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.