Quantitative receptor-based imaging of tumor proliferation with the sigma-2 ligand [(18)F]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(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.
Department of Radiology, Washington University School of Medicine, St. Louis, Missouri, United States of America ; Department of Biomedical Engineering, Washington University School of Medicine, St. Louis, Missouri, United States of America ; Division of Biology and Biomedical Sciences, Washington University School of Medicine, St. Louis, Missouri, United States of America.
Kooresh I
KI
Shoghi
Jinbin
J
Xu
Yi
Y
Su
June
J
He
Douglas
D
Rowland
Ying
Y
Yan
Joel R
JR
Garbow
Zhude
Z
Tu
Lynne A
LA
Jones
Ryuji
R
Higashikubo
Kenneth T
KT
Wheeler
Ronald A
RA
Lubet
Robert H
RH
Mach
Ming
M
You
D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001549:Benzamides; D000077610:Bexarotene; D015153:Blotting, Western; D049109:Cell Proliferation / Q000187:drug effects*; D005260:Female; D005434:Flow Cytometry; D019788:Fluorodeoxyglucose F18; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008024:Ligands; D015674:Mammary Neoplasms, Animal / Q000139:chemically induced / Q000000981:diagnostic imaging* / Q000188:drug therapy / Q000378:metabolism; D008770:Methylnitrosourea / Q000633:toxicity; D051379:Mice; D049268:Positron-Emission Tomography; D019275:Radiopharmaceuticals; D051381:Rats; D017480:Receptors, sigma / Q000378:metabolism*; D013764:Tetrahydronaphthalenes / Q000627:therapeutic use; D014230:Triazoles / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D000477:Alkylating Agents; D016588:Anticarcinogenic Agents; D001549:Benzamides; D008024:Ligands; D019275:Radiopharmaceuticals; D017480:Receptors, sigma; D013764:Tetrahydronaphthalenes; D014230:Triazoles; C106107:sigma-2 receptor; D019788:Fluorodeoxyglucose F18; C060523:vorozole; D008770:Methylnitrosourea; D000077610:Bexarotene