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Amino acid imaging agents for tumors
茨城県立医療大学紀要
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第 25 巻

Review Article

Volume 25

Radiolabeled Molecular Imaging Agents for Amino Acid Transport inTumorsNaoto Shikano1), Keiichi Kawai2)
1)
2)

Department of Radiological Sciences, Ibaraki Prefectural University of Health Sciences
School of Health Sciences, Faculty of Medicine, Kanazawa University

Abstract
About 50 types of amino acid transporter genes have been reported in mammals. Among these transporters, LAT1 (SLC7A5),
LAT3 (SLC43A1), ASCT2 (SLC1A5), ATB0,+ (SLC6A14) and xCT (SLC7A11) are reported as the upregulation-dependenttransporter isoforms in tumors. In the current molecular imaging era, particularly over the past decade, the development ofradiolabeled molecular imaging agents for amino acid transport in tumors using natural/non-natural amino acids based on gene
information and biotechnology is an emerging trend. Promising molecular probes for the post-FDG are 18F-3-iodo-α-methylL-tyrosine, O-(2-18F-fluoroethyl)-L-tyrosine, and 18F-anti-1-amino-3-fluorocyclobutane-1-carboxylic acid. Furthermore,development of immunoPET/SPECT agents for imaging every specific amino acid transporter is anticipated as a new strategy.
This review focuses on membrane transporters belonging to the solute carrier (SLC) superfamily, which is responsible foramino acid transport activity in tumor imaging and radioactive tumor imaging agents.
Key words: amino acid transporter, Post-FDG, solute carrier, tumor

tumor cells gradually became clarified as an imaging

1. Introduction

target. The development of tumor radiopharmaceuticals
In the 1990s, the genes of various transporters werewith radiolabeled amino acid compounds using genecloned, thus rapidly advancing the clarification of

information and biotechnology is a new trend in theexpression, structure and function of those transporters.1) It

current molecular imaging era.

is known that some types of amino acid transport systems

Table shows the classification of solute carrier

The reason behind this istransporter (SLC) transporter superfamily and ATP-attributed to the fact that tumor cells require amino acids

binding cassette transporter (ABC) transporter superfamily

as nutrition blocks for active proliferation.

by Human Genome Organization (HUGO). This review

are upregulated in tumor cells.

2-4)

Our previous report demonstrated the selectivity offocuses on membrane transporters of the SLC superfamily

radiolabeled artificial amino acid accumulation via an

responsible for amino acid transport activity in tumor cells

upregulated transporter isoform in tumors using Xenopus

and the radioactive molecular imaging agents involving

leavis oocytes expressing isoforms of neutral amino acidthem.

transporters.

5,6)

The upregulated transporter isoforms in

Address: Naoto Shikano. Department of Radiological Sciences, Ibaraki Prefectural University of Health Sciences, 4669-2 Ami, Ami-machi,
Inashiki-gun, Ibaraki 300-0394, Japan
Phone: +81-29-840-2217, Fax: +81-29-840-2317, E-mail address: sikano@ipu.ac.jp

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第 25 巻

Table. HUGO (Human Genome Organization) transporter families.
I. SLC (Solute carrier transporter) transporter super-family *There are more than 60 families and more than 300 molecular species.
Amino acid transporters (neutral amino acid transporters: system A, system ASC, system L, etc., acidic amino acid transporters,
basic amino acid transporters): Solute Carrier family 2, 7, 17, 23 and43.
II. ABC (ATP-binding cassette transporter) transporter super-family#
Transporters that use adenosine triphosphate (ATP) as the driving force for mass transport. Currently, 7 families and 49 molecularspecies have been identified.
ABCA: ABC I family
ABCC: MDR/TAP family
ABCD: ALD family
ABCE: OABP family
ABCF: GCN20 family
ABCG: WHITE family
See a home page of HUGO Gene Nomenclature Committee at the European Bioinformatics Institute*: https://www.genenames.org/cgi-bin/genefamilies/set/752#: https://www.ncbi.nlm.nih.gov/books/NBK3/table/A145/

2. Amino acid transport
2.1 Amino acid metabolic pathways.
In addition to sugars and lipids, amino acids are very
important cellular nutrition sources.7) Figure 1 is a scheme
showing amino acid metabolic pathways and the synthetic
precursors of important substances such as proteins andneurotransmitters (biogenic amines). It is known that large
amounts of amino acids accumulate in cells with active
proliferation and metabolic processes via membranetransport systems.8) Moreover, amino acid transporters
and their substrates interact with the mammalian target

Fig. 1. Scheme showing amino acid metabolic pathways.
1. Membrane transport, 2. Free amino acid pool, 3. Protein
synthesis, 4. Biogenic amine synthesis, 5. Energy-producing
metabolism, and 6. Catabolism.

of rapamycin pathway, which regulates protein synthesis
and cell proliferation.9)
Radiolabeled amino acids have the potential to be
used not only for amino acid transport imaging, but also

importance as the first step in elucidating the underlying
metabolic and signaling pathways.

for imaging various amino acid metabolic pathways.
For example, L-[2-18F]fluorotyrosine (2-18F-Tyr) was

2.2 Amino acid transport systems.

evaluated as a tracer of cerebral protein synthesis for

Amino acid transport across the plasma membrane

positron emission computed tomography (PET) by

is mediated via amino acid transporters localized in the

Coenen HH et al..10) The authors reported that 2-18F-Tyr isplasma membrane.12) Since the 1960s, studies on amino

a promising tracer for quantification of protein synthesis

acid transporters have been performed with cell lines orrates with PET.10) Hustinx R et al. evaluated the ability

tissues, using natural and artificial amino acids that inhibitof PET with 2- F-Tyr to visualize cancer lesions in

specific aspects of amino acid transport in the so-called

patients.

“amino acid transport system”.13,14)

18

11)

Amino acid transport imaging for tumor diagnosis is one

Amino acids are classified into neutral amino acids,of the clinical applications, in addition to its fundamental

acidic amino acids and basic amino acids. For neutral

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Amino acid imaging agents for tumorsamino acid transport, according to the classification

Gene Nomenclature Committee (http://ghr.nlm.nih.gov/

as neutral amino acid transport systems, the three main

geneFamily/slc). Genes encoding amino acid transporterstransport systems are system A, ASC and L. System A

belong to the SLC1, SLC3, SLC6 and SLC7 families. Of(alanine preferring: specific inhibitor is N-methylated-α-

these, neutral amino acid transporters belong to the SLC1aminoisobutyrate (MeAIB)) and system ASC (alanine,and SLC3 families. Among these transporters, LAT1

serine and cysteine preferring: specific inhibitor is not(SLC7A5),16) LAT3 (SLC43A1),17) ASCT2 (SLC1A5),18)

known) are Na+-dependent systems that transport amino

ATB0,+ (SLC6A14)19) and xCT (SLC7A11)20) are reported

acids with relatively small residues. System L (leucine

as the upregulation-dependent transporter isoforms

preferring: specific inhibitor is 2-aminobicyclo[2.2.1]heptin tumors. Figure 3 shows the mechanisms and mainane-2-carboxylic acid (BCH)) is a Na -independent system

substrates of those important transporter isoforms.

+

that transports amino acids with bulky and relatively large
residues.14) Among the amino acid transport systems

2.3.1 System L1: L-type amino acid transporter 1

described, system L is a major route for providing cells(SLC7A5).

with large neutral amino acids including branched or
aromatic amino acids.1,13)

In 1998, Kanai et al. isolated a cDNA encoding a
Na+-independent transporter, subserving the amino acid

Previously, we examined amino acid transport system
L selectivity of C(U)-L-tyrosine ( C-Tyr),transport system L by expression cloning from C6 rat

I-4-iodo-L-

glioma cells.16) The authors examined the function of themeta-tyrosine (4-125I-mTyr), 125I-6-iodo-L-meta-tyrosine

human isoform and its expression in human tissues and(6- I-mTyr),I-3-iodo-α-methyl-L-tyrosine ( I-IMT)

tumor cell lines.21) L-type amino acid transporter 1 (LAT1)

I-3-iodo-L-tyrosine (3-125I-Tyr) using Chinese

preferentially transports large neutral amino acids such as

hamster ovary cells (CHO-K1)15) and Xenopus oocytes.

Leu, Ile, Val, Phe, Tyr, Trp, Met and His.16) LAT1 is a

We reported that 125I-4-iodo-L-meta-tyrosine exhibited the

12-segment transmembrane protein that shares about 30%

greatest system L specificity (93.46 ± 0.13%) of five tested

homology with the cationic amino acid transporter (CAT)amino acids, and it could be used as a system L-specificsubfamily. This protein expresses its function by forming

I-labeled system L imaging probe for single photona heterodimer with a single transmembrane protein called

14

125

and

123

14

125

125

125

125

emission computed tomography (SPECT) (Figure 2).

4F2hc.16, 21)

2.3 Important amino acid transporters in tumor cells.
There are two superfamilies of transporter proteins,
SLC and the ATP-binding cassette (ABC) transporters.
Molecular cloning technology has revealed about 50 typesof mammalian amino acid transporters, reflecting aminoacid structural divergence. At present, the SLC genes areclassified into various families, from SLC1 to SLC52,
according to the standards established by the Human

Fig. 2. Tyrosine and iodinated tyrosine analogues as candidate
compounds for system L-specific imaging agents.

Fig. 3. Schematic depiction of important amino acid transporter
isoforms in tumor imaging. Amino acid substrates are shownin one-letter code. The sodium ion gradient is maintained by
the Na-K-ATPase. The system L1 and ASCT2 transporters areamino acid exchangers. ASCT2 co-transports one sodium ion
into the cell, while one amino acid is removed from the cell.
ATB0,+ is a Na+/Cl--coupled co-transporter. LAT3 is a Na+/Cl-independent transporter.

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茨城県立医療大学紀要

Segawa et al. isolated L-type amino acid transporter

第 25 巻Bodoy S et al. reported that L-type amino acid22)

2 (LAT2) cDNA in 1999 from rat small intestine.

transporter 4 (LAT4) as well as LAT3, is Na+, Cl- and pH-

The encoded protein demonstrates amino acid sequence

independent, and is not trans-stimulated.24) LAT4 activity

homology to the system L transporter LAT1 (50%

is detected at the basolateral membrane of proximal

identity). LAT2-mediated transport is not dependent on

convoluted tubule (PCT) kidney cells. In situ hybridization

Na+ or Cl- and is inhibited by a system L-specific inhibitor

experiments show that LAT4 mRNA is restricted to theBCH.22)epithelial cells of the distal tubule and the collecting duct

Among the two isoforms belonging to the system L1

in the kidney. In the intestine, LAT4 is mainly present infamily, LAT2 is expressed in normal tissues including

the cells of the crypt. Human LAT4 exhibits 57% identity

kidney and intestine, whereas LAT1 is expressed in many

to human LAT3.

types of tumors as well as in normal tissues. LAT1 should

In the system L2 family, LAT4 is expressed in normal

be considered as a promising target of molecular imaging

tissues, and LAT3 is expressed in some types of tumors.

agents for amino acid transport in tumor cells, because

However, a LAT3-specific imaging probe has not been

LAT1 is over expressed in higher almost kind of tumor

reported yet.

than normal tissue.
Recently, transporter isoform selectivity of imaging

2.3.3 System xc-: xCT (SLC7A11).

probes has been reported. Shikano N et al. examined theSato H et al. has isolated cDNA encoding the transporter

125

isoform selectivity of 3- I-Iodo-α-methyl-L-tyrosine

for system xc- from mouse activated macrophages by(125I-IMT) transport of the two human L-type amino

expression in Xenopus oocytes.20) Transport system xc-

acid transporters, hLAT1 and hLAT2, with humanfound in the plasma membrane of cultured mammalian

4F2hc-coexpressed Xenopus oocytes. Of the two hLAT

cells is an exchanger for anionic amino acids with highisoforms and h4F2hc-coexpressed Xenopus oocytes, 125I-

specificity for anionic forms of cystine and glutamate. The

IMT uptake via hLAT1 was 5.95-fold higher than that

expression of system xc- activity in oocytes requires two

via hLAT2 (P < 0.005). 125I-IMT transport was hLAT1-

cDNA transcripts, and the sequence analysis revealed that

selective. Investigations on the isoform selectivity of125

one is identical to 4F2hc and the other is a novel protein

23)

of 502 amino acids with 12 putative transmembraneI-

IMT transport with other transporters are anticipated.

domains. Northern blot analysis demonstrated that the
2.3.2 System L2: L-type amino acid transporter 3

expression of both 4F2hc and xCT was enhanced in(SLC43A1).

stimulated macrophages and tumor cells. This transporter

In 2003, a cDNA that encodes a novel Na+-independentis regulated by intracellular reduced glutathione (GSH)

neutral amino acid transporter designated L-type aminolevels in humans. GSH functions as a radical scavenger.

acid transporter 3 (LAT3) was isolated from FLC4

The expression of system xc- is also highly regulated

human hepatocarcinoma cells by expression cloning.17)

in many types of cell lines. These features suggest that

When expressed in Xenopus oocytes, LAT3 transported

xCT could be a potential target in tumor imaging. Baek

neutral amino acids such as Leu, Ile, Val, and Phe. In

S et al. reported that (4S)-4-(3-18F-fluoropropyl)-l-

addition to amino acid substrates, LAT3 recognizedglutamate (18F-FSPG, or BAY 94-9392) is a new tracer

amino acid alcohols. The LAT3-mediated transport

for assessing system xc- transporter activity with PET.

was Na+-independent and inhibited by BCH, consistent

The authors investigated the tumor detection rate of 18F-

with the properties of system L. Distinct from system

FSPG, compared with that of 18F-FDG, in patients with

L1, which forms a heterodimeric complex with 4F2hc,

hepatocellular carcinoma (HCC).25)

LAT3 was functional by itself. The expression of LAT3
is upregulated in prostate cancer. LAT3 is a transporter
subserving system L2.

2.3.4 System ASC: ASCT2 (SLC1A5).
In 1996, ASCT2 was cloned and characterized as an Na+-

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dependent neutral amino acid transporter. It transports Ala,by nitric oxide synthase (iNOS) expression has been

Ser, Thr, Cys and Gln at high affinity (Km values aroundreported.27) Development of ATB0,+-specific labeled20 M), and it also transports Met, Leu, Gly, Val and Glu at

imaging probe is anticipated.

low affinity (Km = 1.6 mM).

18)

A cDNA was isolated frommouse testis. The encoded protein, designated ASCT2,
showed amino acid sequence similarity to ASCT1 (57%

3 Radiolabeled amino acid transport imaging

identity).22) L-Glu transport was enhanced upon lowering

agents in tumors

extracellular pH. Northern blot hybridization revealed
that ASCT2 was mainly expressed in the kidney, large

3.1 General aspects.

intestine, lung, skeletal muscle, testis, and adipose tissue.

The history of labeled amino acid as the imaging

ASCT2 (SLC1A5), as well as LAT1, is a transporter

agent is long. Development of radiopharmaceuticals forthat is ubiquitously expressed in tumor cells.

SPECT has been ongoing since the 1960s.28) A compound

Ploessl K et al. reported the preparation and comparative

for SPECT,

Se-selenomethionine, was originally75

evaluation of 18F-labeled (2S,4R)-4-fluoro-l-glutamine

successfully developed as a labeled amino acid for SPECT(4F-GLN) and 18F-labeled (2S,4R)-4-fluoro-l-glutamate

analysis in the clinical setting.29) However, its development(4F-GLU) as tumor metabolic imaging agents. 4F-GLN

was later abandoned because its physical properties were

has demonstrated high uptake in tumor cells undergoingfound to be unsuitable for clinical nuclear medicine.

high growth and proliferation. Similar tumor targeting

Many types of 131I or 123I-labeled compounds have been

properties have also been observed for 4F-GLU, suggesting

investigated for application in SPECT analysis, due to theirthat both are useful imaging agents. Amino acid transport

relative ease of use and the long half-life of isotope 125I

system ASC in particular, its subtype ASCT2 gene, andobserved in laboratory experimental settings. Regarding

system xc- played an important role in transporting 4F-

chemical properties, the tyrosine phenyl group is readily

GLN and 4F-GLU, respectively, across the membrane.26)

iodinated by oxidants including chloramine-T.30)
Kawai K and colleagues synthesized and evaluated

2.3.5 System B : ATB
0,+

Human ATB

0,+

0,+

(SLC6A14).

radioiodinated tyrosine analogues as membrane amino

is the first cloned B0,+amino acidtransporter discovered by Sloan JL et al. in 1999.19)

acid transport imaging agents for the brain,29-34) the
pancreas,35,36) the kidney37-41) and tumors42-44).

The authors reported that human ATB0,+ (hATB0,+) was

On the other hand, positron emitters of 11C, 13N, 15O

a member of the Na+/Cl--dependent neurotransmitter(biological elements) and 18F (substitutable OH or H

transporter family with the highest sequence similarity togroup) are used for labeling of radiopharmaceuticals forthe glycine and proline transporters. Tissue survey suggests

positron emission computed tomography (PET). There

expression in the lung, trachea, salivary gland, mammary

are two types of labeled amino acids - radioactive natural

gland, stomach, and pituitary gland. Electrophysiology

amino acids and radioactive non-natural amino acids. The

and radiolabeled amino acid uptake measurements wereuse of elements such as radioactive carbon, nitrogen, andused to functionally characterize the transporter expressed

oxygen allows labeling without the change of chemicalin Xenopus oocytes. hATB

was found to transport both

structure of natural amino acids, conferring an advantage

neutral amino acids (e.g. Leu, Ilu, Met) and cationicfor protein synthesis activity imaging. However, theamino acids (e.g. Arg, Lys), with the highest affinity for

half-lives of 11C, 13N and 15O (20 min, 10 min and 2 min,hydrophobic amino acids, moderate affinity for Phe, Tyr,

respectively) are very short, making the process of nuclear

Gly, Ala, Gln and the lowest affinity for Pro. Amino acidreaction, labeling, and application as radiopharmaceuticals

transport was Na and Cl -dependent and was attenuated infor patient data acquisition challenging. On the otherthe presence of BCH, a system B inhibitor. In colorectal

hand, the use of the relatively longer half-life of 18F (110and cervical tumor tissues, upregulation accompaniedmin) enables the transportation and commercial delivery

0,+

+

-

0,+

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茨城県立医療大学紀要

第 25 巻of radiopharmaceuticals and 18F-2-fluoro-2-deoxyglucose

transporters in normal and tumor tissues may be a

(FDG) to hospitals with PET cameras. Therefore, thepromising strategy for molecular design of tumor imaging

delivery of F-labeled compounds and their use in clinicalagents.

18

practice is of great importance.
When radioactive natural amino acids are injected into

3.2 Promising molecular probes for the post-FDG.

patients, a variety of radioactive metabolites are generated

To date, more than 25 types of 18F-labeled amino acids

within several minutes. Thus, the analysis of biodistribution

have been synthesized and evaluated. We here focus onof the metabolized radioactivity is challenging. For

some of these promising compounds.

example, a natural amino acid [S-methyl- C]-L-Met
11

is mostly mediated by system L transporters,

Many tyrosine analogues have been tested because

but thethey have a phenyl group that can be easily labeled withradiolabeled S-methyl group is transferred to a different

radioactive halogen. Among the developed tyrosine

molecule in a cell, and the distribution of radioactivity

analogues, 123I-3-iodo-α-methyl-L-tyrosine (123I-IAMT)

reflects not only protein synthesis but also other metabolichas demonstrated considerable in vivo stability andprocesses. Protein synthesis is one of the targets in the

excellent properties as an amino acid transport imaging

development of these radiolabeled amino acids. But

agent for SPECT by Stöcklin G, Jager PL, Coenen HH

aminoacyl-tRNA synthetase recognize specific neutral

and Langen K-J et al..50) Fluorinated analogue, 18F-

amino acid structure rigidly. Aminoacyl-tRNA synthetase

3-iodo-α-methyl-L-tyrosine (18F-L-FAMT) was also

links an amino acid with the appropriate tRNA, thereby

developed for PET study by Inoue T et al. (Figure 4).51)

forming a specific neutral amino acid binding aminoacyl-

The physiological accumulation of 18F-L-FAMT is lower

tRNA structure. The incorporation of radiolabeled amino

than that of 18F-FDG in the brain, heart, liver, and muscle.

acids without a natural amino acid structure into protein

Brain tumor image is superior to that of 18F-FDG withis very rare, and the accumulation is mostly attributed

high contrast to tumor/normal brain tissue. 18F-L-FAMT

to amino acid transport activity. For radioactive tumor

has superior property in diagnosis of malignant tumors inimaging agents targeting amino acid transporter activity,

the above-mentioned organs. 18F-L-FAMT was clinically

non-metabolizable artificial amino acids that accumulate

tested and reported in many papers by Kaira K et al..52)

in tumors by simple pharmacokinetics are preferable to

D-isomer, 18F-D-FAMT, is also reported.53)

45)

natural amino acids that generate many types of radioactive
metabolites.

Jager PL and Langen KJ et al. reported the utility of O(2-18F-fluoroethyl)-L-tyrosine (18F-FET). This agent has

At the beginning of the 1960s, non-natural amino acids,

favorable properties for brain tumor and head/neck tumor

2-aminoisobutyric acid (AIB), α-aminocyclobutane-

diagnosis, because it accumulates in the kidneys and the

1-carboxylic acid (ACBC), α-aminocyclopentane-1-

brain, and has a lower activity than that of 18F-L-FAMT

carboxylic acid (ACPC) and BCH were developed. BCH

or 123I-IAMT. Generally, tyrosine analogues have highis a system L-specific substrate in Na+-free conditions.

urinary excretion, and are not suitable for the diagnosis in

In the 1970s, these C-labeled non-natural amino acids

the kidney and urinary tract region. 18F-FET is a substratewith α-carboxyl groups were investigated for use in PET.

of system L transporters, and partly accumulates in

AIB , ACBC

tumor cells via system ASC and A transporters. It is not

11

46)

47)

and ACPC48)

are transported into cells

via membrane transport, are metabolically stable, and doincorporated into protein.

not have affinity to protein incorporation processes.
Furthermore, 11C-MeAIB, a system A-specific inhibitor
N-methylated-α-aminoisobutyrate (MeAIB) labeled withC, was synthesized and clinically evaluated.49)

11

Investigation of the qualitative and quantitative
differences in expression of important amino acid

Fig. 4. Fluorine-labeled tyrosine derivatives.

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F-1-amino-3-fluorocyclobutane-1-carboxylic

acid

and thus new strategies are required for imaging LAT1

( F-FACBC) (Figure 5) with high tumor selectivity toprotein localization in systemic cancers. We recently

normal tissues in a C-labeled ACBC study was developed

attempted to develop immunoSPECT agents with thisThe anti-isomer of F-FACBC

type of strategy, but targeting the extracellular domain of(18F-anti-FACBC: 18F-anti-1-amino-3-fluorocyclobutane-

LAT1 was challenging because a proper antibody cannot

1-carboxylic acid) has higher specificity for tumor tissue

be obtained. Ikotun OF et al. described the first report ofthan the cis-isomer. Because of its higher accumulation

this kind of direct PET imaging of LAT1 and demonstrated

selectivity in tumor tissues and a lower accumulation in

the potential of immunoPET agents for imaging specificphysiologically normal organs, such as the brain, muscles,amino acid transporters.56) The authors developed aheart, liver and urinary excretion via the kidney than thosenovel zirconium-89-labeled antibody,of FDG, F-anti-FACBC is thought to be one of the mostand biologically evaluated the specificity for LAT1 inpromising probes as a post-FDG radiopharmaceutical

vitro and in vivo with excellent tumor imaging properties

in the abdominal, prostate and brain tumor PET study.

in mice using a model of colorectal cancer. This tracer

Due to its numerous superior properties, compared toshowed high tumor uptake and optimal tumor/normal

FDG, 18F-anti-FACBC is expected to be used as a post-

tissue contrast was achieved at 7 days post administration.

FDG radiopharmaceutical especially in the diagnosis of

There are still challenges to overcome in the application

glioblastoma, which can be detected by F-FACBC withof immunoagents for imaging, including accumulation inbetter image. Transport ofF-anti-FACBC originally

the normal liver, spleen, kidney and blood, as a generalconsidered to be mediated by system L has been shown toproperty of antibodies. Development of functional imaging

54)

be mainly mediated by system ASC in prostate cancer.

of transporter activity with radiolabeled substrates and

The AIB-induced 18F-labeled compounds, 3-fluoro-transporter protein expression imaging with radiolabeled

2-amino-2-methyl-propionic acid (FAMP), 4-fluoro-2-

antibodies will provide additional information aboutamino-2-methyl-butyric acid (FAMB) and N-methyl-3-

tumors.

18
18

11

by Goodman’s group.

54)

18

18

18

18

Zr-DFO-Ab2

89

fluoro-2-amino-2-methyl-propionic acid (N-MeFAMP)

Therefore, we can make a decision of the way,considered to be the substrates of system A and systemdepending on intending imaging, amino acid transporter

ASC transporters are reported (Figure 6).

function using of radio-labelled substrates or expression

Additionally, we synthesized and evaluated non-naturalusing an immuno PET/SPECT agents. Using of radio-

55)

labelled substrates of a kind of amino acid transporter

Metabolic fate and biodistribution of those compounds

cannot always image the specific amino acid transporter

sulfur-containing amino acids for SPECT (Figure 7).
remain unclear.

3.3 ImmunoPET/SPECT agents for imaging specificamino acid transporters.
Radiolabeled amino acids that are transport substrates
for system L amino acid transporters including LAT1 have
met limited success because of the imperfect selectivity,

Fig. 5. Fluorine-labeled non-natural amino acids with saturated
cyclic alkyl residues.

Fig. 6. Fluorine-labeled α-methylated non-natural amino acids
and a N-Me-derivative.

Fig. 7. Fluorine-labeled sulfur-incorporated non-natural aminoacids.

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茨城県立医療大学紀要

第 25 巻

because there are so many cases that those substrates
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和文抄録
哺乳類では約 50 種類のアミノ酸トランスポーター遺伝子が報告されている。これらのトランスポーターのうち，LAT1（SLC7A5），LAT3（SLC43A1），ASCT2（SLC1A5），ATB 0, +（SLC6A14） および xCT（SLC7A11）は，腫瘍で発現亢進するトランスポーターアイソフォームとして報告されている。最近の分子イメージングの時代において，遺伝子情報とバイオテクノロジーを用いた天然 / 非天然アミノ酸による腫瘍のアミノ酸輸送のための放射性標識分子イメージング剤の開発が，特に過去 10 年間で新しいトレンドになりつつある。 Post-FDG の有望な分子プローブは，18F-3-iodo-alpha-metyl-L-tyrosine, O-（2-18F-fluoroethyl）-L-tyrosine, and 18F-anti-1-amino-3-fluorocyclobutane-1-carboxylic acid である。さらに，すべての特定のアミノ酸トランスポーターをイメージングするための immunoPET / SPECT 薬剤の開発が新しい戦略として期待されている。この総説では，腫瘍イメージングと放射性腫瘍イメージング剤のアミノ酸輸送活性に関わる
solute carrier（SLC）に属するトランスポーターに焦点を当てて解説する。

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