AGTR1 Is Overexpressed in Neuroendocrine Neoplasms, Regulates Secretion and May Potentially Serve as a Target for Molecular Imaging and Therapy

SIMPLE SUMMARY: Clinical management of neuroendocrine neoplasms (NEN), especially of those low in target molecules such as somatostatin receptors, may benefit from the discovery of novel targets. This study identified and confirmed angiotensin II (ATII) as a strong activator of signaling in NEN cells and its cognate receptor AGTR1 as overexpressed in human small intestinal NEN. NEN cells with high AGTR1 expression exhibited cellular activation and secretion upon stimulation with ATII. AGTR1 ligand saralasin coupled to a fluorescent dye demonstrated tumor accumulation in an animal model of NEN. This proof of concept establishes AGTR1 as a novel target in NEN, paving the way for its potential use in diagnostic PET imaging and radioligand therapy. ABSTRACT: This study identified and confirmed angiotensin II (ATII) as a strong activator of signaling in neuroendocrine neoplasm (NEN) cells. Expression analyses of the ATII receptor type 1 (AGTR1) revealed an upregulation of mRNA levels (RT-qPCR) and radioligand binding (autoradiography) in small-intestinal (n = 71) NEN tissues compared to controls (n = 25). NEN cells with high AGTR1 expression exhibited concentration-dependent calcium mobilization and chromogranin A secretion upon stimulation with ATII, blocked by AGTR1 antagonism and Gαq inhibition. ATII also stimulated serotonin secretion from BON cells. AGTR1 ligand saralasin was coupled to a near-infrared fluorescent (NIRF) dye and tested for its biodistribution in a nude mouse model bearing AGTR1-positive BON and negative QGP-1 xenograft tumors. NIRF imaging showed significantly higher uptake in BON tumors. This proof of concept establishes AGTR1 as a novel target in NEN, paving the way for translational chelator-based probes for diagnostic PET imaging and radioligand therapy.