Modular One-Pot Strategy for the Synthesis of Heterobivalent Tracers

Abstract

Bivalent ligands, i.e., molecules having two ligands covalently connected by a linker, have been gathering attention since the first description of their pharmacological potential in the early 80s. However, their synthesis, particularly of labeled heterobivalent ligands, can still be cumbersome and time-consuming. We herein report a straightforward procedure for the modular synthesis of labeled heterobivalent ligands (HBLs) using dual reactive 3,6-dichloro-1,2,4,5-tetrazine as a starting material and suitable partners for sequential S N Ar and inverse electron-demand Diels−Alder (IEDDA) reactions. This assembly method conducted in a stepwise or in a sequential one-pot manner provides quick access to multiple HBLs. A conjugate combining ligands toward the prostate-specific membrane antigen (PSMA) and the gastrin-releasing peptide receptor (GRPR) was radiolabeled, and its biological activity was assessed in vitro and in vivo (receptor binding affinity, biodistribution, imaging) as an illustration that the assembly methodology preserves the tumor targeting properties of the ligands.

Elevating theranostics: The emergence and promise of radiopharmaceutical cell‐targeting heterodimers in human cancers

“…Bailly et al. [136] have investigated a new heterodimer specific for PSMA and GRPR in the context of creating heterobivalent ligands through a simplified “one‐pot” synthetic approach. This strategy seeks to mitigate the challenges associated with the arduous production of intricate dual‐targeting molecules.…”

“…The two targeting moieties in this synthesis were the low molecular weight PSMA‐targeting urea‐based inhibitor KuE (lysine‐urea‐glutamate) and the GRPR‐targeting antagonist JMV594. Evaluation of the pharmacologic properties of the 68 Ga labeled radioconjugate through in vivo and in vitro studies demonstrated that the platform‐based assembly method does not hinder the interaction of the ligands with their receptors [136].…”

Gastrin-releasing peptide receptor (GRPR) as a novel biomarker and therapeutic target in prostate cancer

“…It is highly expressed in the pancreas, inducing the release of endogenous gastric hormones and regulating the secretion of pancreatic enzymes [ 18 ]. Elevated GRPR expression has been observed in lower-grade PCa cases [ 19 , 20 ]. Thus, GRPR holds significant diagnostic and therapeutic potential, particularly in PSMA-negative and low-grade prostate malignancies.…”

Lu-177-Labeled Hetero-Bivalent Agents Targeting PSMA and Bone Metastases for Radionuclide Therapy

“…These studies hypothesize that targeting more than one receptor expressed on the tumor cell surface, or other cancer-specific manifestation, may enhance efficacy. For example, a hetero-bivalent agent targeting fibroblast activation protein alpha (FAPα) and PSMA, both abundantly expressed on or near prostate tumor cells, may enhance cancer detection and therapy. − Another paper investigated a hetero-bivalent agent that targeted both PSMA and the gastrin-releasing peptide receptor (GRPR) for the development of imaging agents by increasing its local concentration and its receptor binding . Additionally, Grus et al reported a PSMA derivative containing an additional bisphosphonate group, [ 177 Lu]­Lu-DOTA-L-Lys­(SA.Pam)-PSMA-617 .…”