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N-[[4'-[(2-Ethyl-5,7-dimethyl-3 H-imidazo[4,5-b]pyridine-3-yl)methyl][1,1'-biphenyl]-2-yl]sul-fonyl]-4-[ 11 C]methoxybenzamide

Kam Leung

PMID: 20641845

Abstract:

Angiotensin II (Ang II), an octapeptide, plays an important role in the regulation of cardiovascular, renal, and endocrine functions (1, 2). Ang II induces a variety of physiologic changes, such as constriction of vascular smooth muscle cells, modulation of glomerular filtration rate, and sodium retention, resulting in an increase in blood pressure. Two subtypes of Ang II receptors, AT1 and AT2, have been well characterized pharmacologically and biochemically (3, 4). AT1 is indicated in all known pressor effects of Ang II, whereas no direct Ang II biological functions have been found for AT2. The AT1 receptor subtype is found mainly in all vascular tissues and the pituitary gland and is the only subtype in the liver. The AT2 receptor subtype is found mainly in the rat adrenal medulla, human uterus, rat ovarian granulosa cells, and rat striatum (4-6). In other tissues, such as the adrenal cortex, kidneys, heart, and brain, there is a mixture of both subtypes.
The AT1 nonpeptide antagonist losartan (MK-954 or DuP753) has been shown to be an effective antihypertensive agent (7). MK-996 (L-159,282), a losartan analog, was found to be a potent and selective AT1 antagonist with high affinity (inhibitory concentration (IC50) = 0.15 nM for AT1 and >300 nM for AT2) (8). L-159,884, the methoxyl analog of MK-996 (IC50 = 0.08 nM) (9), has been synthesized as [11C]L-159,884 (N-[[4´[(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridin-3-yl)methyl][1,1´-biphenyl]-2-yl]sulfonyl]-4-[11C]methoxybenzamide) for in vivo investigation of AT1 expression by positron emission tomography (PET) in the kidneys, adrenal glands, and heart.

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