Abstract

Theranostic applications targeting the gastrin-releasing peptide receptor (GRPR) have shown promising results. When compared with other peptide ligands for radioligand therapy, the most often used GRPR ligand, DOTA-Pip5-d-Phe6-Gln7-Trp8-Ala9-Val10-Gly11-His12-Sta13-Leu14-NH2 (RM2), may be clinically impacted by limited metabolic stability. With the aim of improving the metabolic stability of RM2, we investigated whether the metabolically unstable Gln7-Trp8 bond within the pharmacophore of RM2 can be stabilized via substitution of l-Trp8 by α-methyl-l-tryptophan (α-Me-l-Trp) and whether the corresponding DOTAGA analog might also be advantageous. A comparative preclinical evaluation of 177Lu-α-Me-l-Trp8-RM2 (177Lu-AMTG) and its DOTAGA counterpart (177Lu-AMTG2) was performed using 177Lu-RM2 and 177Lu-NeoBOMB1 as reference compounds. Methods: Peptides were synthesized by solid-phase peptide synthesis and labeled with 177Lu. Lipophilicity was determined at pH 7.4 (logD 7.4). Receptor-mediated internalization was investigated on PC-3 cells (37°C, 60 min), whereas GRPR affinity (half-maximal inhibitory concentration) was determined on both PC-3 and T-47D cells. Stability toward peptidases was examined invitro (human plasma, 37°C, 72 ± 2 h) and invivo (murine plasma, 30 min after injection). Biodistribution studies were performed at 24 h after injection, and small-animal SPECT/CT was performed on PC-3 tumor-bearing mice at 1, 4, 8, 24, and 28 h after injection. Results: Solid-phase peptide synthesis yielded 9%-15% purified labeling precursors. 177Lu labeling proceeded quantitatively. Compared with 177Lu-RM2, 177Lu-AMTG showed slightly improved GRPR affinity, a similar low internalization rate, slightly increased lipophilicity, and considerably improved stability invitro and invivo. In vivo, 177Lu-AMTG exhibited the highest tumor retention (11.45 ± 0.43 percentage injected dose/g) and tumor-to-blood ratio (2,702 ± 321) at 24 h after injection, as well as a favorable biodistribution profile. As demonstrated by small-animal SPECT/CT imaging, 177Lu-AMTG also revealed a less rapid clearance from tumor tissue. Compared with 177Lu-AMTG, 177Lu-AMTG2 did not show any further benefits. Conclusion: The results of this study, particularly the superior metabolic stability of 177Lu-AMTG, strongly recommend a clinical evaluation of this novel GRPR-targeted ligand to investigate its potential for radioligand therapy of GRPR-expressing malignancies.

Highlights

  • Radioligand therapy has emerged as a powerful alternative to conventional treatment options in oncology

  • 50 patients with biochemically recurrent prostate cancer were examined with either 68Ga-PSMA11 or 18F-DCFPyL positron emission tomography/computed tomography (PET/CT) and with 68Ga-RM2 PET/magnetic resonance imaging (PET/MRI). 36 lesions were only visible with 68Ga-PSMA11/18F-DCFPyL PET/CT, and seven only with 68Ga-RM2 PET/MRI, which again suggests a complementary role of gastrin-releasing peptide receptor (GRPR)- and prostate-specific membrane antigen (PSMA)-targeted theranostics[5]

  • The remaining free Lu3+ did not affect the cellbased assay in a brief competition study (Supplemental Fig. 13), purification prior to affinity studies was dispensed. 125I-Iodination of D-Tyr6-MJ9 by means of the Iodo-Gen® method resulted in 3-125I-D-Tyr6-MJ9 with radiochemical yields (RCY) of 33-48% and radiochemical purities (RCP) of >98% after reversed phase high performance liquid chromatography (RP-HPLC) purification. 177Lu-labeling of all compounds was performed manually, each resulting in quantitative RCYs, RCPs of >98% and molar activities of 40 ± 10 GBq/μmol

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Summary

Introduction

Radioligand therapy has emerged as a powerful alternative to conventional treatment options in oncology. This can mainly be attributed in case of neuroendocrine tumors to the success story of DOTATOC- and DOTATATE-based theranostics, and in the case of prostate cancer to prostate-specific membrane antigen (PSMA)-targeted inhibitors [1,2]. 50 patients with biochemically recurrent prostate cancer were examined with either 68Ga-PSMA11 or 18F-DCFPyL positron emission tomography/computed tomography (PET/CT) and with 68Ga-RM2 PET/magnetic resonance imaging (PET/MRI). 36 lesions were only visible with 68Ga-PSMA11/18F-DCFPyL PET/CT, and seven only with 68Ga-RM2 PET/MRI, which again suggests a complementary role of GRPR- and PSMA-targeted theranostics[5]. Successful highcontrasting PET imaging of breast cancer using 68Ga-NOTA-RM26 or 68Ga-RM2 has already been described[8,9]

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