potent than 4a in inhibiting leukotriene biosynthesis in rat peritoneal anaphylaxis (ED50 8 mg/kg oral). Type B hydroxamates are prepared via Scheme I and are valuable tools for evaluating leukotriene roles in animal models and human disease. Serotonin (5-HT) research requires site-selective ligands. [3H]DOB labels 5-HT2 receptor high-affinity state but needs large tissue and can't be used for autoradiography. Radioiodinated [125I]DOI was synthesized via triazene method. Binding data show [125I]DOI has high affinity (Kd ~2.2 nM) and 5-HT2 pharmacology (competition with 5-HT2 antagonists/agonists). It labels the agonist high-affinity state of 5-HT2 receptors, with high specific activity (1625 Ci/mmol), making it useful for binding and autoradiographic studies. Two 2-aryl-1,3,4-thiadiazole amidines (3, 4) were synthesized for anticonvulsant activity, aiming to enhance activity and separate sedation. Most potent were 2-(trifluoromethyl)phenyl type 3 amidines, but they had high neurotoxicity/sedation (rotorod test). Previous 2-aryl-5-hydrazino/guanidino-thiadiazoles (1, 2) had hydrazine group issues (like hydralazine side effects), so amidines were explored as alternatives.

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