Available online at www.sciencedirect.com

Nuclear Medicine and Biology 34 (2007) 1003 – 1008
www.elsevier.com/locate/nucmedbio

Pharmacokinetics of 3-[ 125 I]iodo-α-methyl-L-tyrosine,
a tumor imaging agent, after probenecid loading inmice implanted with colon cancer DLD-1 cells
Syuichi Nakajima a,b , Naoto Shikano a,⁎, Takashi Kotani a , Masato Ogura a , Ryuichi Nishii c ,Mitsuyoshi Yoshimoto b , Naoto Yamaguchi d , Yukio Iwamura e , Nobuo Kubota a ,Nobuyoshi Ishikawa a , Keiichi Kawai baDepartment of Radiological Sciences, Ibaraki Prefectural University of Health Sciences, 4669-2 Ami, Ami-machi, Inashiki-gun, Ibaraki 300-0394, Japanb
Division of Health Science, Graduate School of Health Sciences, Kanazawa University, 5-11-80 Kodatsuno, Kanazawa, Ishikawa 9200-942, Japanc
Research Institute, Shiga Medical Center, 5-4-30 Moriyama, Moriyama-City, Shiga 524-8524, JapandCenter for Medical Sciences, Ibaraki Prefectural University of Health Sciences, 4669-2 Ami, Ami-machi, Inashiki-gun, Ibaraki 300-0394, Japane
Center for Humanities and Sciences, Ibaraki Prefectural University of Health Sciences, 4669-2 Ami, Ami-machi, Inashiki-gun, Ibaraki 300-0394, Japan
Received 25 June 2007; accepted 28 June 2007

Abstract
Introduction: In order to improve tumor imaging, changes in the pharmacokinetics of 3-[123I]iodo-α-methyl-L-tyrosine ([123I]IMT), an
artificial amino acid that exhibits high tumor accumulation, after probenecid (PBC) loading was studied in mice implanted with colon cancer
DLD-1 cells using 125I-labeled IMT ([125I]IMT).
Methods: DLD-1-implanted KSN-slc nude male mice received 740 kBq of [125I]IMT via the tail vein at 5 min after 50 mg/kg body weight
PBC loading, and autoradiography was performed at 5, 15 and 30 min after injection. Male ddY mice then received 670 kBq of [125I]IMT
and 50 mg/kg 2-amino-bicyclo[2,2,1]heptane-2-carboxylic acid (BCH) or p-aminohippurate (PAH) via the tail vein, and kidneyautoradiography was performed at 5 min after injection. In vitro inhibition study was then performed based on the accumulation mechanismsof [125I]IMT in DLD-1, using 1 mM L-tyrosine, BCH, α-(methylamino)-isobutyric acid, N-benzoyl-β-alanine, PBC, PAH, 2,4-dinitrophenol
and sodium azide. Both Na+-dependent and Na+-independent uptake were investigated.
Results: Higher tumor accumulation in PBC-loaded DLD-1-implanted mice was seen when compared to control mice. PAH and BCH,
respectively, reduced renal accumulation in the tubule segment-2 (S2)-like and S1-like regions. We confirmed that [125I]IMT transport ispredominantly mediated by L-type amino acid transporter-1 in DLD-1 cells.
Conclusions: [125I]IMT uptake is mediated by organic anion and amino acid transporters in the kidney. Organic anion transporter inhibitors
may yield better tumor images with good tumor/normal tissue radioactivity ratios if adequate administration plans are developed.
© 2007 Elsevier Inc. All rights reserved.
Keywords: Abdominal tumor imaging; Amino acid transport; Colon cancer cell line; DLD-1; 3-Iodo-α-methyl-L-tyrosine; Organic anion transport inhibitor

1. Introduction
The search for strategies to improve amino acid imaging
may facilitate further research into oncology tracers. Since
the 1970s, the artificial amino acid 3-[123I]iodo-α-methyl-Ltyrosine ([123I]IMT) has been successfully used in single-⁎ Corresponding author. Tel.: +81 29 840 2217; fax: +81 29 840 2317.
E-mail address: sikano@ipu.ac.jp (N. Shikano).
0969-8051/$ – see front matter © 2007 Elsevier Inc. All rights reserved.
doi:10.1016/j.nucmedbio.2007.06.017

photon emission computed tomography (SPECT) imaging of
brain tumors [1–4]. Recent studies indicate that 125I-labeled
IMT ([ 12 5 I]IMT), a substrate of L -type amino acidtransporter-1 (LAT1; component of amino acid transportsystem L) [5], is one of the most promising radiopharmaceuticals for use as a tumor imaging agent in SPECT,
because LAT1 is expressed in numerous tumor tissues athigher levels than in normal tissues [6]. However, relatively
few studies have investigated extracranial tumors with [123I]
IMT, as high physiological [123I]IMT accumulation is

1004

S. Nakajima et al. / Nuclear Medicine and Biology 34 (2007) 1003–1008

observed in the kidney, and this has been an obstacle forabdominal tumor imaging with good tumor/normal tissue
radioactivity ratios. Several α-methylated tyrosine analogues, such as [123 I]IMT and 3-[18F]fluoro-α-methyl-Ltyrosine ([18F]FMT), also exhibit high accumulation in therenal cortex [7]. We recently proposed that α-methylated
tyrosine analogues possess a higher affinity for accumulative
renal organic anion secretion systems than non-α-methylated
tyrosine analogues [8]. Thus, we hoped that organic aniontransporter (OAT) inhibitors could improve abdominal tumor
imaging via inhibition of accumulative secretion of [125I]
IMT in proximal tubules, as OATs are thought to mediate theaccumulative renal elimination of [125I]IMT via proximal
tubule segment-2 (S2) [9,10].
Using in vivo autoradiography, we studied the changes
in [125I]IMT pharmacokinetics by administration of probenecid (PBC, an organic anion secretion inhibitor in thekidney) [11] in DLD-1 (colon cancer cell line)-implanted
male nude mice (KSN-slc). To clarify the renal transport of[125I]IMT, renal autoradiography of normal male ddY micetreated with specific system L inhibitors or specific OAT
inhibitors was conducted. Furthermore, in vitro inhibition
tests into the accumulation mechanisms of [125I]IMT in
DLD-1 were conducted in order to confirm the roles ofamino acid transporter(s).
Based on the results of in vivo whole-body autoradiography in DLD-1-implanted mice administered [125I]IMTwith PBC loading, we also discuss the effects of PBC
loading on target tumor tissue (DLD-1) and nontarget organs(particularly the kidney).
2. Materials and methods
Animal experiments were approved by the ethics
committee of Ibaraki Prefectural University of Health
Sciences. We used longer lived [125I]IMT rather than [123I]
IMT for convenience in this experiment.
2.1. Materials and preparation of [

125

I]IMT

L-Tyrosine (mother compound of [123

I]IMT), 2-aminobicyclo[2,2,1]heptane-2-carboxylic acid (BCH, specific system L inhibitor) [12], α-(methylamino)-isobutyric acid
(MeAIB, specific system A inhibitor) [13], N-benzoyl-βalanine (BBA, OAT inhibitor) [14], PBC, p-aminohippurate(PAH, specific OAT inhibitor) [15], 2,4-dinitrophenol (DNP,
inhibitor of anaerobic mitochondrial energy production)[16, 17], sodium azide (NaN3, inhibitor of aerobic energy
production) [17], α-methyl-L-tyrosine and chloramine-T wereacquired from Sigma-Aldrich Japan K.K. (Tokyo, Japan).
[125I]NaI (629 GBq/mg) was obtained from American
Radiolabeled Chemicals Inc. (St. Louis, MO, USA). NovaPak C-18 (3.9×300 mm; Waters, Milford, MA, USA) wasused for separation and rectification. For cell line studies,
the human colorectal adenocarcinoma cell line DLD-1
was obtained from the Japanese Collection of Research

Bioresources (Tokyo, Japan; catalog number JCRB9094).
Plastic tissue culture dishes (diameter, 60 mm; Nalge Nunc
International, Roskilde, Denmark) and plastic flasks (surface
area, 25 cm2; Nalge Nunc International) were used. Nocarrier-added [125I]IMT was prepared using the conventional
chloramine-T method, as described elsewhere [5].
2.2. Cell cultures
DLD-1 cells were maintained in Dulbecco's modified
Eagle's medium (Sigma-Aldrich Japan) supplemented with
L-glutamine (2 mM) and 10% fetal bovine serum without
antibiotics, in an atmosphere of 10% CO2 and 90% air at
37°C (pH 7.4). Subculturing was performed every 4 days
using 0.02% EDTA and 0.05% trypsin. Approximately
5×105 cells per dish were replanted in plastic tissue culture
dishes (diameter, 60 mm; Nalge Nunc International) 4 days
after experimental use.
2.3. In vivo whole-body autoradiography in
DLD-1-implanted mice administered [125 I]IMT with
PBC loading
At 7 to 10 days after implantation of 3×106 cells per
mouse, DLD-1-implanted male KSN-slc mice (n=6; weight,
20 g; age, 6 weeks) received 0.1 ml of [125I]IMT (740 kBq)
and 50 mg/kg of PBC by injection into the tail vein 5 minprior to [125 I]IMT injection. Mice were sacrificed byinspiration of excess ether at 5, 15 and 30 min after [125I]
IMT injection, placed in carboxymethyl cellulose embedding
medium (Nacalai, Kyoto, Japan) and frozen at −15°C for atleast 12 h.
An Autocryotome CM3050 S (Leica, Tokyo, Japan) wasused to cut 20-μm sagittal sections. Sections were then driedat −5°C for a further 24 h. Tissue slices were kept in contact
with BAS-SR2040 imaging plates (Fuji Photo Film,
Kanagawa, Japan) for 6 h. Images were processed using a
BAS 2500 Bio-Imaging Analyzer (Fuji Photo Film) [9].
2.4. In vivo renal autoradiography in normal mice with
BCH or PAH loading
For renal autoradiography, 0.1 ml of [125I]IMT (670 kBq)
was injected into the tail veins of normal male ddY mice
(n=3, weight, 25 g) administered 20 mg/kg body weight
BCH (simultaneous injection with [125I]IMT) or PAH (5 minprior to [125I]IMT injection) as an inhibitor. Five minutes
after [125I]IMT injection, mice were sacrificed by inspirationof excess ether. Kidneys were placed in carboxymethyl
cellulose embedding medium (Nacalai) and frozen at −15°C
for at least 12 h [8].
2.5. In vitro inhibition study with DLD-1 cells
For the time course study, after removal from culture
medium, cells were preincubated with 2 ml of incubation
medium for 10 min at 37°C, after which 2 ml of incubation
medium containing [125I]IMT (18.5 kBq) was added. Cells
were then incubated for a specified period (5, 10, 15 or

S. Nakajima et al. / Nuclear Medicine and Biology 34 (2007) 1003–1008

30 min) at 37°C. Uptake medium was removed by suction at
the end of the incubation period, and cells were rapidly
washed twice with 2 ml of ice-cold incubation medium. Cells
on the dishes were solubilized in 1.0 ml of 1 N NaOH, andthe radioactivity of each aliquot (100 μl) was counted using
an auto well counter (Aloka, Japan; ARC-380). Based on the
results of this time course study, 10 min was used for uptake
incubation in subsequent experiments.
Inhibition experiments were performed in sodiumcontaining uptake medium (NaCl, 137 mM; KCl, 3.7 mM;
Na2HPO4, 8.0 mM; KH2PO4, 1.5 mM; CaCl2 ·2H2O,
1.8 mM; MgCl·6H2O, 1 mM) and sodium-free uptake
medium. In the sodium-free experiment, NaCl and Na2HPO4
were replaced with the same concentrations of choline
chloride and K2HPO4. After 10-min preincubation in
sodium-containing medium or sodium-free medium, cells
were incubated for 10 min with uptake medium containing[125 I]IMT (18.5 kBq) with inhibitor in the same manner as in
the time course study. The following inhibitors were used at1005

a concentration of 1 mM in order to examine inhibition of[125I]IMT uptake; L-tyrosine, BCH, MeAIB, BBA, PBC,
PAH, DNP and NaN3.
2.6. Statistical analysis
Values obtained in each experiment are expressed asmeans±S.D. Statistical comparisons between groups were
performed using Student's t test.
3. Results
3.1. In vivo whole-body autoradiography in DLD-1implanted mice administered [125 I]IMT with PBC loading
Fig. 1A and B, respectively, shows a typical whole-bodyautoradiograph and relative [125 I]IMT accumulation inorgans and implanted tumors. The highest radioactivity
was seen in the kidneys, followed by the pancreas andimplanted tumor, in all mice. Tumor radioactivity ratios with

Fig. 1. Whole-body autoradiograph of DLD-1 (colon cancer cell line)-bearing KSN-slc male mice (left, without PBC loading, control; right, with PBC loading)(A). Relative accumulation in organs and implanted DLD-1 (B) at 5, 15, and 30 min after [125I]IMT administration. DLD-1 cells were implanted under the backskin of mice. The tumor/muscle ratios were about 5 for control mice and about 7 for PBC-loaded mice at 30 min after [125I]IMT injection. Photostimulated
luminescence (PSL) intensity of luminescence radiation when the imaging plate was scanned with the laser in a Fuji bioimaging analyzer. PSL per millimetersquared is proportional to becquerels per millimeter squared. The highest radioactivity was seen in the kidney, followed by the pancreas and implanted tumor.

1006

S. Nakajima et al. / Nuclear Medicine and Biology 34 (2007) 1003–1008

Fig. 2. Renal autoradiograph of normal male ddY mice administered BCH or
PAH at 5 min after [125I]IMT administration. BCH inhibits systems L, B0
and B0+ in the presence of sodium. PAH is an inhibitor of OATs.

PBC loading were 1.5-fold higher at 5 min and 2.8-foldhigher at 15 and 30 min when compared to control mice.
The tumor/muscle ratios were approximately 5 for control
mice and 6 to 7 for PBC-loaded mice at 30 min after[125I]IMT injection.
3.2. In vivo renal autoradiography in normal mice with
BCH or PAH loading
125[ I]IMT accumulated mainly in the renal cortex, but thiswas reduced by BCH loading in the S1-like region and by
PAH loading in the S2-like region of proximal tubule
segments (Fig. 2).
3.2.1. In vitro inhibition study with DLD-1 cells
Time course analysis of [125I]IMT uptake into DLD-1
cells revealed that steady-state levels were reached 10
min after the start of incubation, as shown in Fig. 3. Thus,
a 10-min incubation time was used for the inhibition study.
The results of the [125I]IMT uptake inhibition experiments are shown in Fig. 4. L-Tyrosine (mother compound of[123I]IMT) and BCH (specific system L inhibitor) significantly inhibited [125I]IMT uptake (Pb.01). BBA (OAT
inhibitor), PBC (OAT inhibitor), PAH (OAT specificFig. 3. Time course of [125I]IMT uptake into DLD-1 cells.

Fig. 4. Effects of inhibitors (1 mM) on uptake of [125I]IMT. Each column
represents the mean±S.D. of five plates of DLD-1 cells. *Pb.001 vs. control;**Pb.01 vs. control; ns, not significant vs. control.

inhibitor), DNP (inhibitor of anaerobic mitochondrial energy
production) and NaN3 (inhibitor of aerobic energy production) had little inhibitory effect on [125I]IMT uptake.
Replacing sodium with choline reduced [125I]IMT transport
into DLD-1 cells, but the effect was not significant.
Transport of [125I]IMT into DLD-1 cells was predominantly (71%) mediated by a Na+-independent system, with aminor contribution from a Na+-dependent system (Fig. 5). At
1 mM, the amino acids BCH (with and without sodium) and125
L-tyrosine inhibited accumulation of [I]IMT to similar
degrees (Pb.001). This suggests that system A and ASC or
another Na+-dependent system(s) may contribute to Na+dependent [125I]IMT transport. MeAIB (specific system A
inhibitor) also exhibited an inhibitory effect, but it was
not significant.

Fig. 5. Experimental determination of neutral amino acid transport systems
involved in [125I]IMT accumulation in DLD-1 cells. Each column represents
the mean±S.D. of five plates of DLD-1 cells. *Pb.001 vs. control; ns, notsignificant vs. control.

S. Nakajima et al. / Nuclear Medicine and Biology 34 (2007) 1003–1008

4. Discussion[123 I]IMT was first synthesized in the 1970s by Biersack
et al. [1]. It is a nonmetabolizable artificial amino acid thathas been used clinically for SPECT imaging of tumors by
Kuwert et al. [2], Jager et al. [3] and Langen et al. [4,18].
[123 I]IMT exhibits high tumor accumulation and rapid renalelimination [19].
It is known that renal physiological accumulation of [125I]
IMT is higher than that of radiolabeled L-tyrosine, its mothercompound [4]. We have also observed marked renal
accumulation and rapid urinary excretion of [125 I]IMT inmice [9]. As shown in Fig. 2, [125I]IMT accumulation was
primarily seen in the renal cortex. Clarification of theseaccumulation mechanisms could aid in developing methods
to reduce physiological accumulation, which obstructs
abdominal tumor imaging [9].
The kidney is an important nontarget organ for improving
obtained images. We examined [125 I]IMT distribution in thekidney by in vivo renal autoradiography in normal mice with
PAH loading. The reduced [125I]IMT accumulation by PAH
loading in the S2-distributed region (inner side of the kidneycortex) suggests that [125I]IMT is transported by OAT(s).
Other substrates of OATs (furosemide and ethacrynic acid)also inhibited the tubular secretion and kidney accumulationof [125I]IMT in mice [9].
We therefore tested whether OAT inhibitors (e.g., PAH,PBC and BBA) could improve abdominal tumor images by
inhibiting accumulative secretion or [125 I]IMT in proximal
tubules, as OATs are thought to mediate the accumulative
renal elimination of [123I]IMT via proximal S2. The wholebody autoradiographs and relative [125I]IMT accumulation
in some organs confirmed that PBC effectively inhibited
renal [125I]IMT elimination. The radioactivity ratio of thetumor with PBC loading was approximately threefold higher
at 15 and 30 min when compared to control mice. The tumor/
muscle ratios were approximately 5 for control mice and 6 to
7 for PBC-loaded mice at 30 min after [125I]IMT injection.
The present results suggest that organic anion inhibitors
can effectively reduce kidney accumulation without inhibiting [125I]IMT uptake into target DLD-1 cells provided
that an adequate administration plan is developed. In
the target tumor cells (DLD-1), there was little or no
significant inhibition of [125I]IMT uptake with PAH, PBC
or BBA (organic anion inhibitors) loading, while BCH and
L-tyrosine (amino acid system L inhibitors) significantly
inhibited [125I]IMT uptake. DNP and NaN3 (inhibitor ofenergy production) had no significant inhibitory effect on[125 I]IMT uptake. Transport of [125I]IMT into DLD-1 cells
was largely mediated by an energy- and Na+-independenttransport system (system L), with a minor contribution by a
Na+-dependent system (e.g., system A, ASC and/or otherunknown systems). Increased expression of system
L transporters has been observed in various tumors [6],and, using DNA chips, we confirmed LAT1 in DLD-1 (datanot shown).

1007
123

It has been reported that the majority of [ I]IMTtransport in tumor cells involves the Na+ -independent
system L, and that Na+-dependent transport systems makea relatively minor contribution [5]. We recently examined theisoform selectivity of [125I]IMT transport using two humanL-type amino acid transporters (components of system L),
LAT1 and LAT2, in Xenopus laevis oocytes coexpressing
human LAT1 and human 4F2hc; [125I]IMT transport was
found to be LAT1 specific. LAT1 is expressed in various
tumor tissues at higher levels than in normal tissues [5,20].
Lahoutte et al. [21] reported that system T also mediates[123I]IMT transport into U266 human myeloma cells.
Amino acid transport systems are involved in [125I]IMT
uptake in the kidney. Our recent in vivo study confirmed that
[125I]IMT uptake into normal human renal proximal tubule
epithelial cells was significantly inhibited by BCH in a Na+dependent manner, which suggests that [125I]IMT was
mainly reabsorbed via system B0 in the apical membraneof the proximal tubules [9]. As shown in Fig. 2, [125I]IMT
uptake into the renal proximal tubule S1-distributed region(outer side of the kidney cortex) was significantly inhibitedby BCH in a Na+-dependent manner, thus suggestingreabsorption via amino acid transport system B0 in theapical membrane of proximal tubules in vivo.
In the kidney, there was significant inhibition of [125 I]
IMT uptake into S2 with PAH and PBC loading. Metabolically stable [125I]IMT is derived from 3-iodo-L-tyrosine,
based on reports that α-methylation confers metabolicstability to L-tyrosine [22,23] and also to 3-iodo-L-tyrosine.
However, we recently proposed that α-methylated tyrosine
analogues possess a higher affinity for accumulative renalorganic anion secretion systems than non-α-methylated
tyrosine analogues, because α-methylated tyrosine analogues such as [125 I]IMT and [18F]FMT exhibit marked
accumulation in the renal cortex [7,8]. Some studies
have indicated that natural amino acid secretion andaccumulation in proximal tubule cells is blocked by OAT
inhibitors [24–26]. The cDNAs of six OAT isoforms havebeen cloned, and the molecular structures of thoseisoforms have been characterized [27]. There are two
structural differences between natural L-tyrosine and [125I]
IMT: α-methylation and iodination of the 3 position of the
L -tyrosine phenol group. These differences may be
responsible for the greater affinity of 125I]IMT for PBCsensitive secretion. L-Tyrosine accumulation in kidney ismoderate, in contrast to the high accumulation of IMT [28].
As described above, OAT inhibitors may have thepotential to yield better tumor images. These compounds
can presumably lead to prolonged and higher distribution of
tracer to the tumor. Although we observed reduced
accumulation in the renal cortex with PBC loading, thiswas insufficient. Improvements in dose and administration
methods are anticipated. Other clinically available substrates
of OATs (e.g., furosemide, ethacrynic acid and BBA) should
also be tested for inhibition of kidney and tumor accumulation of [125 I]IMT.

1008

S. Nakajima et al. / Nuclear Medicine and Biology 34 (2007) 1003–1008

5. Conclusions
We confirmed that [125 I]IMT transport is mediated by
OATs in the proximal tubule S2-like region of the kidney,
and by amino acid transport system L in DLD-1 cells.
Reduced renal [125I]IMT elimination by PBC loading led tohigher tumor accumulation (target tissue) when compared tocontrol conditions. We observed reduced accumulation in therenal cortex (nontarget tissue), but this was insufficient.
Further study should result in improvements in dose andadministration methods.
Acknowledgments
We wish to thank Natsumi Mibuka, Yuki Kitamura,
Yuzou Taguchi, Miho Aoyama, Hironobu Sakai, Misako
Nozaki, Yuko Fujisaku, Mariko Maruyama and Takayoshi
Miyakawa of Ibaraki Prefectural University for theirvaluable technical assistance. This work was supported by
Grants-in-Aid for Scientific Research (10770451, 14770498,
13557075, 15659283, 16659322 and 17390336) from
the Ministry of Education, Science, Sports and Cultureof Japan and the Japan Society for the Promotion of
Science. Financial support was also provided by the
Ibaraki Prefectural University Research Project (9808,
0118, 0220 and 0634) and Grants-in-Aid for the
Encouragement of Young Scientists from Ibaraki Prefectural University of Health Sciences in 2001, 2002, 2004,
2005 and 2006.
References[1] Biersack HJ, Coenen HH, Stöcklin G, Reichmann K, Bockisch A,
Oehr P, et al. Imaging of brain tumors with L-3-[I-123]iodo-α-methyl
tyrosine and SPECT. J Nucl Med 1989;30:110–2.
[2] Kuwert T, Woesler B, Morgenroth C, Lerch H, Schafers M, Palkovic S,
et al. Diagnosis of recurrent glioma with SPECT and iodine-123-αmethyl tyrosine. J Nucl Med 1998;39:23–7.
[3] Jager PL, Franssen EJ, Kool W, Szabo BG, Hoekstra HJ, Groen HJ,
et al. Feasibility of tumor imaging using L-3-[iodine-123]-iodoalpha-methyl-tyrosine in extracranial tumors. J Nucl Med 1998;39:
1736–43.
[4] Langen K-J, Pauleit D, Coenen HH. 3-[123I]Iodo-α-methyl-L-tyrosine:
uptake mechanisms and clinical applications. Nucl Med Biol 2002;29:625–31.
[5] Shikano N, Kanai Y, Kawai K, Ishikawa N, Endou H. Characterizationof 3-[125I]iodo-α-methyl-L-tyrosine transport via human L-type aminoacid transporter 1. Nucl Med Biol 2003;30:31–7.
[6] Yanagida O, Kanai Y, Chairoungdua A, Kim DK, Segawa H, Nii T,
et al. Human L-type amino acid transporter 1 (LAT1): characterizationof function and expression in tumor cell lines. Biochim Biophys Acta
2001;1514:291–302.
[7] Inoue T, Koyama K, Oriuchi N, Alyafei S, Yuan Z, Suzuki H, et al.
Detection of malignant tumors: whole-body PET with fluorine 18
alpha-methyl tyrosine versus FDG-preliminary study. Radiology 2001;
220:54–62.

[8] Shikano N, Kawai K, Flores II LG, Nishii R, Kubota N, Ishikaw N,
et al. An artificial amino acid 4-iodo-L-meta-tyrosine: biodistribution
and excretion via kidney. J Nucl Med 2003;44:625–31.
[9] Shikano N, Kawai K, Nakajima S, Nishii R, Flores II LG, Kubodera A,
et al. Renal accumulation and excretion of radioiodinated 3-iodoalpha-methyl-L-tyrosine. Ann Nucl Med 2004;18:263–70.
[10] Shikano N, Nakajima S, Kotani T, Itoh Y, Nishii R, Yoshimoto M, et al.
Detection of maleate-induced Fanconi syndrome by decreasing
accumulation of 125I-3-iodo-alpha-methyl-L-tyrosine in the proximal
tubule segment-1 region of renal cortex in mice: a trial of separate
evaluation of reabsorption. Ann Nucl Med 2006;20:175–81.
[11] Shikano N, Kanai Y, Kawai K, Ishikawa N, Endou H. Transport of
99cm
Tc-MAG3 via rat renal organic anion transporter 1. J Nucl Med
2004;45:80–5.
[12] Christensen HN. Role of amino acid transport and counter-transport innutrition and metabolism. Physiol Rev 1990;70:43–77.
[13] Palacin M, Estevenz R, Bertran E, Zorano A. Molecular biology of
mammalian plasma membrane amino acid transports. Physiol Rev
1998;78:969-1054.
[14] Hirouchi Y, Naganuma H, Kawahara Y, Okada R, Kamiya A, Inui K,
et al. Protective effect of N-acyl amino acids (NAAs) on cephaloridine(CER) nephrotoxicity in rabbits. Jpn J Pharmacol 1993;63:487–93.
[15] Sekine T, Cha SH, Hosoyamada M, Kanai Y, Watanabe N, Fukuda K,
et al. Cloning, functional characterization and localization of a rat renal
Na-dicarbrboxylate transporter. Am J Physiol 1998;275:F298-F305.
[16] Rosenberg LE, Blair A, Segal S. Transport of amino acids by slices of
rat-kidney cortex. Biochim Biophys Acta 1961;54:479–88.
[17] McDonald TF, MacLeod DP. DNP-induced dissipation of ATP in
anoxic ventricular muscle. J Physiol 1973;229:583–99.
[18] Langen K-J, Muhlensiepen H, Holschibach M, Hautzel H, Jansen P,
Coenen HH. Transport mechanisms of 3-[123I]iodo-α-methyl-Ltyrosine in a human glioma cell line: comparison with [3H-methyl]L-methionine. J Nucl Med 2000;41:1250–5.
[19] Kawai K, Fujibayashi Y, Saji H, Yonekura Y, Konishi J, Kubodera A,
et al. A strategy for study of cerebral amino acid transport using iodine123-labeled amino acid radiopharmaceutical: 3-iodo-alpha-methyl-Ltyrosine. J Nucl Med 1991;32:819–24.
[20] Shikano N, Kanai Y, Kawai K, Inatomi J, Kim DK, Ishikawa N, et al.
Isoform selectivity of 3-125I-iodo-alpha-methyl-L-tyrosine membranetransport in human L-type amino acid transporters. J Nucl Med 2003;
44:244–6.
[21] Lahoutte T, Caveliers V, Dierickx L, Vekeman M, Everaert H, Mertens J,
et al. In vitro characterization of the influx of 3-[125I]iodo-L-alphamethyltyrosine and 2-[125I]iodo-L-tyrosine into U266 human myeloma
cells: evidence for system T transport. Nucl Med Biol 2001;28:129–34.
[22] Cooper JR, Bloom FE, Roth RH. Catecholamine. I. General aspects.
The biochemical basis of neuropharmacology. 5th ed. New York:
Oxford University Press; 1984. p. 203–58.
[23] Mimnaugh MN, Gearien JE. Adrenergic drugs. In: Foye WO, editor.
Principles of medicinal chemistry. 3rd ed. Philadelphia: Lea & Febiger;
1989. p. 343–58.
[24] Williams WM, Huang KC. Structural specificity in the renal tubulartransport of tyrosine. J Pharmacol Exp Ther 1981;219:69–74.
[25] Hang KC. Renal excretion of L-tyrosine and its derivatives.
J Pharmacol Exp Ther 1961;134:257–65.
[26] Hang KC, Knoefel PK. Biochemorphology of renal tubular transport:
halogenated amino acids and derivatives. J Pharmacol Exp Ther 1957;
121:443–8.
[27] Anzai N, Kanai Y, Endou H. Organic anion transporter family: current
knowledge. J Pharmacol Sci 2006;100:411–26.
[28] Jager PL, Vaalburg W, Pruim J, de Vries EGE, Langen K-J, et al.
Radiolabeled amino acids: basic aspects and clinical applications inoncology. J Nucl Med 2001;42:432–45.