AGTR1 is overexpressed in neuroendocrine neoplasms, regulates secretion and may serve as a target for molecular imaging and therapy

Peptide receptor targeting has proven to be a pivotal tool for diagnostic imaging and radioligand therapy of neuroendocrine neoplasms (NENs), which frequently express somatostatin receptors (SSTRs) on their cell surface. However, up to 30 % of NEN patients do not benefit from SSTR-based approaches, others develop a resistance. Consequently, alternative cell surface targets need to be identified. In this study, cell-based dynamic mass redistribution and calcium mobilization screening using a 998-compound library identified and confirmed angiotensin II (ATII) as a strong activator of cellular signaling in NEN cells. Expression analyses of the ATII receptor type 1 (AGTR1) revealed an upregulation of both mRNA levels (RT-qPCR) and radioligand binding (autoradiography) in pancreatic (n=42) and small-intestinal (n=71) NEN tissues compared to healthy controls (n=25). The two NEN cell lines BON (pancreas) and H727 (lung) with elevated AGTR1 expression exhibited concentration-dependent calcium mobilization and chromogranin A secretion upon stimulation with ATII, blocked by AGTR1 antagonism and G αq inhibition. To assess the applicability of AGTR1 for optical in vivo imaging, the receptor ligand saralasin was coupled to the near-infrared dye indotricarbocyanine and tested for its biodistribution in a NMRI Foxn1 nu /Foxn1 nu mouse model bearing AGTR1-positive BON and negative QGP-1 xenograft tumors. Near-infrared fluorescent imaging showed a significantly higher uptake in BON tumors 3-6 hours after injection. This successful targeting in an NEN model establishes AGTR1 as an interesting target in this tumor entity, paving the way for the development of translational chelator-based probes for diagnostic PET imaging and peptide receptor radioligand therapy.