Conjugation to a cell-penetrating peptide drives the tumour accumulation of the GLP1R antagonist exendin(9-39)

• Published in: European journal of nuclear medicine and molecular imaging 2023-03, Vol.50 (4), p.996-1004
• Main Authors: Collado Camps, Estel, van Lith, Sanne A. M., Kip, Annemarie, Frielink, Cathelijne, Joosten, Lieke, Brock, Roland, Gotthardt, Martin
• Format: Article
• Language: English
• Subjects: Beta cells; Cardiology; Cell-Penetrating Peptides - metabolism; Cell-Penetrating Peptides - pharmacology; Conjugation; Exenatide - metabolism; Glucagon; Glucagon-like peptide 1; Glucagon-Like Peptide-1 Receptor - metabolism; Humans; Hypoglycemia; Imaging; Insulinoma - metabolism; Medicine; Medicine & Public Health; Nuclear Medicine; Oncology; Original; Original Article; Orthopedics; Pancreatic Neoplasms - diagnostic imaging; Pancreatic Neoplasms - metabolism; Peptides; Radiology; Receptors; Tissue Distribution; Translational research; Tumors; Venoms - chemistry; Venoms - metabolism; Venoms - pharmacology; Vomiting
• ISSN: 1619-7070; 1619-7089
• DOI: 10.1007/s00259-022-06041-y

Purpose Exendin, an analogue of the glucagon-like peptide 1 (GLP1), is an excellent tracer for molecular imaging of pancreatic beta cells and beta cell-derived tumours. The commonly used form, exendin-4, activates the GLP1 receptor and causes internalisation of the peptide-receptor complex. As a consequence, injection of exendin-4 can lead to adverse effects such as nausea, vomiting and hypoglycaemia and thus requires close monitoring during application. By comparison, the antagonist exendin(9-39) does not activate the receptor, but its lack of internalisation has precluded its use as a tracer. Improving the cellular uptake of exendin(9-39) could turn it into a useful alternative tracer with less side-effects than exendin-4. Methods We conjugated exendin-4 and exendin(9-39) to the well-known cell-penetrating peptide (CPP) penetratin. We evaluated cell binding and internalisation of the radiolabelled peptides in vitro and their biodistribution in vivo . Results Exendin-4 showed internalisation irrespective of the presence of the CPP, whereas for exendin(9-39) only the penetratin conjugate internalised. Conjugation to the CPP also enhanced the in vivo tumour uptake and retention of exendin(9-39). Conclusion We demonstrate that penetratin robustly improves internalisation and tumour retention of exendin(9-39), opening new avenues for antagonist-based in vivo imaging of GLP1R.