Amino acid transporters

Amino acid transporters are ubiquitously expressed in the body. In most types of cancer, amino acid transporters are up-regulated, thus providing a target for diagnostic PET radiopharmaceuticals and anticancer drugs.

Numerous radiolabelled amino acid analogues have been developed; these usually are not only transported into cells but are also metabolized further and incorporated into proteins, and the uptake of these represents the activity of all these processes. The expression of amino acid transporters could be assessed using immuno-PET (Ikotun et al., 2013). Activity of amino acid transport can be assessed using radiopharmaceuticals that are transported normally but that cannot be metabolized or used in peptide synthesis. Fluorine-18 labelled boramino acids (BAAs), where carboxylate group (-COO^-) is substituted with isosteric trifluoroborate (-BF₃^-), are metabolically stable, retaining their transporter specificity, and could be used in BNCT (Liu et al., 2015; Lan et al., 2021).

Amino acid transporters are categorized into at least 17 distinct classes (Bröer, 2008). Neutral amino acids are considered to be mainly transported by 3 systems: A, ASC, and L (Palacín et al., 1998). Systems A and ASC mainly transport amino acids with short, polar, or linear side chains, such as L-alanine and L-serine. Large, branched, and aromatic amino acids, such as L-tyrosine, mainly enter cells via system L (Saier et al., 1988).

System A

System A (alanine-preferring) amino acid transporters are important in regulation of cell growth. These transporters are sodium-dependent active transporters, that is, able to transport amino acids against their concentration gradients. System A transporters are upregulated in several human cancer types, and provide therefore a target for oncological imaging, using radiopharmaceuticals such as [¹¹C]MeAIB (Sutinen et al., 2003; Arimoto et al., 2016).

ASCT2

Alanine-serine-cysteine transporter 2 (ASCT2/SLC1A5) is a sodium-dependent neutral amino acid transporter. Several cancer cell types are dependent on external source of glutamine, and have increased ASCT2 and glutaminase activity. Therefore labelled glutamine analogues, such as (2S,4R)-4-[¹⁸F]fluoroglutamine, are potentially suitable for tumour imaging.

Leucine-derivative [¹⁸F]fluciclovine is predominantly transported by ASCT2 and LAT1.

System L

LAT1 and LAT2

L-type amino acid transporters 1 and 2 (LAT1 and LAT2), the isoforms of system L (leucine-preferring), facilitate the diffusion of large (LAT1/SLC7A5) and smaller (LAT2) neutral amino acids across membranes.

L-type amino acid transporter 1 (LAT1) is overexpressed in many cancer cells, and is associated with poor prognosis. LAT1 is therefore a target for the diagnosis and therapeutics of cancers (Kanai, 2022). Non-cancer type isoform LAT2 is ubiquitously expressed in normal tissues. Normal tissues with high demand for amino acids for peptide synthesis may have high expression of LAT1, too. LAT1 is required for pancreatic islets to sense the concentration of branched-chain amino acids (leucine, isoleucine, valine) and response to that by increasing insulin secretion (Cheng et al., 2016).

The tissue uptake of commonly used PET radiopharmaceuticals L-[methyl-¹¹C]methionine, FDOPA, and tyrosine and tryptophan analogues is largely dependent on these transporters. [¹⁸F]OMFD, metabolite of FDOPA, is also transported by LATs, and it could be used as PET tracer for tumour imaging (Beuthien-Baumann et al., 2003; Bergmann et al., 2004; Alheit et al., 2008).

L-4-borono-2-[¹⁸F]fluoro-phenylalanine ([¹⁸F]FBPA) prefers LAT1 over LAT2, and therefore tumour imaging using [¹⁸F]FBPA does not suffer from the inflammation-induced increase in amino acid uptake, which is the case when using certain other LAT substrates, such as L-[methyl-¹¹C]methionine (Watabe et al., 2017).

Leucine-derivative [¹⁸F]fluciclovine is predominantly transported by LAT1 and ASCT2.

Leucine analog L-α-[5-¹¹C]methylleucine ([5-¹¹C]MeLeu) is not used for protein synthesis and is not metabolized, and mainly transported by LAT1. In rat brain tumours it provides higher tumour-to-normal tissue ratio than L-[methyl-¹¹C]methionine, and does not accumulate in inflamed brain area (Tahara et al., 2023).

Increased O-(2-[¹⁸F]-fluoroethyl)-L-tyrosine ([¹⁸F]FET) uptake in tumours has been assumed to caused by overexpression of LAT1. However, both [¹⁸F]FET positive and negative gliomas express LAT1 (Vettermann et al., 2021).

[¹⁸F]FBY is boramino acid version of tyrosine, showing high uptake in LAT-1 expressing tumours and low reverible uptake in normal and inflamed tissue (Li et al., 2021).

LAT3 and LAT4

LAT4 expression in some cancer cell lines and zenografts has been shown to be even higher than expression of LAT1 (Haase et al., 2007). LAT3 and LAT4 prefer phenylalanine over other neutral amino acids.

x_C^- transporter

The Cystine/glutamate antiporter (system x_C^-) is an active transporter for negatively charged amino acids, such as L-glutamate. System x_C^- can work both ways, depending on the demand.

Literature

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Bröer S. Amino acid transport across mammalian intestinal and renal epithelia. Physiol Rev. 2008; 88: 249–286. doi: 10.1152/physrev.00018.2006.

Crippa F, Alessi A, Serafini GL. PET with radiolabeled aminoacids. Q J Nucl Med Mol Imaging 2012; 56(2): 151-162. PMID: 22617237.

Fotiadis D, Kanai Y, Palacín M. The SLC3 and SLC7 families of amino acid transporters. Mol Aspects Med. 2013; 34(2-3): 139-158. doi: 10.1016/j.mam.2012.10.007.

Juhász C, Dwivedi S, Kamson DO, Michelhaugh SK, Mittal S. Comparison of amino acid positron emission tomographic radiotracers for molecular imaging of primary and metastatic brain tumors. Mol Imaging 2014; 13: 1-16. doi: 10.2310/7290.2014.00015.

Kanai Y, Clémençon B, Simonin A, Leuenberger M, Lochner M, Weisstanner M, Hediger MA. The SLC1 high-affinity glutamate and neutral amino acid transporter family. Mol Aspects Med. 2013; 34(2-3): 108-120. doi: 10.1016/j.mam.2013.01.001.

Kilbourn MR. Small molecule PET tracers for transporter imaging. Semin Nucl Med. 2017; 47(5): 536-552. doi: 10.1053/j.semnuclmed.2017.05.005.

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Mann A, Semenenko I, Meir M, Eyal S. Molecular imaging of membrane transporters' activity in cancer: a picture is worth a thousand tubes. AAPS J. 2015; 17(4): 788-801. doi: 10.1208/s12248-015-9752-6.

Palacín M, Estévez R, Bertran J, Zorzano A. Molecular biology of mammalian plasma membrane amino acid transporters. Physiol Rev. 1998; 78: 969–1054. doi: 10.1152/physrev.1998.78.4.969.

Saier MH Jr, Daniels GA, Boerner P, Lin J. Neutral amino acid transport systems in animal cells: potential targets of oncogene action and regulators of cellular growth. J Membr Biol. 1988; 104: 1–20. doi: 10.1007/BF01871898.

Smith QR, Momma S, Aoyagi M, Rapoport SI. Kinetics of neutral amino acid transport across the blood-brain barrier. J Neurochem. 1987; 49(5): 1651-1658. doi: 10.1111/j.1471-4159.1987.tb01039.x.

Young JD, Jones SEM, Ellory JC, Glynn IM. Amino acid transport in human and in sheep erythrocytes. Proc R Soc Lond B Biol Sci. 1980; 209(1176): 355-375. doi: 10.1098/rspb.1980.0100.

Tags: Amino acid, Transporter, Tumour

Updated at: 2023-03-08
Created at: 2017-12-03
Written by: Vesa Oikonen