Improved Tumour Targeting with Radiolabelled Peptidomimetics

Cancer is one of the most common causes for death in western countries (www.cancer.org). Radiolabelled peptides which target receptors that are over expressed by tumors hold great promise for the development of radiodiagnostics and therapeutics useful in nuclear oncology for the management of the cancer. Regulatory peptides are a class of biomolecules with ideal characteristics for the development of tumour-targeting radiopharmaceuticals. They exhibit a high, specific accumulation in tumours but not in healthy tissue and a favourable pharmacokinetic profile. A drawback of using such peptides for the selective delivery of attached radionuclides to tumours is their low stability due to rapid degradation by enzymes (proteases) before they can reach their target (tumours). It is known from the literature that enhancing the metabolic stability of a peptide carrier can substantially increase its uptake in tumours and metastases. Despite considerable research efforts directed towards the stabilization of the peptides without influencing their favourable biological characteristics, no general approach has yet been identified. We have recently introduced a novel click chemistry methodology to achieve this goal. We use metabolically stable 1,2,3-triazole heterocycles as mimics of labile amide bond of the peptides. We were able to show that the obtained, radiolabelled peptidomimetics exhibit an increased stability and as a result, a significantly improved tumour uptake in mice. Based on previous research results, we will apply our new methodology to different regulatory peptides for application in tumour-targeting. The compounds will be equipped with a chelator for the labelling with radioactive metals via complex formation and evaluated in vitro (with cells) and in vivo (mice) for their biological properties (stability, receptor affinity, pharmacokinetics, and tumour- targeting) in comparison to reference compounds. Lead compounds identified in the course of the work will be further optimized by structural modifications with the goal of obtaining a radiotracer for initiation of clinical trials together with the physicians of the department nuclear medicine of the general hospital of Vienna. If we are successful, the project will lead to a new generation of peptide-based radiopharmaceuticals for the diagnosis and therapy of cancer for the benefit of patients.

Improved Tumour Targeting with Radiolabelled Peptidomimetics Project Nr. P 31477-B28 In this FWF project (2017-2023) we aimed at the improvement of the tumour-targeting properties of the somatostatin peptide SST-14, which belongs to a class of radiolabelled cyclic peptides well established in nuclear medicine for the diagnosis (imaging) and radiotherapy of neuroendocrine tumours. Unlike the approved truncated version of the peptide (octreotides), SST-14 displays pan-ligand properties, meaning that it is specific not only towards the somatostatin receptor subtype 2 (sstr2) found over-expressed in neuroendocrine tumours but also to other receptors subtypes (sstr1, 3, 4, and 5) that play an important role in other cancers. The tumour-targeting properties of radiolabelled peptides can be improved by increasing their metabolically stability, which results in an improved tumour-to-background signal important for diagnostic applications (nuclear imaging) as well as in an increased tumour uptake in general, a crucial factor for delivering the necessary radiation dose to malignant lesions for radiotherapy. We thus applied our previously established "amide-to-triazole-switch" methodology for the first time to a cyclic peptide, SST-14. By introduction of the metabolically stable amide bond bioisostere 1,2,3-triazole, readily accessible by "click chemistry", in the backbone of the peptide at or nearby known enzymatic cleavage sites, we were able to identify novel triazolo-peptidomimetic analogues of SST-14 that display improved stability and tumour uptake in vitro and in vivo (X. Guarrochena et al. Pharmaceutics 2024, accepted). Biological evaluation of the novel compounds was greatly facilitated by the collaboration with colleagues of the research centre Demokritos, Athens, Greece. In course of our studies, we have also developed and implemented successfully the fully automated synthesis of triazolo-peptidomimetics by adapting our protocols to a set-up using a microwave-assisted peptide synthesizer (X. Guarrochena et al. J Pept Sci 2023; 29; e3488). This will allow us in the future to apply more efficiently our "amide-to-triazole-switch" methodology to other peptides of medicinal interest in an effort to provide personalized nuclear medicine approaches to the benefit of patients. The biological studies of radiolabelled SST-14 peptidomimetic analogues revealed, that their pharmacokinetic and therefore applicability for nuclear medicinal applications depends on their metabolic fate, or more precisely on the properties of metabolites formed. We believe that the metabolic fate of our first generation of SST-14 peptidomimetics can be further adjusted and improved by different peptide chemistry approaches. Drawing from the results of this successful FWF project, we are currently continuing our work on the optimization of radiolabelled SST-14 analogues with the financial support of the University of Vienna.