title: Imaging the L-type amino acid transporter-1 (LAT1) with Zr-89 immunoPET.
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-[(18)F]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, [(89)Zr]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 [(18)F]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 [(89)Zr]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.
authors.affiliation: Department of Radiology, Washington University School of Medicine, St. Louis, Missouri, United States of America.
authors.forename: Oluwatayo F
authors.initials: OF
authors.lastname: Ikotun
authors.forename: Bernadette V
authors.initials: BV
authors.lastname: Marquez
authors.forename: Chaofeng
authors.initials: C
authors.lastname: Huang
authors.forename: Kazue
authors.initials: K
authors.lastname: Masuko
authors.forename: Miyamoto
authors.initials: M
authors.lastname: Daiji
authors.forename: Takashi
authors.initials: T
authors.lastname: Masuko
authors.forename: Jonathan
authors.initials: J
authors.lastname: McConathy
authors.forename: Suzanne E
authors.initials: SE
authors.lastname: Lapi
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000493:pharmacokinetics; D002471:Cell Transformation, Neoplastic; D045325:HCT116 Cells; D006367:HeLa Cells; D006801:Humans; D007553:Isotope Labeling; D027283:Large Neutral Amino Acid-Transporter 1 / Q000276:immunology / Q000378:metabolism*; D008297:Male; D051379:Mice; D049268:Positron-Emission Tomography / Q000379:methods*; D011868:Radioisotopes; D051381:Rats; D015040:Zirconium
chemical_list: D000911:Antibodies, Monoclonal; D027283:Large Neutral Amino Acid-Transporter 1; D011868:Radioisotopes; D015040:Zirconium