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

Abstract

Background: The GRPR-antagonist 68Ga-SB3 visualized prostate cancer lesions in animal models and in patients. Switching radiometal from 68Ga to 111In impaired tumor targeting in mice, but coinjection of the neprilysin (NEP)-inhibitor phosphoramidon (PA) stabilized 111In-SB3 in circulation and remarkably increased tumor uptake. We herein report on the biological profile of 111In-SB4: 111In-[dAla11]SB3. Methods: The biological responses of 111In-SB3/SB4 were compared in PC-3 cells and animal models. Results: Gly11/dAla11-replacement deteriorated GRPR-affinity (SB4 IC50: 10.7 ± 0.9 nM vs. SB3 IC50: 4.6 ± 0.3 nM) and uptake in PC-3 cells (111In-SB4: 1.3 ± 0.4% vs. 111In-SB3 16.2 ± 0.8% at 1 h). 111In-SB4 was more stable than 111In-SB3, but PA-coinjection stabilized both radiotracers in peripheral mice blood. Unmodified 111In-SB3 showed higher uptake in PC-3 xenografts (8.8 ± 3.0%ID/g) vs. 111In-SB4 (3.1 ± 1.1%ID/g) at 4 h pi. PA-coinjection improved tumor uptake, with 111In-SB3 still showing superior tumor targeting (38.3 ± 7.9%ID/g vs. 7.4 ± 0.3%ID/g for 111In-SB4). Conclusions: Replacement of Gly11 by dAla11 improved in vivo stability, however, at the cost of GRPR-affinity and cell uptake, eventually translating into inferior tumor uptake of 111In-SB4 vs. unmodified 111In-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 111In-SB3, and potentially other peptide radiotracers.

• Authors: Emmanouil Lymperis, Aikaterini Kaloudi, Panagiotis Kanellopoulos, Marion de Jong, Eric P Krenning, Berthold A Nock, Theodosia Maina
• Journal: Molecules (Basel, Switzerland) (Molecules) Vol. 24 Issue 6 (Mar 13 2019) ISSN: 1420-3049 [Electronic] Switzerland
• PMID: 30871262 (Publication Type: Comparative Study, Journal Article)

Chemical References

• Biosimilar Pharmaceuticals
• Glycopeptides
• Indium Radioisotopes
• Ontruzant
• Receptors, Bombesin
• Indium-111
• Neprilysin
• Trastuzumab
• Bombesin
• phosphoramidon

Topics

• Animals
• Biosimilar Pharmaceuticals (chemistry)
• Bombesin (metabolism)
• Cell Line, Tumor
• Drug Stability
• Glycopeptides (administration & dosage, chemistry, pharmacokinetics)
• Humans
• Indium Radioisotopes (chemistry)
• Male
• Mice
• Neprilysin (antagonists & inhibitors)
• Prostatic Neoplasms (diagnostic imaging, metabolism)
• Receptors, Bombesin (metabolism)
• Tissue Distribution
• Trastuzumab (chemistry)