Karra S R, Schibli R, Gali H, Katti K V, Hoffman T J, Higginbotham C, Sieckman G L, Volkert W A
Department of Radiology, University of Missouri-Columbia, Columbia, Missouri 65211, USA.
Bioconjug Chem. 1999 Mar-Apr;10(2):254-60. doi: 10.1021/bc980096a.
Recent progress in the synthesis of water-soluble phosphine ligand systems and their corresponding 99mTc complexes prompted the development of a new bifunctional chelating agent (BFCA) based on a tetradentate dithiadiphosphine framework (P2S2-COOH). The detailed synthesis of this new BFCA is described here. The corresponding 99mTc complex, 99mTc-P2S2-COOH, can be formed in >95% yield. To demonstrate the potential of this chelate to efficiently label peptides, 99mTc-P2S2-COOH was coupled to the N-terminal region of the truncated nine-amino acid bombesin analogue, 5-Ava-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2 [BBN(7-14)], to form 99mTc-P2S2-BBN(7-14). Conjugation to the peptide was performed in borate buffer (pH 8.5) by applying the prelabeling approach in yields of >60%. In competitive binding assays, using Swiss 3T3 mouse fibroblast cells against [125I-Tyr4]bombesin, Re-P2S2-BBN(7-14) exhibited an IC50 value of 0.8 +/- 0.4 nM. The pharmacokinetic studies of 99mTc-P2S2-BBN(7-14) and its ability to target tissue expressing gastrin-releasing peptide (GRP) receptors were performed in normal mice. The 99mTc-P2S2-BBN(7-14) exhibited fast and efficient clearance from the blood pool (0.6 +/- 0.1% ID, 4 h postinjection) and excretion through the renal and hepatobiliary pathways (56.4 +/- 8.2 and 28.1 +/- 7.9% ID, 4 h postinjection, respectively). Significant uptake in the pancreas was observed (pancreatic acini cells express bombesin/GRP receptors), producing pancreas:blood and pancreas:muscle ratios of ca. 22 and 80, respectively, at 4 h postinjection.
水溶性膦配体系统及其相应的99mTc配合物合成方面的最新进展促使人们基于四齿二硫代二膦框架（P2S2-COOH）开发一种新型双功能螯合剂（BFCA）。本文描述了这种新型BFCA的详细合成过程。相应的99mTc配合物99mTc-P2S2-COOH的产率可超过95%。为了证明这种螯合物有效标记肽的潜力，将99mTc-P2S2-COOH与截短的九氨基酸蛙皮素类似物5-Ava-Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2 [BBN(7-14)]的N端区域偶联，形成99mTc-P2S2-BBN(7-14)。通过预标记方法在硼酸盐缓冲液（pH 8.5）中进行与肽的偶联，产率超过60%。在竞争性结合试验中，使用瑞士3T3小鼠成纤维细胞对抗[125I-Tyr4]蛙皮素，Re-P2S2-BBN(7-14)的IC50值为0.8±0.4 nM。在正常小鼠中进行了99mTc-P2S2-BBN(7-14)的药代动力学研究及其靶向表达胃泌素释放肽（GRP）受体组织的能力研究。99mTc-P2S2-BBN(7-14)从血池中的清除快速且高效（注射后4小时为0.6±0.1% ID），并通过肾和肝胆途径排泄（注射后4小时分别为56.4±8.2和28.1±7.9% ID）。观察到胰腺有明显摄取（胰腺腺泡细胞表达蛙皮素/GRP受体），注射后4小时胰腺与血液和胰腺与肌肉的比值分别约为22和80。
