Evaluation of cobalt-labeled octreotide analogs for molecular imaging and Auger electron-based radionuclide therapy

Abstract

The somatostatin receptor, which is overexpressed by many neuroen-docrine tumors, is a well-known target for molecular imaging and peptide receptor radionuclide therapy. Recently, 57 Co-labeled DOTA-TOC, an octreotide analog, was shown to have the highest affinity yet found for somatostatin receptor subtype 2. The aim of this study was to evaluate the biologic effects of novel cobalt-labeled octreotide analogs targeting the somatostatin receptor to identify promising candidates for molecular imaging and Auger electron-based radionuclide therapy. Methods: Cobalt-labeled DOTATATE, DOTATOC, and DOTANOC were prepared with 57 Co or 58m Co for SPECT or Auger electron-based therapy, respectively. The cellular uptake and intracellular distribution of the radioligands were characterized with the pancreatic tumor cell line AR42J in vitro, including assessment of the therapeutic effects of 58m Co-DOTATATE via DNA double-strand break and proliferation assays. Comparisons with the therapeutic effects of 111 In-and 177 Lu-DOTATATE were also performed. Tumor uptake and normal tissue uptake were characterized in a subcutaneous pancreatic tumor mouse model. Results: All 3 cobalt-conjugated peptides resulted in time-dependent and receptor-specific uptake, with a high level (≥88%) of cellular in-ternalization in vitro of the total cell-associated radioactivity. The DNA double-strand break yield showed a dose-dependent increase with activity, whereas cell survival showed a dose-dependent decrease. 58m Co- DOTATATE was significantly more efficient in cell killing per cumulated decay than 111 In- and 177 Lu-DOTATATE. The in vivo phar-macokinetic studies showed a high level of receptor-specific tumor uptake. Conclusion: All cobalt-labeled radioligands showed a high level of receptor-specific uptake both in vitro and in vivo in tumor-bearing mice. Furthermore, 58m Co-DOTATATE showed considerable therapeutic effects in vitro and, thus, could be an effective agent for eradicating disseminated tumor cells and micrometastases. COPYRIGHT © 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.