Influence of Labelling Methods on Biodistribution and Imaging Properties of Radiolabelled Peptides for Visualisation of Molecular Therapeutic Targets

Abstract

Progress in genomics and proteomics provides clinical oncology with new anti-cancer drugs, which target selectively aberrantly expressed membrane proteins and associated signalling pathways in malignant cells. Molecular targeting also enables specific delivery of cytotoxic substances to tumours sparing healthy tissues. Improved selectivity of the treatment reduces side effects and widens the therapeutic window. However, only a part of the patients might benefit from such treatment due to inter- and intrapatient heterogeneity of therapeutic target expression. This makes it necessary to identify patients, who may benefit from targeting therapy. Radiolabelled peptides can provide selective and sensitive detection of molecular therapeutic targets in both primary tumours and metastases in a single non-invasive procedure, making personalised treatment possible. The choice of detection method (single photon emission tomography or positron emission tomography), radionuclide for labelling and labeling chemistry can appreciably influence the imaging property of a tracer. The labelling method might affect the binding affinity, the cellular processing and retention of a radionuclide, the biodistribution of a targeting peptide, and excretion pathways of a non-bound tracer and radiocatabolites. This influences the sensitivity and specificity of the imaging. This influence is exemplified by three classes of tumour-targeting peptides: somatostatin analogues, bombesin analogues and Affibody molecules. The review suggests approaches for selection of an optimal labelling chemistry.

Same-Day Imaging Using Small Proteins: Clinical Experience and Translational Prospects in Oncology

“…This might affect on-target and off-target interactions, excretion, and intracellular retention of the radionuclide after internalization (41). In this way, changes in radiolabeling chemistry might have important effects on the imaging contrast obtained and optimal imaging time point.…”

Incorporation of a Triglutamyl Spacer Improves the Biodistribution of Synthetic Affibody Molecules Radiofluorinated at the N-Terminus via Oxime Formation with 18F-4-Fluorobenzaldehyde

“…Importantly, preclinical data demonstrated that different labeling approaches appreciably influence the biodistribution and targeting properties of Affibody molecules, and a careful optimization of the combination of nuclide and chelator or linker is required to obtain maximum imaging contrast 16 .…”

Tumor Targeting Using Affibody Molecules: Interplay of Affinity, Target Expression Level, and Binding Site Composition

“…Internalization of the targeting protein followed by metabolism and intracellular trapping of residualizing labels, such as radiometals, might make cellular binding of targeting proteins and peptides less dependent on their affinity (15). However, internalization of HER2-binding Affibody molecules is relatively slow, typically around 30% of bound conjugate per day, and in this case cellular retention of radioactivity results from the strong target binding (16)(17)(18).…”