Technetium(V) Oxo Complexes of Substituted Propylene Diamine Dioxime (PnAO) Ligands:  Water-Dependent Interconversion between Syn and Anti Isomers

Cyr, John E.; Nowotnik, David P.; Pan, Yolanda; Gougoutas, Jack Z.; Malley, Mary F.; Marco, J. D. Di; Nunn, and Adrian D.; Linder, Karen E.

doi:10.1021/ic991381o

Cited by 14 publications

(8 citation statements)

References 31 publications

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“…9,24 RP 294, (Me) 2 -Gly-Ser-Cys(Acm)-Gly-NH 2 , a hydrophilic, unencumbered peptide ligand that binds technetium and rhenium, forms diastereomers that rapidly interconvert and cannot be individually isolated ( Figure 3). 1 H NMR and 13 C NMR confirmed that the 99 Tc and Re products of RP 294 are diastereomers, and indeed, a crystal structure showing the syn diastereomer was solved. However, the crystal was isolated from a mixture of syn and anti diastereomers (as shown by NMR and HPLC), and rapid interconversion precluded clean isolation and correlation with the HPLC profile.…”

Section: Introductionmentioning

confidence: 76%

MO Tripeptide Diastereomers (M =^99/99^mTc, Re): Models To Identify the Structure of⁹⁹^mTc Peptide Targeted Radiopharmaceuticals

et al. 2007

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Biologically active molecules, such as many peptides, serve as targeting vectors for radiopharmaceuticals based on 99mTc. Tripeptides can be suitable chelates and are easily and conveniently synthesized and linked to peptide targeting vectors through solid-phase peptide synthesis and form stable TcVO 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 used to image lung cancer. [99mTcO]depreotide indeed exhibits two product peaks in its HPLC profile, but assignment of the product peaks to the diastereomers has proven to be difficult because the metal peptide complex is difficult to crystallize for structural analysis. In this study, we isolated diastereomers of [99TcO] and [ReO] complexes of several tripeptide ligands that model the metal chelator region of [99mTcO]depreotide. Using X-ray crystallography, we observed that the early eluting peak (A) corresponds to the anti diastereomer, where the Tc=O group is on the opposite side of the plane formed by the ligand backbone relative to the pendant groups of the tripeptide ligand, and the later eluting peak (B) corresponds to the syn diastereomer, where the Tc=O group is on the same side of the plane as the residues of the tripeptide. 1H NMR and circular dichroism (CD) spectroscopy report on the metal environment and prove to be diagnostic for syn or anti diastereomers, and we identified characteristic features from these techniques that can be used to assign the diastereomer profile in 99mTc peptide radiopharmaceuticals like [99mTcO]depreotide and in 188Re peptide radiotherapeutic agents. Crystallography, potentiometric titration, and NMR results presented insights into the chemistry occurring under physiological conditions. The tripeptide complexes where lysine is the second amino acid crystallized in a deprotonated metallo-amide form, possessing a short N1-M bond. The pKa measurements of the N1 amine (pKa approximately 5.6) suggested that this amine is rendered more acidic by both metal complexation and the presence of the lysine residue. Furthermore, peptide chelators incorporating a lysine (like the chelator of [TcO]depreotide) likely exist in the deprotonated form in vivo, comprising a neutral metal center. Deprotonation possibly mediates the interconversion process between the syn and anti diastereomers. The N1 amine group on non-lysine-containing metallopeptides is not as acidic (pKa approximately 6.8) and does not deprotonate and crystallize as do the metallo-amide species. Three of the tripeptide ligands (FGC, FSC, and FKC) were radiolabeled with 99mTc, and the individual syn and anti isomers were isolated for biodistribution studies in normal female nude mice. The main organs of uptake were the liver, intestines, and kidneys, with the FGC compounds exhibiting the highest liver uptake. In comparing the diastereomers, the syn compounds had substantially hi...

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Section: Introductionmentioning

confidence: 76%

MO Tripeptide Diastereomers (M =^99/99^mTc, Re): Models To Identify the Structure of⁹⁹^mTc Peptide Targeted Radiopharmaceuticals

et al. 2007

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“…For such ligands, the technetium complex can form with the substituents either syn or anti to the Tc=O group. 21 Three chiral centers are incorporated into the coordination plane of [ 99m TcO]depreotide, therefore, two distinct diastereomers are predicted, and these are shown in Figure 1. For discussion here, the two diastereomers will be referred to as syn or anti with regard to the position of the Lys 2 (the lysine which chelates to the technetium) side chain relative to the Tc=O bond.…”

Section: Introductionmentioning

confidence: 99%

“…Diasteromers of technetium (V) are known to form when ligands contain chiral centers on the portion of the chelate which constitutes the coordination plane. For such ligands, the technetium complex can form with the substituents either syn or anti to the TcO group . Three chiral centers are incorporated into the coordination plane of [ 99m TcO]depreotide, therefore, two distinct diastereomers are predicted, and these are shown in Figure .…”

Section: Introductionmentioning

confidence: 99%

Isolation, Characterization, and Biological Evaluation ofSynandAntiDiastereomers of [^99mTc]Technetium Depreotide: a Somatostatin Receptor Binding Tumor Imaging Agent

et al. 2007

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The early and later eluting [ 99m TcO]depreotide products on RP-HPLC were confirmed to be the anti and syn diastereomers, respectively, based on proton NMR and circular dichroism spectroscopy. NMR provided evidence of a folded, conformationally constrained structure for the syn diastereomer. The syn diastereomer is predominant (anti/syn ~ 10:90) in the [ 99m TcO]depreotide preparation and shows a slightly higher affinity (IC 50 = 0.15 nM) for the somatostatin receptor than the anti diastereomer (IC 50 = 0.89 nM). Both diastereomers showed higher binding affinities than the free peptide (IC 50 = 7.4 nM). Biodistribution studies in AR42J tumor xenograft nude mice also showed higher tumor uptake for syn [ 99m TcO]depreotide (6.58% ID/g) than for the anti [ 99m TcO]depreotide (3.38% ID/g). Despite the differences in biological efficacy, the favorable binding affinity, tumor uptake, and tumor-to-background ratio results for both diastereomeric species predict that both are effective for imaging somatostatin receptor-positive tumors in vivo.

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“…138 Interconversion of the syn and anti isomers of alkylated analogues of these complexes suggests that they undergo inversion via a dioxo or oxo-hydroxo intermediate. 139 The butylene amine oxime derivative is a putative hypoxia imaging agent (known as Tc-(bnao) or HL-91) but although hypoxia selectivity was confirmed in vitro in cultured mammalian cells, 140 workers were unable to find a correlation between tumour uptake in vivo and oxygen concentration in the tumour measured with an oxygen electrode. 141 With increasing emphasis on pharmacologically active peptides as carriers of radionuclides, it is important to achieve maximum specific activity to ensure that physiological effects of the peptides are minimised.…”

Section: Technetiummentioning

confidence: 99%

30 Inorganic pharmaceuticals

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2002

Annu. Rep. Prog. Chem., Sect. A: Inorg. Chem.

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Technetium(V) Oxo Complexes of Substituted Propylene Diamine Dioxime (PnAO) Ligands: Water-Dependent Interconversion between Syn and Anti Isomers

Cited by 14 publications

References 31 publications

MO Tripeptide Diastereomers (M =^99/99^mTc, Re): Models To Identify the Structure of⁹⁹^mTc Peptide Targeted Radiopharmaceuticals

MO Tripeptide Diastereomers (M =^99/99^mTc, Re): Models To Identify the Structure of⁹⁹^mTc Peptide Targeted Radiopharmaceuticals

Isolation, Characterization, and Biological Evaluation ofSynandAntiDiastereomers of [^99mTc]Technetium Depreotide: a Somatostatin Receptor Binding Tumor Imaging Agent

30 Inorganic pharmaceuticals

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Technetium(V) Oxo Complexes of Substituted Propylene Diamine Dioxime (PnAO) Ligands: Water-Dependent Interconversion between Syn and Anti Isomers

Cited by 14 publications

References 31 publications

MO Tripeptide Diastereomers (M =99/99mTc, Re): Models To Identify the Structure of99mTc Peptide Targeted Radiopharmaceuticals

MO Tripeptide Diastereomers (M =99/99mTc, Re): Models To Identify the Structure of99mTc Peptide Targeted Radiopharmaceuticals

Isolation, Characterization, and Biological Evaluation ofSynandAntiDiastereomers of [99mTc]Technetium Depreotide: a Somatostatin Receptor Binding Tumor Imaging Agent

30 Inorganic pharmaceuticals

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Product

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MO Tripeptide Diastereomers (M =^99/99^mTc, Re): Models To Identify the Structure of⁹⁹^mTc Peptide Targeted Radiopharmaceuticals

MO Tripeptide Diastereomers (M =^99/99^mTc, Re): Models To Identify the Structure of⁹⁹^mTc Peptide Targeted Radiopharmaceuticals

Isolation, Characterization, and Biological Evaluation ofSynandAntiDiastereomers of [^99mTc]Technetium Depreotide: a Somatostatin Receptor Binding Tumor Imaging Agent