Evaluation of a Fluorescent and Radiolabeled Hybrid Somatostatin Analog In Vitro and in Mice Bearing H69 Neuroendocrine Xenografts.

UNLABELLED In the treatment of neuroendocrine tumors (NETs), complete surgical removal of malignancy is generally desirable, because it offers curative results. Preoperative guidance with radiolabeled somatostatin analogs, commonly used for NET diagnosis and preoperative planning, is limited by its low resolution, with the risk that tumor margins and small metastases will be incompletely resected with subsequent recurrence. A single hybrid probe combining radiotracer and optical dye would enable high-resolution optical guidance, also during surgery. In the current study, the hybrid labeled somatostatin analog Cy5-DTPA-Tyr(3)-octreotate (DTPA is diethylene triamine pentaacetic acid) was synthesized and evaluated for its ability to specifically trace NET cells in vitro and in an animal model. The performance of the hybrid tracer was compared with that of octreotate with only radiolabel or only optical label. METHODS The binding affinity and internalization capacity of Cy5-DTPA-Tyr(3)-octreotate were assessed in vitro. Biodistribution profiles and both nuclear and optical in vivo imaging of Cy5-(111)In -DTPA-Tyr(3)-octreotate were performed in NET-bearing mice and compared with the performance of (111)In-DTPA-Tyr(3)-octreotate. RESULTS In vitro studies showed a low receptor affinity and internalization rate for Cy5-DTPA-Tyr(3)-octreotate. The dissociation constant value was 387.7 ± 97.9 nM for Cy5-DTPA-Tyr(3)-octreotate, whereas it was 120.5 ± 18.1 nM for DTPA-Tyr(3)-octreotate. Similarly, receptor-mediated internalization reduced from 33.76% ± 1.22% applied dose for DTPA-Tyr(3)-octreotate to 1.32% ± 0.02% applied dose for Cy5-DTPA-Tyr(3)-octreotate. In contrast, in vivo and ex vivo studies revealed similar tumor uptake values of Cy5-(111)In-DTPA-Tyr(3)-octreotate and (111)In -DTPA-Tyr(3)-octreotate (6.93 ± 2.08 and 5.16 ± 1.27, respectively). All organs except the kidneys showed low background radioactivity, with especially low activities in the liver, and high tumor-to-tissue ratios were achieved-both favorable for the tracer's toxicity profile. Hybrid imaging in mice confirmed that the nuclear and fluorescence signals colocalized. CONCLUSION The correlation between findings with the optical and the nuclear probes underlines the potential of combining SPECT imaging with fluorescence guidance and shows the promise of this novel hybrid peptide for preoperative and intraoperative imaging of NET.