Design, synthesis and in vitro evaluation of heterobivalent peptidic radioligands targeting both GRP- and VPAC(1)-Receptors concomitantly overexpressed on various malignancies - Is the concept feasible?

• Published in: European journal of medicinal chemistry Vol. 155; pp. 84 - 95
• Main Authors: Lindner, Simon, Fiedler, Luise, Waengler, Bjoern, Bartenstein, Peter, Schirrmacher, Ralf, Waengler, Carmen
• Format: Journal Article
• Language: English
• Published: ISSY-LES-MOULINEAUX Elsevier 15.07.2018
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; Prostate carcinoma; CANCER-CELL-LINES; Bivalent tumor targeting; GRPR; BREAST-CANCER; LIGANDS; Heterobivalent peptidic ligands; BOMBESIN ANALOGS; VPACR; PROSTATE-CANCER; RECEPTOR AVIDITIES; MOLECULAR-BASIS; DUAL INTEGRIN; EXPRESSION; HUMAN TUMORS
• ISSN: 0223-5234; 1768-3254
• DOI: 10.1016/j.ejmech.2018.05.047

Radiolabeled heterobivalent peptidic ligands (HBPLs), being able to address different receptors, are highly interesting tumor imaging agents as they can offer multiple advantages over monovalent peptide receptor ligands. However, few examples of radiolabeled HBPLs have been described so far. One promising approach is the combination of gastrin-releasing peptide receptor (GRPR)- and vasoactive intestinal peptide receptor subtype 1 (VPAC(1)R)-targeting peptides into one single radioligand since gastrinomas, prostate and breast cancer have been shown to concomitantly or complementarily overexpress both receptors. Here we report the design and synthesis of different HBPLs, comprising a GRPR-binding (BBN7-14) and a VPAC(1)R-targeting (PACAP-27) peptide. The heterodimers were varied with regard to the distance between the peptide binders and the steric rigidity of the systems. We radiolabeled the HBPLs 19 23 as well as their monomeric reference standards 26 and 27 with Ga-68, achieving radiochemical yields and purities of 95-99% and non-optimized molar activities of 25-61 GBq/mu mol. We tested the stability of the radioligands and further evaluated them in vitro regarding their uptake in different prostate carcinoma cell lines (PC-3, DU-145 and VCaP cells). We found that the heterobivalent substances [Ga-68]19-[Ga-68]23 showed comparable uptakes into the tumor cells to those of the respective monomers [Ga-68]26 and [Ga-68]27, indicating that both peptides are still able to address their target receptors. Furthermore, the obtained results indicate that in case of overall low receptor densities, heterobivalent peptides surpass peptide monomers in tumor cell uptake. Most importantly, it could be shown by blocking studies that both peptide parts of the HBPL [Ga-68]19 contributed to tumor cell uptake in VCaP cells, expressing both receptor types. Thus, we describe here the first examples of HBPLs being able to address the GRPR as well as the VPAC(1)R and have the potential to - by several mechanisms improve tumor targeting for several malignancies compared to monospecific peptides. (C) 2018 Elsevier Masson SAS. All rights reserved.