固相胜肽合成DOTA-Tyr3-Octreotide

Direct Synthesis of DOTA-Tyr3-Octreotide Using Solid Phase Peptide Synthesis

陳淑玲(Shu-Ling Chen)

指導教授 ： 楊嘉喜

中原大學/理學院/化學研究所/碩士(2004年)

https://doi.org/10.6840/cycu200500129

摘要

雙官能基螯合物DOTA( 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid )能與金屬化合物形成錯合物，再以共價鍵方式接上胜肽化合物、蛋白質或是抗體，則可以鎖定病灶用來做照影或診斷。在醫學上有許多應用，由於DOTA可與二價及三價的金屬鍵結，種種因素證明DOTA雙官能基螯合物的價值性，本實驗利用固相胜肽合成方法(solid-phase peptide synthesis)，及配合新穎的雙硫鍵環化方法合成DOTA-Tyr3-Octreotide。改進傳統空氣氧化法及碘氧化法無法避免分子間雙硫鍵形成的盲點。產物環型DOTA-Tyr3-Octreotide以質普儀（High Performance Mass Spectrometer ）及核磁共振儀( Fourier-Transfer Nuclear Magentic Resonance Spectrometer FT-NMR ）佐證。在接受體結合實驗中，DOTA-Tyr3-Octreotide可以有效的取代125I-Tyr1-Somatostatin(Ki= 3.95 0.75nM)，證明DOTA-Tyr3-Octreotide保有結合受體的活性，以種有AR42J腫瘤的Lewis鼠，打入67Ga-DOTA-Tyr3-Octreotide後以MicroSPECT造影時，可以發現腫瘤有明顯的吸收，這些實驗證明了DOTA-Tyr3-Octreotide保有體內及體外的生物活性。

關鍵字

雙硫鍵 ； 雙官能基螯合物

並列摘要

A bifunctional chelating agent, DOTA (1,4,7,10- tetraazacyclododecane-1,4,7,10-tetraacetic acid), chelates with metal to forming a complex. When peptides、protein or antibodies were linked by a covalent bonds with DOTA complex, those could use as image or diagnostic agents. Due to chelating with 2+ and 3+ of metals, the value of these DOTA bifunctional chelating agents has been proved in medical applications. In this experiment, we synthesized DOTA-Tyr3-Octreotide by a solid-phase peptide synthesis and a novel disulfide bond methods. The method improved the traditional air oxidation and iodine oxidation method that couldn’t avoid the drawback of intermolecular disulfide bond. The cyclic DOTA-Tyr3-Octreotide demonstrated in MS and NMR. The DOTA-Tyr3-Octreotide efficiently inhibited the binding of 125I-Tyr1-Somatostatin (Ki= 3.95 0.75nM) in Somatostatin receptor binding assay, which confirmed the retention of receptor-binding affinity. MicroSPECT imaging also showed the tumor significantly utilized the 67Ga-DOTA-Tyr3-Octreotide in AR42J tumor-bearing rats. Those studies demonstrated that DOTA-Tyr3-Octreotide keep bioactivities in vitro and in vivo.

並列關鍵字

bifunctional chelating ； disulfide bond

參考文獻

8.張湘戎，中原大學化學研究所碩士學位論文，中華民國九十二年六月

1.Gluschankof, P.; Morel, A.; Benoit, R.; and Cohen, P., Biochem. Biophys. Res. Commun., 1985, 128, 1051-1057.

2.Pless, P., Metabolism., 1992, 41, 5-6.

11.Fields, G. B.; Noble, R. B., Int. J. Peptide Protein Res. 1990, 35, 161-214.

伍、參考文獻