MO Tripeptide Diastereomers (M = 99/99mTc, Re): Models To Identify the Structure of 99mTc Peptide Targeted Radiopharmaceuticals

详细信息    查看全文

• 作者：Melchor V. Cantorias ; Robertha C. Howell ; Louis Todaro ; John E. Cyr ; Dietmar Berndorff ; Robin D. Rogers ; Lynn C. Francesconi
• 刊名：Inorganic Chemistry
• 出版年：2007
• 出版时间：September 3, 2007
• 年：2007
• 卷：46
• 期：18
• 页码：7326 - 7340
• 全文大小：305K
• 年卷期：v.46,no.18(September 3, 2007)
• ISSN：1520-510X

文摘

Biologically active molecules, such as many peptides, serve as targeting vectors for radiopharmaceuticals basedon ^99mTc. Tripeptides can be suitable chelates and are easily and conveniently synthesized and linked to peptidetargeting vectors through solid-phase peptide synthesis and form stable Tc^VO complexes. Upon complexation with[TcO]³⁺, two products form; these are syn and anti diastereomers, and they often have different biological behavior.This is the case with the approved radiopharmaceutical [^99mTcO]depreotide ([^99mTcO]P829, NeoTect) that is usedto image lung cancer. [^99mTcO]depreotide indeed exhibits two product peaks in its HPLC profile, but assignment ofthe product peaks to the diastereomers has proven to be difficult because the metal peptide complex is difficult tocrystallize for structural analysis. In this study, we isolated diastereomers of [⁹⁹TcO] and [ReO] complexes of severaltripeptide ligands that model the metal chelator region of [^99mTcO]depreotide. Using X-ray crystallography, we observedthat the early eluting peak (A) corresponds to the anti diastereomer, where the Tc=O group is on the oppositeside of the plane formed by the ligand backbone relative to the pendant groups of the tripeptide ligand, and thelater eluting peak (B) corresponds to the syn diastereomer, where the Tc=O group is on the same side of theplane as the residues of the tripeptide. ¹H NMR and circular dichroism (CD) spectroscopy report on the metalenvironment and prove to be diagnostic for syn or anti diastereomers, and we identified characteristic featuresfrom these techniques that can be used to assign the diastereomer profile in ^99mTc peptide radiopharmaceuticalslike [^99mTcO]depreotide and in ¹⁸⁸Re peptide radiotherapeutic agents. Crystallography, potentiometric titration, andNMR results presented insights into the chemistry occurring under physiological conditions. The tripeptide complexeswhere lysine is the second amino acid crystallized in a deprotonated metallo-amide form, possessing a short N₁-Mbond. The pK_a measurements of the N₁ amine (pKa ~5.6) suggested that this amine is rendered more acidic byboth metal complexation and the presence of the lysine residue. Furthermore, peptide chelators incorporating alysine (like the chelator of [TcO]depreotide) likely exist in the deprotonated form in vivo, comprising a neutral metalcenter. Deprotonation possibly mediates the interconversion process between the syn and anti diastereomers. TheN₁ amine group on non-lysine-containing metallopeptides is not as acidic (pK_a ~6.8) and does not deprotonateand crystallize as do the metallo-amide species. Three of the tripeptide ligands (FGC, FSC, and FKC) wereradiolabeled with ^99mTc, and the individual syn and anti isomers were isolated for biodistribution studies in normalfemale nude mice. The main organs of uptake were the liver, intestines, and kidneys, with the FGC compoundsexhibiting the highest liver uptake. In comparing the diastereomers, the syn compounds had substantially higherorgan uptake and slower blood clearance than the anti compounds.