Synthesis of a beta-tetrapeptide analog as a mother compound for the development of matrix metalloproteinase-2-imaging agents.
Matrix metalloproteinase-2 (MMP-2) is an attractive target for the diagnosis of cancer and atherosclerosis in nuclear imaging. A cyclic decapeptide, cCTTHWGFTLC (cCTT), has been used as the mother compound for the development of MMP-2-imaging agents with high potency and selectivity. Most of radiolabeled derivatives of cCTT currently developed for in vivo studies of MMP-2, however, suffer from low accumulation in the target tissues, such as tumors. For enhanced in vivo stability and tissue penetration, we designed a linear beta-tetrapeptide analog, H-beta 3-Phe-beta-Ala-beta 3-Trp-beta 3-His-OH (1), to mimic cCTT. The component beta-amino acids were prepared by reduction of N-protected alpha-amino acid methyl esters to the alcohols, followed by conversion into the cyanides, and subsequent hydrolysis. Compound 1 was obtained from these beta-amino acids by the conventional solution method. In MMP-2 inhibition assay, compound 1 displayed desirably significant inhibition, which was comparable to cCTT. These findings suggest that compound 1 may serve as a mother compound in the design and development of in vivo MMP-2-imaging agents.
Mukai
Takahiro
T
Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka 812-8582, Japan. mukai@phar.kyushu-u.ac.jp <mukai@phar.kyushu-u.ac.jp>
Suganuma
Noriko
N
Soejima
Kenta
K
Sasaki
Junichi
J
Yamamoto
Fumihiko
F
Maeda
Minoru
M
D015195:Drug Design; D005780:Gelatin / Q000737:chemistry; D007202:Indicators and Reagents; D009682:Magnetic Resonance Spectroscopy; D020778:Matrix Metalloproteinase 2 / Q000737:chemistry*; D061965:Matrix Metalloproteinase Inhibitors; D010455:Peptides / Q000138:chemical synthesis* / Q000737:chemistry; D010456:Peptides, Cyclic / Q000138:chemical synthesis* / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D019275:Radiopharmaceuticals / Q000138:chemical synthesis*; D013056:Spectrophotometry, Ultraviolet
C415426:CTTHWGFTLC peptide; D007202:Indicators and Reagents; D061965:Matrix Metalloproteinase Inhibitors; D010455:Peptides; D010456:Peptides, Cyclic; D011480:Protease Inhibitors; D019275:Radiopharmaceuticals; D005780:Gelatin; D020778:Matrix Metalloproteinase 2