Bioorganic & medicinal chemistry

Rationally designed PKA inhibitors for positron emission tomography: Synthesis and cerebral biodistribution of N-(2-(4-bromocinnamylamino)ethyl)-N-[11C]methyl-isoquinoline-5-sulfonamide.

PMID 18346896


Protein kinase A (PKA) is an important signal transduction target for drug development because it influences critical cellular processes implicated in neuropsychiatric illnesses such as major depressive disorder. The goal of the present study was to develop the first imaging agent for measuring the levels of PKA with positron emission tomography (PET). By rational derivatization of 5-isoquinoline sulfonamides, it was found that the introduction of a methyl group to the sulphonamidic nitrogen on the known PKA inhibitors N-(2-aminoethyl)isoquinoline-5-sulfonamide (H-9, 1) and N-(2-(4-bromocinnamylamino)ethyl)isoquinoline-5-sulfonamide (H-89, 2), (yielding N-(2-aminoethyl)-N-methyl-isoquinoline-5-sulfonamide (4) and N-(2-(4-bromocinnamylamino)ethyl)-N-methyl-isoquinoline-5-sulfonamide (5), respectively) does not appreciably reduce in vitro potency toward PKA. We have facilitated the synthesis of 4 by reacting isoquinoline-5-sulfonyl chloride with N-methylethylenediamine (20% yield). Several techniques were used to thoroughly characterize 4 including multi ((1)H, (13)C and (15)N) NMR spectroscopy and X-ray crystallography. Compound 4 and 1-(4-bromophenyl)-1-propen-3-yl bromide were reacted to produce 5 in 16% yield. Compound 2 was reacted with [(11)C]CH(3)I to prepare N-(2-(4-bromocinnamylamino) ethyl)-N-[(11)C]methyl-isoquinoline-5-sulfonamide ([(11)C]5), with a decay-corrected radiochemical yield of 32%, based on [(11)C]CO(2). [(11)C]5 was produced with >98% radiochemical purity and 1130mCi/mumol specific activity after 40min (end of synthesis). Conscious rats were administered [(11)C] 5 and sacrificed at 5, 15, 30 and 60min after injection. Radioactivity from all excised brain regions was <0.2%ID/g at all time points. The modest brain penetration of [(11)C]5 may limit its use for studying PKA in the central nervous system.

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N-Methylethylenediamine, 95%