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Background : The GRPR-antagonist 68 Ga-SB3 visualized prostate cancer lesions in animal models and in patients. Switching radiometal from 68 Ga to 111 In impaired tumor targeting in mice, but coinjection of the neprilysin (NEP)-inhibitor phosphoramidon (PA) stabilized 111 In-SB3 in circulation and remarkably increased tumor uptake. We herein report on the biological profile of 111 In-SB4: 111 In-[dAla 11 ]SB3. Methods : The biological responses of 111 In-SB3/SB4 were compared in PC-3 cells and animal models. Results : Gly 11 /dAla 11 -replacement deteriorated GRPR-affinity (SB4 IC 50 : 10.7 ± 0.9 nM vs. SB3 IC 50 : 4.6 ± 0.3 nM) and uptake in PC-3 cells ( 111 In-SB4: 1.3 ± 0.4% vs. 111 In-SB3 16.2 ± 0.8% at 1 h). 111 In-SB4 was more stable than 111 In-SB3, but PA-coinjection stabilized both radiotracers in peripheral mice blood. Unmodified 111 In-SB3 showed higher uptake in PC-3 xenografts (8.8 ± 3.0%ID/g) vs. 111 In-SB4 (3.1 ± 1.1%ID/g) at 4 h pi. PA-coinjection improved tumor uptake, with 111 In-SB3 still showing superior tumor targeting (38.3 ± 7.9%ID/g vs. 7.4 ± 0.3%ID/g for 111 In-SB4). Conclusions : Replacement of Gly 11 by dAla 11 improved in vivo stability, however, at the cost of GRPR-affinity and cell uptake, eventually translating into inferior tumor uptake of 111 In-SB4 vs. unmodified 111 In-SB3. On the other hand, in-situ NEP-inhibition turned out to be a more efficient and direct strategy to optimize the in vivo profile of 111 In-SB3, and potentially other peptide radiotracers.

molecules/molecules online/molecules annual

Comparing Gly11/dAla11-Replacement vs. the in-Situ Neprilysin-Inhibition Approach on the Tumor-targeting Efficacy of the 111In-SB3/111In-SB4 Radiotracer Pair