Substitution of L-Trp by α-methyl-L-Trp in 177Lu-RM2 results in 177Lu-AMTG, a high affinity GRPR ligand with improved in vivo stability


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, RM2 (DOTA-Pip5-D-Phe6-Gln7-Trp8-Ala9-Val10-Gly11-His12-Sta13-Leu14-NH2), may be clinically impacted by limited metabolic stability. Aim: With the aim to improve 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 analogue might also be advantageous. A comparative preclinical evaluation of 177Lu-α-Me-L-Trp8-RM2 (177Lu-AMTG) and its DOTAGA counterpart (177Lu-AMTG2) was carried out using 177Lu-RM2 and 177Lu-NeoBOMB1 as reference compounds...

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