Efficacy of [Cu]Cu-EB-TATE Theranostic Against Somatostatin Receptor Subtype-2-Positive Neuroendocrine Tumors.

β-emitting Lu-octreotate is an approved somatostatin receptor subtype 2 (SSTR2)-directed peptide receptor radionuclide therapy for the treatment of gastroenteropancreatic neuroendocrine tumors (NETs). However,Lu-octreotate has fast pharmacokinetics, requiring up to 4 treatment doses. Moreover, Lu is less than ideal for theranostics because of the low branching ratio of its γ-emissions, which limits its SPECT imaging capability. Compared with Lu, Cu has better decay properties for use as a theranostic. Here, we report the preclinical evaluation of a long-lived somatostatin analog, [Cu]Cu-DOTA-Evans blue-TATE (EB-TATE), against SSTR2-positive NETs. The in vitro cytotoxicity of [Cu]Cu-EB-TATE was investigated on 2-dimensional cells and 3-dimensional spheroids. In vivo pharmacokinetics and dosimetry were studied in healthy BALB/c mice, whereas ex vivo biodistribution, micro-SPECT/CT imaging, and therapy studies were done on athymic nude mice bearing QGP1.SSTR2 and BON1.SSTR2 xenografts. Therapeutic efficacy was compared with [Lu]Lu-EB-TATE. Projected human effective doses of [Cu]Cu-EB-TATE for male (0.066 mSv/MBq) and female (0.085 mSv/MBq) patients are tolerable. In vivo micro-SPECT/CT imaging of SSTR2-positive xenografts with [Cu]Cu-EB-TATE showed tumor-specific uptake and prolonged accumulation. Biodistribution showed tumor accumulation, with concurrent clearance from major organs over a period of 72 h. [Cu]Cu-EB-TATE was more effective (60%) at eliminating tumors that were smaller than 50 mm within the first 15 d of therapy than was [Lu]Lu-EB-TATE (20%) after treatment with 2 doses of 15 MBq administered 10 d apart. Mean survival of [Cu]Cu-EB-TATE-treated groups was 90 d and more than 90 d, whereas that of [Lu]Lu-EB-TATE was more than 90 d and 89 d against vehicle control groups (26 d and 53 d), for QGP1.SSTR2 and BON1.SSTR2 xenografts, respectively. [Cu]Cu-EB-TATE exhibited high SSTR2-positive NET uptake and retention, with favorable dosimetry and SPECT/CT imaging capabilities. The antitumor efficacy of [Cu]Cu-EB-TATE is comparable to that of [Lu]Lu-EB-TATE, with [Cu]Cu-EB-TATE being slightly more effective than [Lu]Lu-EB-TATE for complete remission of small tumors. [Cu]Cu-EB-TATE therefore warrants clinical development.