Evaluation of Cobalt-Labeled Octreotide Analogs for Molecular Imaging and Auger Electron–Based Radionuclide Therapy

Abstract

The somatostatin receptor, which is overexpressed by many neuroendocrine 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 internalization 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 pharmacokinetic 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 tumorbearing 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. Thesomat ostatin receptor, which is overexpressed by many neuroendocrine tumors, is a well-known target for molecular imaging (i.e., PET and SPECT) and for peptide receptor radionuclide therapy (1,2). One of the most widely used radiopharmaceuticals for SPECT imaging of these tumors is 111 In-diethylenetriaminepentaacetic acid ( Recently, 57 Co-labeled DOTATOC was shown to have the highest affinity yet found for the somatostatin receptor subtype 2 (SSTR2) (6). Furthermore, the rate of internalization of this compound into the pancreatic tumor cell line AR42J was the highest found for any somatostatin-based radioligand. In a study by Uusijärvi et al. (7) of 59 therapeutic radionuclides (a, b, and Auger electron emitters), the Auger electron emitter 58m Co was the radionuclide that resulted in the second highest theoretic tumor-to-normal tissue dose rate ratio. Therefore, the therapeutic potency of the 58m Co radionuclide and the remarkable obtainable internalization rates and affinities for SSTR2-expressing tumor cells mak...

Auger electron-based targeted radioimmunotherapy with 58mCo, a feasibility study

“…Experimentally, Thisgaard et al demonstrated that 58m Co-DOTATATE was significantly more efficient in cell killing per cumulated decay than 111 In-and 177 Lu-DOTATATE after exposing pancreatic tumor cells AR42J in vitro [13]. However, as far as we know, the therapeutic potential of 58m Co has not been demonstrated in vivo.…”

“…The therapeutic potential of 58m Co has been recognized theoretically [10][11][12] and experimentally [13]. Experimentally, Thisgaard et al demonstrated that 58m Co-DOTATATE was significantly more efficient in cell killing per cumulated decay than 111 In-and 177 Lu-DOTATATE after exposing pancreatic tumor cells AR42J in vitro [13].…”

Cyclotron production and radiochemical separation of 55Co and 58mCo from 54Fe, 58Ni and 57Fe targets

“…The therapeutic potential of 58m Co has been recognized theoretically (Bernhardt et al, 2001; Thisgaard et al, 2011a; Uusijarvi et al, 2006) and experimentally (Thisgaard et al, 2014). Experimentally, Thisgaard et al demonstrated that 58m Co-DOTATATE was significantly more efficient in cell killing per cumulated decay than 111 In- and 177 Lu-DOTATATE after exposing pancreatic tumor cells AR42J in vitro (Thisgaard et al, 2014).…”

“…Experimentally, Thisgaard et al demonstrated that 58m Co-DOTATATE was significantly more efficient in cell killing per cumulated decay than 111 In- and 177 Lu-DOTATATE after exposing pancreatic tumor cells AR42J in vitro (Thisgaard et al, 2014). However, as far as we know, the therapeutic potential of 58m Co has not been demonstrated in vivo.…”

“…The production of 58m Co can be carried out either by proton bombardment on isotopically enriched 58 Fe as it was done by Thisgaard et al (2011a, 2014), or by deuteron bombardment on 57 Fe. From the excitation functions of the 58 Fe(p,n) and 57 Fe(d,n) reactions published by Sudar and Qaim (1996), the thick target yields of 58m Co with the 16 MeV protons and 8.2 MeV deuterons available from our GE PETtrace cyclotron are 395 and 33 MBq/μAh, respectively.…”