Structure-activity relationship of octreotide analogues labeled with rhenium and technetium-99m

Abstract

The goal of this research is to cyclize octreotide analogues with ⁹⁹[supersript-m]Tc and ¹⁸⁶/¹⁸⁸Re radiometals to be used as diagnostic and therapeutic agents for neuroendocrine tumors, respectively. Several series of octreotide analogues that differ in their sequences, and/or coordination systems (S₂N₂ and S₃N) were developed. Their in vitro receptor binding affinity toward somatostatin receptors was measured via IC₅₀ studies. In vitro stability studies were carried out under physiological conditions on ⁹⁹[superscript-m]Tc-cyclized analogues in phosphate buffered saline, mouse serum, and under high cysteine concentration. The only analogue that expressed high receptor binding affinity was not stable at the tracer level; however, the other analogues were stable at the tracer level but at the expense of their receptor affinity. The effect of metal-cyclization on Tyr³-octreotate's receptor binding site was determined via three-dimensional molecular structure calculation, using two-dimensional NMR experiments as experimental constraints. From the obtained structures, it was concluded that the metal-cyclized Tyr³-octreotate's receptor binding site configuration was, to some extent, similar to that of the usually disulfide-cyclized counterpart.