Rationally designed PKA inhibitors for positron emission tomography: Synthesis and cerebral biodistribution of N-(2-(4-bromocinnamylamino)ethyl)-N-[11C]methyl-isoquinoline-5-sulfonamide.
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.
Vasdev
Neil
N
Centre for Addiction and Mental Health, 250 College Street, Toronto, Ont., Canada M5T 1R8. neil.vasdev@camhpet.ca
LaRonde
Frank J
FJ
Woodgett
James R
JR
Garcia
Armando
A
Rubie
Elizabeth A
EA
Meyer
Jeffrey H
JH
Houle
Sylvain
S
Wilson
Alan A
AA
D000818:Animals; D001921:Brain / Q000000981:diagnostic imaging* / Q000378:metabolism; D018360:Crystallography, X-Ray; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors*; D004305:Dose-Response Relationship, Drug; D015195:Drug Design; D007546:Isoquinolines / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D008297:Male; D008958:Models, Molecular; D015394:Molecular Structure; D049268:Positron-Emission Tomography / Q000379:methods*; D047428:Protein Kinase Inhibitors / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D013329:Structure-Activity Relationship; D013449:Sulfonamides / Q000138:chemical synthesis* / Q000737:chemistry / Q000494:pharmacology*; D013997:Time Factors; D014018:Tissue Distribution
D007546:Isoquinolines; C530901:N-(2-(4-bromocinnamylamino)ethyl)-N-(11C)methyl-isoquinoline-5-sulfonamide; D047428:Protein Kinase Inhibitors; D013449:Sulfonamides; D017868:Cyclic AMP-Dependent Protein Kinases