Synthesis, Characterization, and In Vitro Evaluation of New 99mTc/Re(V)-Cyclized Octreotide Analogues: An Experimental and Computational Approach

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• 作者：Yawen Li ; Lixin Ma ; Vikram Gaddam ; Fabio Gallazzi ; Heather M. Hennkens ; Michael Harmata ; Michael R. Lewis ; Carol A. Deakyne ; Silvia S. Jurisson
• 刊名：Inorganic Chemistry
• 出版年：2016
• 出版时间：February 1, 2016
• 年：2016
• 卷：55
• 期：3
• 页码：1124-1133
• 全文大小：462K
• ISSN：1520-510X

文摘

Radiolabeled proteolytic degradation-resistant somatostatin analogues have been of long-standing interest as cancer imaging and radiotherapy agents for targeting somatostatin receptor-positive tumors. Our interest in developing ¹⁸⁶Re- and ¹⁸⁸Re-based therapeutic radiopharmaceuticals led to investigation of a new Re(V)-cyclized octreotide analogue, Re(V)-cyclized, thiolated-DPhe¹-Cys²-Tyr³-DTrp⁴-Lys⁵-Thr⁶-Cys⁷-Thr(OH)⁸ (Re-SDPhe-TATE) using both experimental and quantum chemical methods. The metal is directly coordinated to SDPhe-TATE through cyclization of the peptide around the [ReO]³⁺ core. Upon complexation, four isomers were observed; the isolated/semi-isolated isomers exhibited different somatostatin receptor (sstr) binding affinities, 0.13 to 1.5 μM, in rat pancreatic tumor cells. Two-dimensional NMR experiments and electronic structure calculations were employed to elucidate the structural differences among the different isomers. According to NMR studies, the metal is coordinated to three thiolates and the backbone amide of Cys² in isomers 1 and 4, whereas the metal is coordinated to three thiolates and the backbone amide of Tyr³ in isomer 2. Quantum chemical methods clarified the stereochemistry of Re-SDPhe-TATE and the possible peptide arrangements around the [ReO]³⁺ core. The re-cyclization reaction was translated to the ^99mTc radiotracer level with four isomers observed on complexation with comparable HPLC retention times as the Re-SDPhe-TATE isomers. About 85% total ^99mTc labeling yield was achieved by ligand exchange from ^99mTc-glucoheptonate at 60 °C for an hour. About 100% and 51% of ^99mTc(V)-cyclized SDPhe-TATE remained intact in phosphate buffered saline and 1 mM cysteine solution under physiological conditions at 6 h, respectively.