L-[5-11C]-Glutamine and Metabolic Imaging in Cancer Cells

Abstract

It is well-established now that position emission tomography (PET) with 2-[18F]fluoro-2-deoxy-glucose (FDG) is a common imaging procedure for mapping cellular glucose metabolism. The uptake of FDG in tumors with higher rates of glycolysis leads to high signal to noise ratios. Despite the tremendous promise of using FDG-PET to detect and monitor tumor metabolism, many indolent tumors are FDG-negative; the tumors may have switched their energy source from glucose to glutamine, thus escaping detection. Glutamine is the most abundant amino acid in the human body. It was recognized early (1960) that glutamine plays an important role in tumor growth and proliferation. We report herein two radiolabeled glutamines, namely L-[5-11C]-glutamine and [18F](2S,4R)4-fluoro-glutamine. These two radioactive glutamines might be useful to map glutamine metabolism in vivo in tumor tissue. We recently developed an efficient method to make L-[5-11C]-glutamine and we could show that L-[5-11C]-glutamine is taken into tumor cells (9L and SF188) and incorporated into protein. Small animal imaging studies on F344 rats bearing 9L xenographed tumors confirmed uptake of the tracer into tumor. But with a short half-life of only 20 minutes, it requires a cyclotron nearby and thus hindering its widespread application. We therefore developed a [18F] fluorinated version (half life of 18F is 110 min)of glutamine, namely [18F](2S,4R)4-fluoro-glutamine. This tracer can be produced and distributed centralized, making it more suitable for clinical use. [18F](2S,4R)4-fluoro-glutamine displayed high cell uptake in 9L and SF188 (derived from human glioblastoma) cell lines and is incorporated into tumor protein. It appears that the transport mechanism may be predominantly through system ASC and may prefer its subtype ASCT2. Small animal imaging studies in F344 rats bearing 9L xenographed tumors, showed rapid uptake into tumor (maximum was reached at 20 min post injection) and the uptake remained constant during the imaging study. The in vivo imaging studies may provide an interesting tool for measuring glutamine metabolism and monitor changes of tumor metabolism.