Quantitative receptor-based imaging of tumor proliferation with the sigma-2 ligand [(18)F]ISO-1.

Abstract

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(1H)-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.

• Authors: Kooresh I Shoghi, Jinbin Xu, Yi Su, June He, Douglas Rowland, Ying Yan, Joel R Garbow, Zhude Tu, Lynne A Jones, Ryuji Higashikubo, Kenneth T Wheeler, Ronald A Lubet, Robert H Mach, Ming You
• Journal: PloS one (PLoS One) Vol. 8 Issue 9 Pg. e74188 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 24073202 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Alkylating Agents
• Anticarcinogenic Agents
• Benzamides
• Ligands
• Radiopharmaceuticals
• Receptors, sigma
• Tetrahydronaphthalenes
• Triazoles
• sigma-2 receptor
• Fluorodeoxyglucose F18
• vorozole
• Methylnitrosourea
• Bexarotene

Topics

• Alkylating Agents (toxicity)
• Animals
• Anticarcinogenic Agents (therapeutic use)
• Apoptosis (drug effects)
• Benzamides
• Bexarotene
• Blotting, Western
• Cell Proliferation (drug effects)
• Female
• Flow Cytometry
• Fluorodeoxyglucose F18
• Humans
• Image Processing, Computer-Assisted
• Ligands
• Mammary Neoplasms, Animal (chemically induced, diagnostic imaging, drug therapy, metabolism)
• Methylnitrosourea (toxicity)
• Mice
• Positron-Emission Tomography
• Radiopharmaceuticals
• Rats
• Receptors, sigma (metabolism)
• Tetrahydronaphthalenes (therapeutic use)
• Triazoles (therapeutic use)
• Tumor Cells, Cultured