In Silico Modelling in the Development of Novel Radiolabelled Peptide Probes

This review describes the usefulness of in silico design approaches in the design of new radiopharmaceuticals, especially peptide-based radiotracers (including peptidomimetics). Although not part of the standard arsenal utilized during radiopharmaceutical design, the use of in silico strategies is steadily increasing in the field of radiochemistry as it contributes to a more rational and scientific approach. The development of new peptide-based radiopharmaceuticals as well as a short introduction to suitable computational approaches are provided in this review. The first section comprises a concise overview of the three most useful computeraided drug design strategies used, namely i) a Ligand-based Approach (LBDD) using pharmacophore modelling, ii) a Structure-based Design Approach (SBDD) using molecular docking strategies and iii) Absorption-Distribution-Metabolism-Excretion-Toxicity (ADMET) predictions. The second section summarizes the challenges connected to these computer-aided techniques and discusses successful applications of in silico radiopharmaceutical design in peptide-based radiopharmaceutical development, thereby improving the clinical procedure in Nuclear Medicine. Finally, the advances and future potential of in silico modelling as a design strategy is highlighted.

Oxidant and Antioxidant Effects of Gentisic Acid in a 177Lu-Labelled Methionine-Containing Minigastrin Analogue

Background: The radiolabelling of receptor-binding peptides for therapy is a challenge since the peptide itself is exposed (during labelling, storage and transport) to radiation-induced damage, directly or indirectly, in aqueous solution. Hence, the use of radiostabilizers seems to be mandatory, especially in peptide molecules that contain radiation-sensitive amino acids. Objective: The aim of this study was to investigate the effect of two stabilizers, gentisic acid and methionine, to delve into how each of them affects the radiolabelling and stability of the minigastrin analogue [177Lu]Lu-DOTA-His-His-Glu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2 through the analysis of the 22 species distinguished over time by an optimized HPLC system. Methods: The stabilizers, in different combinations, were present from the beginning of the labelling process carried out at 96 °C for 15 min. The stability was studied for up to 7 days. Results: The unexpected selective oxidation of the methionine residue of the radiolabelled peptide, promoted by gentisic acid, led to studying the effect of pH, from 3.5 to 6.0, in the presence of only this stabilizer. A pH-dependent antioxidant behaviour was revealed, showing a decrease in peptide impurities but an increase in the selective oxidation as the pH was increased. Conclusion: The selective oxidation of the methionine residue could be induced by oxidizing species probably produced in the reaction between gentisic acid and free radicals of water, during the protection of the radiolabelled peptide from the attack of these harmful species. Therefore, the addition of methionine becomes necessary to effectively decrease this selective oxidation in the methioninecontaining peptide.

PET/PDT theranostics: synthesis and biological evaluation of a peptide-targeted gallium porphyrin

In pursuit of the goal of a molecular theranostic suitable for use as a PET radiotracer and a photosensitiser for PDT, a novel 68Ga radiolabelled peptide–porphyrin conjugate targeting the α6β1-integrin has been developed.

Targeted radionuclide therapy for neuroendocrine tumours.

Evidence supporting the potential contribution of targeted radiotherapy to the management of neuroendocrine tumours is now strong. Acting systemically, this is an effective option for patients with inoperable or multi-site disease. Toxicity is generally low, being limited to reversible myelosuppression and theoretical nephrotoxicity. Prerequisites for treatment success include demonstration of high tumour uptake relative to non-target tissues on quantitative diagnostic radionuclide imaging and stable haematological and biochemical function. In addition to (131)I metaiodobenzylguanidine therapy, which is now well established, there is growing interest in radiolabelled peptide therapy using a range of somatostatin receptor analogues such as (90)Y DOTATOC and (90)Y lanreotide. The results of clinical experience are summarised and the direction for future research is discussed.