Lead optimization of radiopharmaceuticals for molecular radiotherapy and preclinical evaluation


Emma Renard2  | Olivier Raguin1 | Victor Goncalves2 | Céline Mothes1 | Mathieu Moreau2 | Claire Bernhard2 | Peggy Provent1 | Pierre Adumeau1,2 | Romane Vizier2 | Frederic Boschetti3 | Franck Denat2 | Cyril Berthet1

1 – Oncodesign | 2 – ICMUB UMR 6302, CNRS, Université Bourgogne Franche-Comté | 3 – CheMatech


Molecular Radiotherapy (MRT) targeting SSTR2 or PSMA have proven to be highly efficient for treatment of neuroendocrine or metastatic prostate cancer respectively. Beyond the leading radiopharmaceutical molecules 177Lu-DOTATATE or 177Lu-PSMA-617, a variety of vectors (small molecules, peptides, panel of biologics) have been developed on the same targets in order to improve the biodistribution within the tumor, the blood clearance, the route of elimination or the dosimetry.

Labeling of the targeting ligand, whatever its nature, is a crucial step as it may affect significantly the properties of the theranostic conjugate, i.e. its binding affinity, PK and biodistribution. The addition of linkers, such as albumin binding domain or PEG, and choice of chelating agents have a major impact on the chemical and biological properties of the vectors. Random or site-specific bioconjugation, click chemistry, have also to be considered in the early stage as the choice of the selected technology will modify your development plan and manufacturing.

New ligands and biological platforms are now being developed based on this historical knowledge, improved Target Product Profiles are built to conduct optimal lead optimization of MRT. Herein, we will present our lead optimization and preclinical evaluation process to select efficiently good radiolabeled molecules and list the key parameters to be checked. To date, it remains hard to predict the behavior of the modified bioconjugated molecules, and versatile synthesis strategies are needed to screen various combinations of radiometal complexes / linker / conjugation function, in order to converge rapidly to the optimized bioconjugate. For instance, we will present a study case where the conjugation of various bifunctional chelating agents on a small NTS1 receptor antagonist resulted in drastically different in vivo behavior of the resulting 68Ga-labeled compounds.

Once optimal in vivo tumor uptake has been achieved, preclinical evaluation requires the selection of appropriate and relevant models, driven by target expression, radioresistance, and potentially tumor immune infiltrate for combination studies with immunotherapies. The therapeutic evaluation should take into consideration the dose and specific activity, tolerance of the model related to ionizing radiations and the scheduling of treatment (cumulated dose, fractionation).

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