Peptide receptor scintigraphy and peptide receptor radionuclide therapy using radiolabeled somatostatin receptor (SSTR) agonists are successfully used in the clinic for imaging and treatment of neuroendocrine tumors. Contrary to the paradigm that internalization and the resulting accumulation of radiotracers in cells is necessary for efficient tumor targeting, recent studies have demonstrated the superiority of radiolabeled SSTR antagonists for imaging purposes, despite little to no internalization in cells. However, studies comparing the therapeutic antitumor effects of radiolabeled SSTR agonists versus antagonists are lacking. The aim of this study was to directly compare the therapeutic effect of 177Lu-DOTA-octreotate, an SSTR agonist, and 177Lu-DOTA-JR11, an SSTR antagonist.
Methods: We analyzed radiotracer uptake (both membrane-bound and internalized fractions) and the produced DNA double-strand breaks, by determining the number of p53 binDing protein 1 foci, after incubating SSTR2-positive cells with 177Lu-diethylene triamine pentaacetic acid, 177Lu-DOTA-octreotate, or 177Lu-DOTA-JR11. Also, biodistribution studies were performed in tumor-xenografted mice to determine the optimal dose for therapy experiments. Afterward, in vivo therapy experiments comparing the effect of 177Lu-DOTA-octreotate and 177Lu-DOTA-JR11 were performed in this same animal model.
Results: We found a 5-times-higher uptake of 177Lu-DOTA-JR11 than of 177Lu-DOTA-octreotate. The major part (88% ± 1%) of the antagonist uptake was membranebound, whereas 74% ± 3% of the total receptor agonist uptake was internalized. Cells treated with 177Lu-DOTA-JR11 showed 2 times more p53-binDing protein 1 foci than cells treated with 177Lu-DOTAoctreotate. Biodistribution studies with 177Lu-DOTA-JR11 (0.5 ?g/30 MBq) resulted in the highest tumor radiation dose of 1.8 ± 0.7 Gy/MBq, 4.4 times higher than the highest tumor radiation dose found for 177Lu-DOTA-octreotate. In vivo therapy studies with 177Lu-DOTAoctreotate and 177Lu-DOTA-JR11 resulted in a tumor growth delay time of 18 ± 5 and 26 ± 7 d, respectively. Median survival rates were 43.5, 61, and 71 d for the control group, 177Lu-DOTA-octreotate group, and the 177Lu-DOTA-JR11-treated group, respectively.
Conclusion: On the basis of these results, we concluded that the use of radiolabeled SSTR antagonists such as JR11 might enhance peptide receptor scintigraphy and peptide receptor radionuclide therapy of neuroendocrine tumors and provide successful imaging and therapeutic strategies for cancer types with relatively low SSTR expression.

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The Journal of Nuclear Medicine
Department of Nuclear Medicine

Dalm, S.U, Nonnekens, J, Doeswijk, R.Q, de Blois, E, van Gent, D.C, Konijnenberg, M, & de Jong, M. (2015). Comparison of the therapeutic response to treatment with a 177Lu-labeled somatostatin receptor agonist and antagonist in preclinical models. The Journal of Nuclear Medicine, 57(2), 260–265. doi:10.2967/jnumed.115.167007