Enhanced Dual SST2 and SST5 Tumor Targeting with a Novel 68Ga-Labeled Somatostatin Analog

The study focuses on developing a new imaging agent for neuroendocrine tumors, which often display multiple somatostatin receptor (SST) subtypes. The compound ST8950, featuring two iodo-amino acids, shows strong binding to SST2 and SST5, two of the receptor subtypes. Researchers have created a version of this compound, DOTA-ST8950, labeled with gallium-68 (^68Ga) for positron emission tomography (PET) imaging.

In vitro and in vivo experiments were conducted to compare the new ^68Ga-DOTA-ST8950 with other SST-targeting agents, including a de-iodinated version, DOTA-ST8951, and two reference compounds, DOTA-TATE and DOTA-NOC. Results indicate that ^68Ga-DOTA-ST8950 has a higher affinity for SST2 and SST5 compared to ^natGa-DOTA-NOC. It also demonstrates similar potency in inducing SST2-mediated cAMP accumulation as ^natGa-DOTA-TATE and slightly better than ^natGa-DOTA-NOC.

Furthermore, ^67Ga-DOTA-ST8950 exhibits an internalization rate in SST2-expressing cells comparable to ^67Ga-DOTA-NOC. In animal models, ^68Ga-DOTA-ST8950 shows high and specific accumulation in tumors expressing SST2 and SST5, similar to ^68Ga-DOTA-NOC. The PET/CT images obtained from a dual tumor xenograft model highlight the ability of ^68Ga-DOTA-ST8950 to visualize both SST2 and SST5 expressing tumors with a high contrast to background tissues.

The study concludes that ^68Ga-DOTA-ST8950 is a promising candidate for PET imaging of SST2 and SST5 expressing tumors. It has comparable tumor uptake to the clinically used ^68Ga-DOTA-NOC, but the liver uptake poses a challenge for its clinical application. The iodo-substitutions at positions 1 and 3 in ^68Ga-DOTA-ST8950 are crucial for maintaining receptor affinity, as evidenced by the loss of affinity in the de-iodinated ^68Ga-DOTA-ST8951.