STABILITY AND CONFORMATIONAL-ANALYSIS OF TC-RC160 AND RE-RC160 - EXPERIMENTAL AND THEORETICAL-ANALYSIS OF THE INFLUENCE OF METAL COMPLEXATION ON THE STRUCTURAL REQUISITES FOR ACTIVITY

The biological significance of somatostatin and related synthetic pept ide analogs is well documented. These peptide analogs have demonstrate d inhibitory effects on the growth of certain tumor lines including pr ostate, breast, and pancreas. Metal-peptide analogs have been develope d for imaging small tumors overexpressing somatostatin receptors, i.e. receptor-based scintigraphy. Receptor-based scintigraphy requires tha t the binding constant of the metal-peptide analog be competitive with that of the native somatostatin analog. For these applications an iso tope of technetium, Tc-99m is a particularly useful label. To address the effect of added label on the native peptide conformation and predi cted impact on its efficacy as a therapeutic imaging agent, a combinat ion of experimental and computational techniques were used. In this wo rk, a complete analysis of an active Tc- or Re-labeled somatostatin an alog is provided through comparison of optical, MS, and NMR data. Comp utational modeling has assisted in providing a profile of energetic pr eferences for the various coordination isomers. Coupled with optical s pectral data this modeling also provides a description of the electron ic states, giving the characteristic bands in the optical spectra and helps to describe the redox activity and stability of the complex. On the basis of this information the structure of a major isomer is propo sed. The analysis suggests that only certain coordination isomers will be accommodated by peptide without significant distortion of the ''ac tive'' conformation. Furthermore, this work provides useful informatio n for the rational design of labeled peptides with increased stability .