[89Zr]Zr-DFO-TOC: a novel radiopharmaceutical for PET imaging of somatostatin receptor positive neuroendocrine tumors

Background

Neuroendocrine tumors (NETs) are clinically diverse types of tumors that can arise anywhere in the body. Previous studies have shown that somatostatin receptors (SSTRs) are overexpressed on NET cell membranes relative to healthy tissue, allowing for tumor targeting through radiolabeled somatostatin analogs (SSAs). This work aims to develop a novel ⁸⁹Zr-labeled tracer incorporating the SSA, octreotide (TOC), for positron emission tomography (PET) imaging of SSTR + NETs and predictive dosimetry calculations, leveraging the excellent nuclear (t_½ = 3.27 days, β+ = 22.3%, β⁺_avg = 395.5 keV) and chemical characteristics (+ 4 oxidation state, preferential coordination number of 7/8, favorable aqueous chemistry) of ⁸⁹Zr. In combination with ⁸⁹Zr, the known radiochemistry with the chelator deferoxamine (DFO) gives reason to believe that this radiopharmaceutical incorporating an octreotide conjugate will be successful in studying the suitability of detecting SSTR + NETs.

Results

Radiochemical tracer assessment indicated that amounts as low as 0.1 nmol DFO-TOC can be effectively radiolabeled with ⁸⁹Zr, while maintaining ≥ 95% radiochemical yield. The stability of the compound was found to maintain radiochemical yields of 89.6% and 88.7% on the benchtop and in mouse serum, respectively, after 9 days. Receptor binding and competitive receptor blocking assays compared AR42J (high SSTR expression), PC-3 (moderate SSTR expression), and PANC-1 (minimal SSTR expression) cell lines at time points up to 6 days. In vitro studies demonstrated highest uptake in AR42J cells, and statistically significant differences in tracer uptake were seen after 1 h. Internalization assays showed maximum internalization after 3 h for all cell lines.

Conclusions

In this work, [⁸⁹Zr]Zr-DFO-TOC was synthesized with radiochemical yields ≥ 95% and was found to remain stable in vitro at extended time points. In vitro cell studies demonstrated a statistically significant difference between receptor binding and blocking experiments. The development of this work shows potential to positively impact patient care through the predictive dosimetry calculations for the FDA-approved therapeutic agent [¹⁷⁷Lu]Lu-DOTA-TATE, while allowing for imaging at extended timepoints and should be studied further.