ORIGINAL ARTICLE
Annals of Nuclear Medicine Vol. 20, No. 3, 175–181, 2006

Detection of maleate-induced Fanconi syndrome by decreasing accumulationof 125I-3-iodo-α-methyl-L-tyrosine in the proximal tubule segment-1 regionof renal cortex in mice: a trial of separate evaluation of reabsorption
Naoto SHIKANO,* Syuichi NAKAJIMA,*,** Takashi KOTANI,* Yusuke ITOH,* Ryuichi NISHII,*** Mitsuyoshi YOSHIMOTO,**
Leo Garcia FLORES II,**** Hideo SAJI,***** Nobuyoshi ISHIKAWA* and Keiichi KAWAI***Department of Radiological Sciences, Ibaraki Prefectural University of Health Sciences**School of Health Sciences, Faculty of Medicine, Kanazawa University***Department of Experimental Diagnostic Imaging, University of Texas, MD Anderson Cancer Center****Department of Medical Physics, University of Wisconsin Medical School*****Graduate School of Pharmaceutical Sciences, Kyoto University

Objective: Fanconi syndrome is a renal dysfunction characterized by various combinations of renal
tubular transport dysfunction involving amino acids, glucose, protein and other substances. Most
reabsorption of amino acids occurs in proximal renal tubule segment 1 (S1). The present study
evaluated the possibility of early detection of drug-induced Fanconi syndrome, based on decreased
renal accumulation of 125I-3-iodo-α-methyl-L-tyrosine (125I-IMT), an amino acid transport marker,
in the S1 region of renal cortex. The present experimental model used maleate (MAL)-induced
Fanconi syndrome in mice. Results were compared between 125I-IMT and 3 other clinical renal
radiopharmaceuticals: 99mTc-2,3-dimercaptosuccinic acid (99mTc-DMSA); 99mTc-mercaptoacetylglycylglycylglycine (99mTc-MAG3); and 99mTc-diethylenetriaminepentaacetic acid (99mTc-DTPA).
Methods: Male ddY mice (age, 6 weeks; body weight, 25 g) were used to create a Fanconi modelof renal dysfunction. A single dose of maleate disodium salt was administered by intraperitoneal
injection (6 mmol/kg). Hematoxylin and eosin (HE) staining of the renal cortex, renal autoradiography and measurement of renal radioactivity of labeled compounds were performed at 30, 60, 90
and 120 min after MAL injection. At 5 min after injection of labeled compounds (18.5 kBq for
accumulation experiment, 670 kBq for autoradiography), animals were sacrificed by ether overdoseand kidneys were removed. For the accumulation experiment, radioactivity was measured using awell-type scintillation counter. For autoradiography, 20-µm sections of frozen kidney were usedwith Bio-Imaging Analyzer. Results: At 30 min after MAL injection, HE staining showed pyknosis
in some proximal tubule cells. At that time, accumulations of 125I-IMT and 99mTc-DMSA in the S1
region were approximately 67% and 55% of control levels (p < 0.005). MAL increased accumulation of 99mTc-DTPA in the S1 region, but had no effect on accumulation of 99mTc-MAG3 in the S1
region. Conclusions: Decreased accumulation of 123I-IMT in the S1 region appears to represent a
useful marker for detection of MAL-induced Fanconi syndrome. In future, we plan to assess theefficacy of using 125I-IMT to monitor renal dysfunction induced by nephrotoxic clinical drugs.
Key words: reabsorption, 3-iodo-α-methyl-L-tyrosine, maleate-induced Fanconi syndrome, renal
cortex, proximal tubule segment 1

Received July 4, 2005, revision accepted November 30, 2005.
For reprint contact: Naoto Shikano, Ph.D., Department ofRadiological Sciences, Ibaraki Prefectural University of Health
Sciences, 4669–2 Ami, Ami-machi, Inashiki-gun, Ibaraki 300–
0394, JAPAN.
E-mail: sikano@ipu.ac.jp

Vol. 20, No. 3, 2006

INTRODUCTIONFANCONI SYNDROME is a renal dysfunction associated witha variety of metabolic disorders, including tyrosinemia,
cystinosis, Wilson’s disease, glycogen storage disease,1
galactosemia and oculocerebrorenal syndrome of Lowe.2,3

Original Article 175

This syndrome is characterized by various combinationsof proteinuria, aminoaciduria, glucosuria, phosphaturia,
bicarbonaturia, increased electrolyte excretion, uricosuria
and proximal renal tubular acidosis.2 Fanconi syndrome
is often observed in patients with drug-induced acuterenal failure after nephrotoxic treatment. Cases have been
observed after exposure to tetracycline,4 streptozotocin,2,3
gentamycin, 5 valproate, 4,6 4-pentenoate,7 cystine, 8,9
ifosfamide, 10–13 maleate, 14,15 heavy metals 16 andsuccinylacetone.17
Clinically, 99mTc-2,3-dimercaptosuccinic acid (99mTcDMSA) has been used not only to visualize the kidneys,
but also to assess individual kidney function.18 Fanconi
syndrome is associated with low renal uptake of 99mTcDMSA, despite a relatively normal glomerular filtration
rate (GFR).19 However, the mechanisms of 99mTc-DMSA
accumulation remain unclear.18
Dysfunction of amino acid resorption is characteristicof Fanconi syndrome, and begins in the early phase ofdrug-induced nephrotoxicity. In heavy metal-induced
Fanconi syndrome, for example, renal amino acid handling is a highly sensitive marker of nephrotoxicity.16
Markers of amino acid transport may thus be effectively
used to monitor Fanconi syndrome.
After glomerular filtration, most amino acids undergo
intensive resorption in proximal renal tubule segment 1(S1). Accumulation of amino acids in the S1 region of therenal cortex may reflect renal handling of amino acids. We
postulated that decreased accumulation of amino acids in
the S1 region could be used to detect Fanconi syndrome,
which is a multiple transport dysfunction of the proximal
tubule. The present study evaluated use of 123I-3-iodo-αmethyl-L-tyrosine (123I-IMT) as a renal functional imaging agent for detection of Fanconi syndrome. Originally,
123I-IMT was developed as a functional imaging agent for
L-tyrosine (L-Tyr) transport mechanisms in the brain andpancreas (Fig. 1).20–22 Use of 123I-IMT has been seen
clinically for single photon emission computed tomography (SPECT) of tumors, as a marker of up-regulatedamino acid transport.23–26
The present study used an experimental model consisting of maleate (MAL)-induced Fanconi syndrome inmice,15,17,27 as established by Dimopoulou et al.27 Thismodel has been successfully used in urine biochemical
studies to characterize multiple transport dysfunctions in
the proximal tubule of MAL-induced Fanconi syndromein mice.27
Particularly for changes to renal accumulation in the S1
region of the renal cortex, the results obtained for 125IIMT were compared with results for 3 clinical renal
radiopharmaceuticals: 99mTc-DMSA, 99mTc-mercaptoacetylglycylglycylglycine (99mTc-MAG3), and 99mTcdiethylenetriaminepentaacetic acid (99mTc-DTPA).

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Naoto Shikano, Syuichi Nakajima, Takashi Kotani, et al

A

B

Fig. 1 Comparison of chemical structures of 123/125I-3-iodo-αmethyl-L-tyrosine (123/125I-IMT) (A) and L-Tyr, the mothercompound (B).

MATERIALS AND METHODS
Materials and preparation of labeled compounds
Reagent-grade MAL and α-methyl-L-tyrosine were acquired from Sigma-Aldrich Japan (Tokyo, Japan).
Chloramine-T and other chemicals of reagent grade werepurchased from Kanto Chemical (Tokyo, Japan). In thepresent basic study, for convenience, 125I-labeled IMT(125I-IMT) was used instead of 123I. The radioisotope 125INaI (8.1 × 1019 Bq/mol) was obtained from Amersham
Pharmacia Biotech UK (Buckinghamshire, UK).
Non-carrier-added 125I-IMT was prepared using the conventional chloramine-T method, with α-methyl-L-tyrosine
as the precursor, as previously reported.20–22 A Nova-Pak
C18 chromatography column (3.9 × 300 mm; Waters,
Milford, MA, USA) was used for separation and purification of 125I-IMT. To assess labeling efficiency and radiochemical purity, a silica gel thin-layer chromatography kit(TLC, catalogue number Art. 5553; Merck, Darmstadt,
Germany) was used.
99mTc-DMSA, 99mTc-MAG and 99mTc-DTPA were all3
obtained from Nihon Medi-Physics (Hyogo, Japan) andDaiichi Radioisotope Laboratories (Tokyo, Japan). Animals used in all experiments were male ddY mice (bodyweight, 25 g; age, 6 weeks). All animal experiments wereapproved by the ethical committees of Ibaraki Prefectural
University of Health Sciences.
Fanconi model of renal dysfunction in miceGroups of 3 mice were administered MAL by intraperitoneal injection of a single dose of 6 mmol/kg body weight.27
Control mice received intraperitoneal injection (i.p.) of
saline. Injected mice were allowed free movement in a
separate cage for each mouse. Proximal tubule cells in therenal cortex of control and MAL-treated mice were examined using hematoxylin and eosin (HE) staining and a
CX41 optical microscope (Olympus, Tokyo, Japan).
Measurement of renal accumulation
For assessment of whole-kidney accumulation (Fig. 5),
groups of 5 control or MAL-treated mice were administered 0.1 ml of 125I-IMT, 99mTc-DMSA, 99mTc-MAG3, or
99mTc-DTPA (18.5 kBq) by injection into the tail vein.
Mice were anesthetized with ether inspiration and sacrificed by heart puncture at 30, 45, 60, 90 and 120 min afteradministration of the labeled compounds, and kidneys
were resected. Radioactivity of samples was quantified

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Fig. 3Fig. 2

Fig. 4

Fig. 6

Fig. 5Vol. 20, No. 3, 2006

Fig. 2 Accumulation of 125I-IMT in control kidney (no MAL
treatment). Images were processed using a Bio-Imaging Analyzer.
S1 is located on the outer side of the fringe of the renal cortex (green
region), while S2 is located on the inner side (red region). Opensquares in the S1 region represent regions of interest (ROIs) for
evaluation of amino acid transport based on 125I-IMT accumulation. Numbers 0 to 65535 (16 bits/pixel) under the color bar
represent the full range of gradation fitted on an exponential
contrast curve that corresponds to the photo-stimulated luminescence (PSL) value of the Bio-Imaging Analyzer. The original
range of 0 to 65535 was changed to 0 to 54272, so the red area
indicates the S2 region.
Fig. 3 Optical microscopy of mouse renal cortex in MAL-induced
Fanconi syndrome model. Control mice (A, B) and MAL-treatedmice at 30 min (C) and 120 min (D) after 6 mmol/kg MAL
administration. Magnification: 40× (A); 200× (B–D).
Fig. 4 Mouse kidney autoradiography in MAL-induced Fanconi
syndrome model after 125I-IMT administration.
Fig. 5 Accumulation of 125I-IMT, 99mTc-DMSA, 99mTc-DTPA
and 99mTc-MAG3 in mouse kidney in a model of MAL-induced
Fanconi syndrome. Left: whole kidneys (quantified using a welltype scintillation counter). Right: S1 region (quantified using a
Bio-Imaging Analyzer system). *p < 0.005 vs. control
Fig. 6 Putative major membrane transport of 125I-IMT in proximal
tubule cells. Systems A, L and B0 are neutral amino acid transportsystems that mediate 125I-IMT transport into proximal tubule cells.
Some studies using tumor cell lines have indicated that system A
does not contribute to 125I-IMT transport. In S2 cells, cumulative
excretion of 125I-IMT via organic anion transporter 1 (OAT1) andmulti-drug-resistant protein 2 (MRP2) is thought to be probenecidsensitive.

Original Article 177

using an ARC-380 well-type scintillation counter (Aloka,
Tokyo, Japan).28,29
In vivo autoradiography of kidneys
For assessment of accumulation in the S1 region (Fig. 5),
groups of 4 control or MAL-treated mice were administered 0.1 ml of 125I-IMT (670 kBq) by injection into thetail vein. After 5 min, mice were sacrificed by inspirationof excess ether, placed in carboxymethyl cellulose embedding medium (Nacalai, Kyoto, Japan), and frozen at−15°C for at least 12 h. A CM3050 S autocryotome(Leica, Nussloch, Germany) was used to cut 20-µm
coronal sections from posterior to anterior. Sections weredried at −15°C for another 24 h, then kept in contact with
BAS-SR2040 imaging plates (Fuji Photo Film, Kanagawa,Japan) for 6 days. Images were processed using a BAS
5000 Bio-Imaging Analyzer (Fuji Photo Film).28,29 Accumulation of IMT in the S1 region was measured. Figure 2
show regions of interest (ROIs) for evaluation of aminoacid transport. High levels of organic anion transporter 1(OAT1) are reportedly expressed in S2 cells.30 OAT1 isthought to be the main contributor to the marked 125I-IMT
accumulation that has been observed in S2 cells.31 The S1
region is located on the outer side of the fringe of the renal
cortex (green region in Fig. 2). In the S1 region, mean
count of 296 pixels in the ROIs was 14,400 counts/pixel/
6 days of contact with imaging plates.
Statistical analysis
Data were collated as mean ± standard deviation of 3–5
measurements. Results were analyzed using Student’s ttest. Values of p < 0.005 were considered indicative of
statistical significance.
RESULTS
Fanconi model of renal dysfunction
HE staining showed pyknosis in some proximal tubule
cells 30 min after MAL injection (Fig. 3). No otherobvious changes were observed in the glomerulus or
proximal tubule. At 120 min after MAL injection, pyknosis was observed in distal tubules and some proximal
tubule cells.
Renal accumulation
Figure 4 shows renal accumulation of 125I-IMT versus
time after MAL injection. Time-dependent decreases inrenal accumulation of 125I-IMT were apparent.
Figure 5 shows relative renal accumulation of labeled
compounds (compared to control) versus time after MAL
injection. Total 125I-IMT radioactivity in MAL-treatedkidneys decreased to 24.32% ± 25.10% of the control
level (p < 0.005) at 30 min after MAL injection. In S1(where most amino acid resorption occurs), 125I-IMT
radioactivity of MAL-treated kidneys decreased to 66.83%± 15.63% of control level (p < 0.005) at 30 min after MAL

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Naoto Shikano, Syuichi Nakajima, Takashi Kotani, et al

injection (Fig. 5). Accumulation of 99mTc-DMSA in the
S1 region was reduced to approximately 54.67% ± 22.93%
of control levels (p < 0.005) at 30 min after MAL injection. Accumulation of 99mTc-DTPA in the S1 region wasincreased about 3.5-fold, compared to controls, at 30 min
after MAL injection. Accumulation of 99mTc-MAG3 had
not decreased at 120 min after MAL injection.
DISCUSSION
Fanconi syndrome is an inherited or acquired disorderinvolving transport defects in the proximal renal tubule,including impaired resorption of amino acids, glucose,
sodium, potassium, calcium, phosphate, bicarbonate, uricacid and low-molecular-weight proteins.19
In clinical settings, dysfunction of resorption in theproximal tubule can be assessed by testing for decreased
accumulation of 99mTc-DMSA in the renal cortex. In
addition, biochemical indications of multiple transport
dysfunctions in the proximal tubule suggest the presenceof Fanconi syndrome. Tests using 99mTc-DTPA and 99mTcMAG3 frequently demonstrate relatively normal GFR
and proximal tubular secretion.
Despite the clinical use of 99mTc-DMSA in assessing
relative renal function, the mechanisms by which 99mTcDMSA accumulates in the kidney remain unclear.18 Evaluation of renal handling of amino acids may allow direct
detection of Fanconi syndrome. The present basic study
was thus performed to evaluate the usefulness of detecting
decreased accumulation of amino acid in the renal cortex
as an indicator of Fanconi syndrome.
We selected 123/125I-IMT as a candidate amino acidtransport marker, as 123/125I-IMT is a metabolically stableartificial amino acid that was developed as a functional
imaging agent for the brain and pancreas.20–22 Clinical use
has also been made of 123I-IMT for SPECT imaging oftumors, as high levels of amino acids accumulate inactively proliferating tumor cells, and this process can bemonitored by assessing 123I-IMT accumulation.23–26
In the present study, we expected to be able to assess
dysfunction of amino acid transport by testing for decreased accumulation of 123I-IMT in the S1 region of therenal cortex, as most resorption of amino acids occurs in
S1.
The present MAL-induced mouse Fanconi syndromemodel was described by Dimopoulou et al.27 The model
includes urine biochemistry changes similar to thosereported for patients with Fanconi syndrome. In the study
by Dimopoulou et al., urinary excretion of amino acids
was significantly elevated within 30 min after injection of
MAL (6 mmol/kg body weight intraperitoneal), and continued to increase with time.27 Marked aminoaciduria inmice after MAL injection is characterized by multifold
increases in levels of most amino acids present in urine ofnormal mice, and by significant concentrations of neutralamino acids (e.g., phenylalanine, leucine and tyrosine)

Annals of Nuclear Medicine

that are not present in significant quantities in normal
urine.27
Dimopoulou et al. also reported that 99mTc-DTPA, aradiopharmaceutical freely excreted by glomerular filtration, exhibits significantly delayed pharmacokinetics as adose-dependent effect. Although 99mTc-DTPA does notaccumulate in normal renal cortex, accumulation is seenin the renal cortex of the present model of Fanconi syndrome, suggesting that the renal cortex in the present
model is abnormal.27 Dimopoulou et al. suggested that
99mTc-DTPA is an effective marker for early detection ofabnormal GFR in Fanconi syndrome. Significantly disturbed 99mTc-DTPA pharmacokinetics are seen in allorgans of MAL mice by 90 min after administration of asingle MAL-dose of 6 mmol/kg.27 According to the report, a mix of proximal tubule transport defects withabnormal glomerular function seems to be obtained by 90
min after MAL injection in this model.27 The present
study identified accumulation of 99mTc-DTPA by 30 min
after MAL injection, suggesting some degree of abnormal
GFR (Fig. 5).
Whether proximal tubular secretion remains normal isunclear, but no significant change in accumulation of
99mTc-MAG was observed until 120 min after MAL
3
injection (Fig. 5). Due to this late response to MAL
administration, 99mTc-MAG3 is not suitable for early
detection of MAL-induced Fanconi syndrome. In contrast, accumulation of 125I-IMT and 99mTc-DMSA significantly and rapidly decreased within 30 min after
MAL injection (Fig. 5).
Accumulation of 125I-IMT due to resorption in theapical membrane of S1 cells may be affected by bothabnormal GFR and nephrotoxicity of filtrated MAL. Thissecond factor appears to have a greater effect on renal
handling of amino acids in the present model, as urinary
excretion of natural amino acids continued to increaseover time.27
Recent findings regarding the mechanism of Fanconi
syndrome have led to the following hypothesis: administration of MAL to mice induces dysfunction of Na+-K+ATPase.9 Sodium-concentration-linked, energy-dependent amino acid transport systems such as system B0,
which is thought to be the main contributor to resorptionof neutral amino acids, are functionally damaged by
MAL.27 These effects of MAL lead to Fanconi syndrome
with aminoaciduria.
In a recent study, we observed marked accumulation of
125I-IMT in the renal cortex,28 whereas moderate accumulation of radiolabeled L-Tyr was observed in anotherstudy.26 The 125I-IMT used in the present study wasderived from L-Tyr, which was modified by α-methylation for metabolic stability, and 3-iodination of the phenolgroup for radiolabeling (Fig. 1).29 Due to structural differences between 125I-IMT and natural L-Tyr, renal physiological accumulation of 125I-IMT is greater than that of
14C-labeled L -Tyr, particularly in S2 of the proximal

Vol. 20, No. 3, 2006

tubule.29 Greater accumulation of 125I-IMT in the S2located region may be due to α-methylation of natural LTyr.29
A recent theory concerning 125I-IMT accumulation inrenal proximal S1–S3 cells is consistent with the present
findings (Fig. 6).28 Clarification of these accumulation
mechanisms may aid in the development of 125I-IMT as arenal imaging agent. Two major types of transport pathway are responsible for 125I-IMT accumulation in therenal cortex proximal tubule cells, as described below.
The first category includes pathways involving aminoacid transport systems. Systems L, A and B0, and perhaps
some minor amino acid transporters, contribute to thesepathways. Langen et al. reported that system A does notcontribute to 125I-IMT transport in certain tumor celllines.26 However, 2-(methylamino)isobutyric acid significantly inhibits 125I-IMT transport in normal humanproximal tubule cells.28 After glomerular filtration, mosttubular resorption of neutral amino acids via system B0
occurs in the apical membranes of S1 cells. This suggeststhat the S1 region (green region of renal cortex in Fig. 2)
is suitable for evaluation of amino acid transport using
123/125I-IMT. L-type amino acid transporter 2 (LAT2) inthe basolateral membranes of S1 cells mediates transportof neutral amino acids from S1 cells into the blood. The
isoform of system L that contributes to 125I-IMT resorption in the basolateral membrane is thought to be LAT1,
rather than LAT2. We recently reported that LAT1 mediates influx of 125I-IMT, while LAT2 does not.30 In futurestudies, we plan to examine efflux of IMT via LAT1 and
LAT2.
The second category includes pathways involving organic anion transport systems in S2 cells. Mother L-Tyr
does not show affinity for OAT1,31,32 but 125I-IMT renal
accumulation and excretion via the kidneys are inhibitedby probenecid and p-aminohippurate (PAH). This suggests that 125I-IMT has affinity for organic anion transportsystems. OAT1 is expressed in the basolateral membraneof the middle segment of the proximal tubule (S2 cells),
and mediates cumulative secretion of PAH and otherorganic anions with multi-drug-resistant protein 2 (MRP2)
and other proteins in the apical membrane.33 We recently
reported that MAL displays affinity for OAT1.31 In thepresent study, autoradiography (ARG) at 30 min after
injection of MAL (Fig. 4) showed that accumulation of
125I-IMT was markedly inhibited by MAL in the S2 region(red region of renal cortex in Fig. 2). Total 125I-IMT
accumulation in the whole kidney was reduced 30 min
after injection of MAL (Fig. 5), but this may be due toinhibition of 125I-IMT accumulation by MAL in S2.
Accumulation of 125I-IMT in S2 cells is the result of a
combination of contributions from organic anion andamino acid transport systems. This suggests that the S2
region is not suitable for evaluation of amino acid transport or resorption using 125I-IMT.
Overall, most 125I-IMT accumulation in the S1 and S2Original Article 179

regions of mouse renal cortex is due to activity of neutralamino acid transport systems (S1 cells) and organic aniontransport systems (S2 cells) in the proximal tubule, respectively.
The present experimental study suggests that 123/125IIMT is an effective marker for detecting renal tubulartransport dysfunction in drug-induced Fanconi syndrome.
Methods such as tumor imaging with renal imaging in thesame study by 123I-IMT may thus help improve the safetyof treatment with nephrotoxic anticancer drugs. In futurestudies, we plan to assess the efficacy of using 125I-IMT tomonitor renal dysfunction induced by nephrotoxic clinical drugs.
CONCLUSIONS
We evaluated use of 123I-IMT as a renal functional imaging agent for detection of drug-induced Fanconi syndrome. MAL-induced Fanconi syndrome was detected as
decreases in accumulation of 125I-IMT and 99mTc-DMSA
in the S1 region of the proximal tubule of mouse renal
cortex within 30 min after MAL administration by intraperitoneal injection (6 mmol/kg). The present findings
suggest that decreases in 123I-IMT accumulation by aminoacid transporters in the S1 region offer a useful marker for
detection of MAL-induced Fanconi syndrome.
ACKNOWLEDGMENTS
We wish to thank Jyunichi Ohyama, Masato Ogura, Yusuke
Kishi, Misako Tanaka and Asami Teraoka of Ibaraki Prefectural
University for their excellent 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 Culture of Japan and the Japan Society for the
Promotion of Science. Financial support was also provided by
the Ibaraki Prefectural University Research Project (9808, 0118
and 0220) and Grants-in-Aid for Encouragement for Young
Scientists from Ibaraki Prefectural University of Health Sciences 2001, 2002 and 2004.

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