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. 2007 Sep 6;50(18):4295-303.
doi: 10.1021/jm060887v. Epub 2007 Aug 11.

Isolation, characterization, and biological evaluation of syn and anti diastereomers of [(99m)Tc]technetium depreotide: a somatostatin receptor binding tumor imaging agent

John E Cyr  1 , Daniel A Pearson, Carol A Nelson, Barbara A Lyons, Yongyong Zheng, Judit Bartis, Jiafang He, Melchor V Cantorias, Robertha C Howell, Lynn C Francesconi
Affiliations

Isolation, characterization, and biological evaluation of syn and anti diastereomers of [(99m)Tc]technetium depreotide: a somatostatin receptor binding tumor imaging agent

John E Cyr et al. J Med Chem. .

Abstract

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 approximately 10:90) in the [(99m)TcO]depreotide preparation and shows a slightly higher affinity (IC50 = 0.15 nM) for the somatostatin receptor than the anti diastereomer (IC50 = 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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Figures

Figure 1
Figure 1
Top left: [TcO]depreotide. Sequence and labeling system used for NMR analysis. Bottom left: [TcO]depreotide model peptide. Right: technetium binding regions of [TcO]depreotide showing possible syn and anti diastereomers (syn and anti relative to the Lys side chain).
Figure 2
Figure 2
HPLC chromatogram (radiometric detection) of radiolabeled product (a) [99mTcO]depreotide and (b) [99mTcO]P2540. Product A (anti diastereomer) and product B (syn diastereomer) are noted (conditions: Zorbax 300SB C18 column; mobile phases 0.1% v/v TFA in acetonitrile/ water; gradients, (a) 24–27% B over 25 min, then 27–68% B over 17 min; flow rate 1.2 mL/min; (b) 10–14% B over 20 min; flow rate 1.0 mL/min).
Figure 3
Figure 3
Circular dichroism spectra for [99TcO]depreotide and [99TcO]P2540. Left, products A, anti diastereomers; and right, products B, syn diastereomers.
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