Synthesis and Preliminary Evaluation of 5-[18F]fluoroleucine

Abstract

Background: Amino acid transporters, such as LAT1, are overexpressed in aggressive prostate and breast carcinomas, directly influencing pathways of growth and proliferation.Objective: The purpose of this study was to synthesize and characterize a novel 18 F labeled leucine analog, 5-[18 F]fluoroleucine, as a potential imaging agent for aggressive tumors which may not be amenable to imaging by FDG PET.Methods: 5-fluoroleucine was synthesized and characterized, and its 18 F-labeled analog was synthesized from a mesylate precursor. First, breast cancer cell line assays were performed to evaluate uptake of 3 H-or 14 C-labeled L-leucine and other essential amino acids. Both L-leucine and 5-[ 18 F]fluoroleucine were tested for uptake and accumulation over time, and for uptake via LAT1. Biodistribution studies were performed to estimate radiation dosimetry for human studies. Small animal PET / CT studies of a breast cancer were performed to evaluate in vivo 5-[18 F]fluoroleucine tumor uptake. Results: Breast cancer cell lines showed increasing high net accumulation of L-[14 C]leucine. Both L-leucine and 5-[18 F]fluoroleucine showed increasing uptake over time in in vitro tumor cell assays, and uptake was also shown to occur via LAT1. The biodistribution study of 5-[18 F]fluoroleucine showed rapid renal excretion, no significant in vivo metabolism, and acceptable dosimetry for use in humans. In vivo small animal PET / CT imaging of a breast cancer xenograft showed uptake of 5-[ 18 F]fluoroleucine in the tumor, which progressively increased over time. Conclusion: 5-[18 F]fluoroleucine is a leucine analog which may be useful in identifying tumors with high or upregulated expression of amino acid transporters, providing additional information that may not be provided by FDG PET.

The Role of Amino Acids in the Diagnosis, Risk Assessment, and Treatment of Breast Cancer: A Review

“…Trp analogs, primarily using L-type amino acid transport, have been developed by several research groups and have also been shown to be taken up by breast cancer cells in small animal studies [ 172 ]. An analogue of Leu, 5-[ 18 F]fluoroleucine, was synthesized with primary transport via LAT1 [ 173 ]. Unlike 18 F-fluciclovine, the absorption of 5-[ 18 F]fluoroleucine gradually increases over time.…”

Amino Acid Metabolism as a Target for Breast Cancer Imaging

“…19,52 Recently, a newer leucine analog, 5-[ 18 F]fluoroleucine, was synthesized, with primary transport via LAT1. 53 Both cell lines and breast cancer xenografts demonstrate 5-[ 18 F]fluoroleucine uptake. As opposed to 18 F-fluciclovine, 5-[ 18 F]fluoroleucine uptake progressively increases over time.…”

“…As opposed to 18 F-fluciclovine, 5-[ 18 F]fluoroleucine uptake progressively increases over time. 53 The glutaminolysis pathway is highly active in many malignancies, including triple-negative breast cancers. 54 Preclinical work with the glutamine analog [ 18 F](2S,4R)4-Fluoroglutamine 55,56 has demonstrated the ability of this tracer to track changes in the cellular glutamine pool size and the glutaminolysis pathway following glutaminase inhibition.…”