[¹⁸F](2S,4S)-4-(3-Fluoropropyl)glutamine as a Tumor Imaging Agent

Abstract

Although the growth and proliferation of most tumors is fueled by glucose, some tumors are more likely to metabolize glutamine. In particular, tumor cells with the upregulated c-Myc gene are generally reprogrammed to utilize glutamine. We have developed new 3-fluoropropyl analogs of glutamine, namely [18F](2S,4R)- and [18F](2S,4S)-4-(3-fluoropropyl)glutamine, 3 and 4, to be used as probes for studying glutamine metabolism in these tumor cells. Optically pure isomers labeled with 18F and 19F (2S,4S) and (2S,4R)-4-(3-fluoropropyl)glutamine were synthesized via different routes and isolated in high radiochemical purity (≥95%). Cell uptake studies of both isomers showed that they were taken up efficiently by 9L tumor cells with a steady increase over a time frame of 120 min. At 120 min, their uptake was approximately two times higher than that of l-[3H]glutamine ([3H]Gln). These in vitro cell uptake studies suggested that the new probes are potential tumor imaging agents. Yet, the lower chemical yield of the precursor for 3, as well as the low radiochemical yield for 3, limits the availability of [18F](2S,4R)-4-(3-fluoropropyl)glutamine, 3. We, therefore, focused on [18F](2S,4S)-4-(3-fluoropropyl)glutamine, 4. The in vitro cell uptake studies suggested that the new probe, [18F](2S,4S)-4-(3-fluoropropyl)glutamine, 4, is most sensitive to the LAT transport system, followed by System N and ASC transporters. A dual-isotope experiment using l-[3H]glutamine and the new probe showed that the uptake of [3H]Gln into 9L cells was highly associated with macromolecules (>90%), whereas the [18F](2S,4S)-4-(3-fluoropropyl)glutamine, 4, was not (<10%). This suggests a different mechanism of retention. In vivo PET imaging studies demonstrated tumor-specific uptake in rats bearing 9L xenographs with an excellent tumor to muscle ratio (maximum of ∼8 at 40 min). [18F](2S,4S)-4-(3-fluoropropyl)glutamine, 4, may be useful for testing tumors that may metabolize glutamine related amino acids.

Fluorination at the 4 position alters the substrate behavior of l-glutamine and l-glutamate: Implications for positron emission tomography of neoplasias

“…Moreover, it was shown that [ 18 F](2 S ,4 R )-4-FGln is metabolized in vivo in part to [ 18 F](2 S ,4 R )-4-FGlu and to 18 F − in both tumor types [16]. In other experiments it was shown that uptake of [ 18 F]FP-Gln by amino acid transporters into 9L tumor cells in F344 9L rats was even more effective than that noted with L-[ 3 H]Gln [19]. The results of a dual labeling experiment with L-[ 3 H]Gln and [ 18 F]FP-Gln showed that the label associated with administered L-[ 3 H]Gln was largely incorporated into macromolecules in 9L tumor cells, whereas label associated with [ 18 F]FP-Gln was not appreciably incorporated into macromolecules [19].…”

“…Subsequently, the glutamine analogue [ 18 F](2 S ,4 S )-4-(3-fluoropropyl)glutamine ([ 18 F]FP-Gln) was synthesized as a tumor PET imaging agent [19]. This compound is unlikely to undergo defluorination in vivo .…”

Metabolic pathways promoting cancer cell survival and growth

“…New PET tracers that probe emerging aspects of cancer metabolism are being developed, and some are already used in clinical studies or practice. These tracers, which include 18 F-glutamine, 18 F-glutamate, and 11 C-acetate 80–86 , are designed to detect tumours in which 18 FDG uptake is non-diagnostic because the tumour displays relatively little glucose uptake or is in the vicinity of a glucose-avid organ like the brain.…”

11CO bonds made easily for positron emission tomography radiopharmaceuticals

“…This tracer was prepared and characterized in cells and rodent tumor models by PET, and indicated the need for a radiotracer with a longer half-life for in vivo imaging, resulting in a number of 18 F-labeled analogues that have now been designed. 203–205 …”