Abstract
The L-type amino acid transporter-1 (LAT1, SLC7A5) is upregulated in a wide range of human cancers, positively correlated with the biological aggressiveness of tumors, and a promising target for both imaging and therapy. Radiolabeled amino acids such as O-(2-[18F]fluoroethyl)-L-tyrosine (FET) that are transport substrates for system L amino acid transporters including LAT1 have met limited success for oncologic imaging outside of the brain, and thus new strategies are needed for imaging LAT1 in systemic cancers. Here, we describe the development and biological evaluation of a novel zirconium-89 labeled antibody, [89Zr]DFO-Ab2, targeting the extracellular domain of LAT1 in a preclinical model of colorectal cancer. This tracer demonstrated specificity for LAT1 in vitro and in vivo with excellent tumor imaging properties in mice with xenograft tumors. PET imaging studies showed high tumor uptake, with optimal tumor-to-non target contrast achieved at 7 days post administration. Biodistribution studies demonstrated tumor uptake of 10.5 ± 1.8 percent injected dose per gram (%ID/g) at 7 days with a tumor to muscle ratio of 13 to 1. In contrast, the peak tumor uptake of the radiolabeled amino acid [18F]FET was 4.4 ± 0.5 %ID/g at 30 min after injection with a tumor to muscle ratio of 1.4 to 1. Blocking studies with unlabeled anti-LAT1 antibody demonstrated a 55% reduction of [89Zr]DFO-Ab2 accumulation in the tumor at 7 days. These results are the first report of direct PET imaging of LAT1 and demonstrate the potential of immunoPET agents for imaging specific amino acid transporters.
Highlights
Alterations in metabolism and nutrient transport are hallmarks of neoplastic cells and represent important targets for molecular imaging
A prototypic example is the Warburg effect, the upregulation of the conversion of glucose to lactate via glycolysis, which occurs in many cancers and is the basis of clinical oncologic positron emission tomography (PET) imaging with the glucose analogue, 2-deoxy-2-[18F]fluoro-D-glucose (FDG)
The majority of amino acidbased tracer development has focused on system L amino acid transport, in particular, the solute carrier (SLC) protein L-type amino acid transporter-1 (LAT1, SLC7A5) which preferentially mediates the sodium-independent cellular transport of amino acids with large neutral amino acid side chains such as leucine, phenylalanine, methionine, tyrosine, and tryptophan [1,2,3]
Summary
Alterations in metabolism and nutrient transport are hallmarks of neoplastic cells and represent important targets for molecular imaging. A prototypic example is the Warburg effect, the upregulation of the conversion of glucose to lactate via glycolysis, which occurs in many cancers and is the basis of clinical oncologic positron emission tomography (PET) imaging with the glucose analogue, 2-deoxy-2-[18F]fluoro-D-glucose (FDG). Amino acid transport is increased in many cancers and has been effectively targeted with radiolabeled amino acid substrates for PET and single photon emission computed tomography (SPECT) imaging. In addition to providing amino acids for protein synthesis and other metabolic pathways, LAT1 is involved in promoting cellular growth and proliferation, angiogenesis, and mTOR pathway signaling [6,7,8]. Higher levels of LAT1 are positively correlated with increased biological aggressiveness and higher mortality in a range of human cancers including gliomas, breast, lung, prostate, and ovarian cancers and is a promising target for tumor imaging and therapy [2,9,10,11,12]
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