Quantitative Receptor-Based Imaging of Tumor Proliferation with the Sigma-2 Ligand [18F]ISO-1

The sigma-2 receptor is expressed in higher density in proliferating (P) tumor cells versus quiescent (Q) tumor cells, thus providing an attractive target for imaging the proliferative status (i.e., P:Q ratio) of solid tumors. Here we evaluate the utility of the sigma-2 receptor ligand 2-(2-[ 18 F]fluoroethoxy)- N -(4-(3,4-dihydro-6,7-dimethoxyisoquinolin-2(1 H )-yl)butyl)-5-methyl-benzamide, [ 18 F]ISO-1, in two different rodent models of breast cancer. In the first study, small animal Positron Emission Tomography (PET) imaging studies were conducted with [ 18 F]ISO-1 and 18 FDG in xenografts of mouse mammary tumor 66 and tracer uptake was correlated with the in vivo P:Q ratio determined by flow cytometric measures of BrdU-labeled tumor cells. The second model utilized a chemically-induced ( N -methyl- N -nitrosourea [MNU]) model of rat mammary carcinoma to correlate measures of [ 18 F]ISO-1 and FDG uptake with MR-based volumetric measures of tumor growth. In addition, [ 18 F]ISO-1 and FDG were used to assess the response of MNU-induced tumors to bexarotene and Vorozole therapy. In the mouse mammary 66 tumors, a strong linear correlation was observed between the [ 18 F]ISO-1 tumor: background ratio and the proliferative status (P:Q ratio) of the tumor (R = 0.87). Similarly, measures of [ 18 F]ISO-1 uptake in MNU-induced tumors significantly correlated (R = 0.68, P<0.003) with changes in tumor volume between consecutive MR imaging sessions. Our data suggest that PET studies of [ 18 F]ISO-1 provide a measure of both the proliferative status and tumor growth rate, which would be valuable in designing an appropriate treatment strategy.