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

The goal of this research is to cyclize octreotide analogues with Tc and Re 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 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 Tyr-octreotate’s receptor binding site was determined via three-dimensional molecular structure calculation, using twodimensional NMR experiments as experimental constraints. From the obtained structures, it was concluded that the metal-cyclized Tyr-octreotate’s receptor binding site configuration was, to some extent, similar to that of the usually disulfide-cyclized counterpart.