Page 147 - Cellular Imaging in Regenerative Medicine, Cancer and Osteoarthritis

SPECT imaging of pro-inflammatory macrophages
Introduction
Macrophages play a crucial role in the development and progression of various diseases, for example osteoarthritis (OA) (1, 2), atherosclerotic plaque (3, 4), type 2 diabetes (5, 6), rheumatoid arthritis (7, 8) and schizophrenia (9, 10). Knowing the role of macrophages during disease development and progression opens possibilities for therapeutic interference . Macrophages varied roles can exacerbate and/or resolve diseases. To detect the presence of macrophage during disease processes, a specific target for imaging is needed. Depending on the activation state, macrophages express various proteins that may be used as imaging target such as the folate receptor β (11), mannose receptor (also known as CD206) (12) and translocator protein (TSPO) (13). These have been proposed as targets for a subtype of macrophages referred to as anti-inflammatory macrophages (14, 15).
Previous studies suggested that the somatostatin receptor subtype 2 (SSTR2) is also a marker for macrophages (16, 17). More recently, it was shown that inflammation-related uptake of an SSTR2-targeting tracer was elevated in atherosclerotic plaques and it was confirmed that the tracer had macrophage specificity (18-20). Somatostatin is a peptide hormone which induces inhibitory effects on two key cellular processes, secretion and cell proliferation. It can bind to five distinct receptors subtypes named SSTR1, SSTR2, SSTR3, SSTR4 and SSTR5. These somatostatin receptors belong to the G-protein coupled receptor family. SSTR2 are highly expressed in human tumors, and are also present in pancreas, spleen, cerebrum, kidney, jejunum, colon, and liver (21, 22). Upon differentiation of human monocytes into pro-inflammatory macrophages, SSTR2 mRNA was found to be upregulated (23) in activated macrophages making it an interesting molecular target for these cells.
The aim of this preclinical study was to evaluate the potential of SSTR2 as a novel marker to monitor pro-inflammatory macrophages. We therefore determined gene expression levels of SSTR2 in unstimulated and IFNγ+TNFα stimulated human macrophages, and evaluated SSTR2 protein expression via binding of a SSTR2-binding tracer. We further used osteoarthritis (OA) as disease model to investigate a SSTR2-targeting tracer for macrophage imaging in an osteoarthritic joint. During development of OA, macrophages
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