A Strategy for the Study of CerebralAmino Acid
Transport Using Iodine-123-Labeled Amino Acid
Radiopharmaceutical: 3-Iodo-alpha-methyl-Ltyrosine
Keiichi Kawai, Yasuhisa
Akira Yokoyama

Fujibayashi,

Hideo Saji, Yoshiharu

Yonekura,

Junji Konishi,

Akiko Kubodera,

andFaculty ofPharmaceutical Sciences, Science University of Tokyo, Tokyo, Japan and School ofMedicine and Faculty of
Pharmaceutical Sciences, Kyolo University, Kyoto, Japan

We examined the brain accumulation of iodine-i 23-iodo-alpha-methyl-L-tyrosine (123I-L-AMT)in mice and rats. l-L-AMT
showed high brain accumulation in mice, and in rats; rat brain
uptake index exceeded that of 14C-L-tyrosine.The brain up
take index and the brain slice studies indicated the affinity ofl-L-AMT for earner-mediatedand stereoselective active transport systems, respectively; both operating across the blood
brain barrier and cell membranes of the brain. The tissue
homogenate analysis revealed that most of the accumulated
radioactivity belonged to intact l-L-AMT, an indication of its
stability. Thus, 1231-L-AMTappears to be a useful radiophar

maceutical for the selective measurement of cerebral aminoacid transport.
J Nucl Med 1991; 32:819-824

arious mental disorders have been associated withalterations in cerebral amino acid metabolism (1 ); in
schizophrenic patients, for example, a defect of tyrosine
transport has been suggested (2). Although some studies
on the use of radiolabeled amino acids with cyclotron
produced ultra short-lived radionuclides have been at
tempted (3), they are limited to PET centers; a radioiodi
nated amino acid, providing similar data, would offer
wider applicability.

The multifunctional role of amino acids, participating
not only in protein synthesis but also as substrate forvarious metabolic pathway, are well known (4). Our previous work indicated that the election of radioiodinatedamino acid derivatives with metabolic selectivity or highactive membrane transport affinity was possible (5,6).

Received Oct. 31, 1989; revision accepted Oct. 19, 1990.
For reprintscontact:KelichiKawal, PhD, Facultyof PharmaceuticalSd

ences,ScienceUniversityof Tokyo,12, lchigayaFunagawara-machi,
Shinjuku
ku, Tokyo, 162, Japan.

Cerebral Amino Acid Transport â€¢
Kawai et al

In the present work, a search for radioiodinated tyrosine
derivatives for the cerebral tyrosine transport is attempted.

In the screening process, in vitro accumulation studies in
rat brain slices, measurement ofbrain uptake index (BUI),
and in vivo mouse biodistribution are followed by the
analysis of metabolites. In a preliminary study, the radio
iodinated monoiodotyrosine in its L- and D-form (L-MIT

and D-MIT) and its noniodinated counterpart (â€˜4C-Ltyrosine) are tested.
The initial part of the work provided the basis for aradioiodinated tyrosine derivative to be used for the meas
urement of cerebral tyrosine transport. In particular, thedata on conformational
isomerism and the enzymatic
deiodination ofamino acids appeared as important factors
to be considered.Thus, methylation of the L-tyrosine isestimated as the most plausible approach for providing theneeded stability; and the alpha-methylated derivative, the3-iodo-alpha-methyl-L-tyrosine(I-L-AMT, Fig. 1) is cho
sen. Compatibility ofthis I-L-AMT is comparatively tested
with its parent, L-MIT, molecule and its use as the radio
iodinated agent for the selective measurement of cerebral
amino acid transport is discussed.

MATERIALSAND METhODS
Preparation of 125l-L-AMTand 1231-L-AMT!odine-l25-Na! was obtained from Amersham Japan and 1231
Na! was provided by Nihon Medi-Physics, Japan. All otherchemicals used were of reagent grade. Iodine-l25-L-AMT andâ€˜23ILAMT
werepreparedby theconventional
chloramine-T
method as follows. Chloramine-T (Aldrich) at a concentration of

2.0x lO_8molin 10MlofO.05M phosphatebuffer(pH6.2)wasadded to a mixture of L-AMT (1.0 x l08 mol, Aldrich) andcarrier-free â€˜25!-Na!
(7.4-37 MBq) in 35 zl of 0.4 M phosphatebuffer (pH 6.2). To prepare 123!-L-AMT,L-AMT (I .0 x l0_6 molin 25 @tl
of 1 N phosphoric acid) and chloramine-T (2.0 x lO_6
mol in 20 Mlof 0.4 M phosphate buffer) were added to 500 @zl
ofcarrier-free 123!-Na!(74-1 11 MBq) solution adjusted to pH 10.
The resultant solution was allowed to stand for 2 mm, and 20 zl

819

1231

CH3
HO@

CH2-@-COOH

injected with 200 @d
ofsaline containing 3.7 kBq ofthe radioactive
sample and 3H-H20 via the right common carotid artery. The

rats weredecapitated 15sec after injection,and the radioactivity
ofthe right halfofthe brain rostral to the midbrain was measured.
The BUI was calculated by the following equation:
tissue 25!or â€˜4C'tissue
3H

@

NH2

BUI = . .

inj. soln

124@!or â€C̃/inj.

soln

3 x 100.
H

In competition studies, the injected solution contained 1 x
iO-@M cold L-tyrosine or L-AMT, a concentration that is about
FiGURE1. Structureof 123l-3-iodo-alpha-methyl-L-tyrosmne(1@l-L-AMfl.

14 times that of the endogenous tyrosine in normal rat plasma(10).

of 10% saturated sodium metabisulfite solution were then added.
The radioiodinated L-AMT was purified by Sephadex LH-20(Pharmacia) column chromatography (10 x 200 mm, eluant,ethylacetate:methanol:2 N ammonia = 40:lO:4)(7). The labelingefficiency and radiochemical purity were studied by silica gel
thin-layer chromatography (TLC, MERCK; Art. 5553) using twosolvent systems, i.e., methanol: acetic acid = 100: 1 (Rf value: IL-AMT, 0.50; I, 0.75) and methanol: 10% ammonium acetate

In Vitro Accumulation Studies in Rat Brain Slices
In vitro accumulation studies using rat brain slices were performed as previouslyreported (11). Male Wistar rats weighing

250â€”300
g were killed by decapitation and the brains were quickly
dissected. The brain tissue was washed with ice-cold Krebs-Ringer
phosphate buffer (pH 7.4) and then sliced with a conventional
Stadie-Riggs slicer (12). The slices (each weighing 100 Â±5 mg)
were next placed into a vial containing 1.9 ml of Krebs-Ringer=
10:
1 (Rfvalue:
I-L-AMT,0.55;
1,0.80).
phosphate buffer as the incubation medium and preincubated for
As references, we used [U-'4C]-L-tyrosine (NEN; NEC-289E)
10 mm for temperature equilibration. Then, 0.1 ml ofthe buffer
as a labeled natural amino acid, â€˜251-3-iodo-L-tyrosine(â€˜251-L-containing a radioactive amino acid was added and incubation
MIT) and â€˜251-3-iodo-D-tyrosine(â€˜25I-D-MIT)
prepared by the was performed at 37Â°Cfor 30 mm. At the end of the incubation
method mentioned above, and 123I-N-isopropyl-p-iodoamphe period, the medium was removed, and the slices were washedtamine ([â€˜23111MP,
Nihon Medi-Physics).
twice in 2 ml of ice-cold buffer. The radioactivity of the slices
was then measured by the above-mentioned method. The per
In Vivo MouseBiodistributionStudiesand Analysisof
centage of the dose accumulated per gram of slice was calculated
Metabolites
as follows:

DdY male mice weighing25 g received0.1 ml of radioactive

amino acids (â€˜251-L-AMT,â€˜25I-L-MIT,or â€˜251-D-MIT
at 1.6 x Accumulation % dose/g slicei0'@ mol and 11.1 kBq; â€˜4C-L-tyrosine
at 4.0 x l0@Â°mol and@@iÃ§e1251or
7.4 kBq) via the tail vein and were then killed at various time
x 100.
inj. soln 125!or â€˜4C
x slice weightintervals. For the measurement of radioactivity, a well-type scm
tillation counter(Aloka; ARC-300) was used for the 125J..
and 123!..
Inhibition studies of the membrane active transport systemlabeled compounds. For â€˜4C-L-tyrosine,100 mg of tissue was were performed using incubation at 4Â°Cand ouabain inhibition.
dissolved in 1 ml of NCS tissue solubilizer (Amersham) and For the ouabain inhibition study, brain slices were preincubatedincubated at 50Â°Cfor 3 hr, followed by the addition of 8 ml of at 37Â°C
for 20 mm in medium containing 1 x l0@ M of ouabain
toluene scintillator containing DPO and POPOP. The radioactiv
before addition of the radioactive sample. In the competitive
ity was measured using a liquid scintillation counter (Aloka; inhibition studies, cold L- or D-tyrosine solution at a final con
ARC-900).
centration of I x l0@ M and the radioactive samples wereAn aliquot oftissue was homogenizedand the 5% trichloroa

cetic acid-precipitated fraction was trapped on a glass filter (Toyo;
GC-50) to allow measurement of the radioactivity incorporated
in the protein. Furthermore, the tissue supernatant was separated
by TLC using the solvents mentioned above to examine themetabolites.
Measurement of Partition Coefficients
The partition coefficients of â€˜231-L-AMT,â€˜4C-L-tyrosine,
and[23!JIMP were measured using 2.0 ml ofn-octanol as the organic

phaseand 2.0 ml ofO.l M phosphatebufferas the aqueousphase(pH 7.0 for brain tissue and pH 7.4 for plasma).N-octanoland
the bufferwere pre-mixedtwice usinga mechanicalmixer for 1
mm at room temperature. Then, 20 @lofradioactive sample wereadded and mixed twice using a mechanical mixer for 1 mm at
room temperature. The radioactivity of 200 @tl
ofeach phase wasmeasured after centrifugation.

Measurementof BUIBUIstudieswereconductedbasedon the method reportedby

simultaneously injected. The final radioactive amino acid con
centration was 2.7 xâ€M̃ (1.85 kBq/ml, no-carrier-added)for â€˜251-L-AMT
and 1.0 x l0@ M (1.85 kBq/ml) for â€˜4C-Ltyrosine.

RESULTS
Preparationof 125l-L-AMT
and 123l-L-AMT
No-carrier-added â€˜251-L-AMTand â€˜23I-L-AMTwith radiochemical purities greater than 95% and radiochemicalyields of 50%â€”60%were obtained after purification.

In Vivo Mouse BiodistributionStudiesand Analysisof
Metabolites

The brain accumulation of â€˜251-L-AMT
in mice is shownin Figure 2 compared with â€˜251-L-MIT,â€˜251-D-MIT,andâ€˜4C-L-tyrosine.Comparison of â€˜251-L-MIT
with â€˜251-DMIT showed that the L-isomer exhibited higher brain

Oldendorf (8,9). Male Wistar rats weighing 250â€”300g wereaccumulation than the D-isomer, indicating that stereo
selectivity for the L-isomer occurred in the brain. The

820

The Journal of Nuclear Medicine â€¢Vol. 32 â€¢
No. 5 â€¢May 1991

100

)O.O

Jâ€¢__@@@@%4TI â€˜@C-L-Tyr

@

o/@

@
@

0

@â€¢

1.0

50

T
o@o

I j

125@LMIT@T

I

125I-L-A@0@â€˜

9â€”.@------@
251-D-MIT
0
I

0

I

15

6'O

1251.LAMT

30

11@C-L-tyrosine

Time (mm)FIGURE 4. Fateof 1251-L-AMT
andâ€œC-L-tyrosine
inthemouse
FIGURE 2. Brainaccumulationof 125l-L-AMT,
1251-L-MIT,1251.. brain 10 mmafter injection.Eachbar representsthe meanÂ±s.d.
D-MIT, and â€œC-L-tyrosine
in mice. Each point represents the of three animals. Analysis for the amino acid and acid solublemeanÂ±s.d. of four to five animals.(S, 125l-L-AMT;
0, 125l-L-MIT; metabolitefractions of 14C-L-tyrosineare from only one animal.
(Vertically striped bar, amino acid fraction; open bar, protein
0, 1251-D-MIT;A, â€œC-L-tyrosine).
fraction; obliquely striped bar, acid soluble metabolite fraction;solid bar, free iodinefraction).
alpha-methyl derivative, â€˜25I-L-AMT,showed higher ac
cumulation than â€˜25I-L-MIT.Moreover, in the early stage
up to 10 mm after injection, â€˜251-L-AMT
showed superior
5% of the radioactivity in the brain as L-tyrosine, while
uptake to its parent compound, â€˜4C-L-tyrosine,although
37.4% and 56.8% was found in the protein precipitate andafter that â€˜25I-L-AMTlevels rapidly decreased in the brain.
the acid soluble metabolites, respectively. In the case of
As shown in Figure 3, rapid clearance of â€˜25I-L-AMT â€˜25I-L-AMT,
more than 93% of the radioactivity in thefrom the blood was observed and the clearance curve wasbrain was found as free amino acid, and not as protein or
found to be similar to that of â€˜25I-D-MIT,which was stable
as free iodine. In Table 1, the percentages of radioactivity
against enzymatic deiodination (6). Redistribution in thein the amino acid and free iodine fractions of â€˜25I-L-AMT
blood, which was shown with â€˜4C-L-tyrosine, was notin mouse tissues are shown compared with â€˜25I-L-MIT.In
observed. As a result, 30 mm after injection, â€˜251-L-AMT the case of â€˜251-L-AMT,free iodine was about 1% of theshowed lower blood levels than â€˜4C-L-tyrosine.
radioactivity in the brain and less than 4% in the liver,
The chemical forms of the radioactive compounds in kidney, and urine in contrast with 1251-L-MIT.
the mouse brain 10 mm after injection are shown in Figure
4. Mice injected with â€˜4C-L-tyrosine
exhibited less than Partition Coefficients

The partition coefficients of â€˜231-L-AMT,â€˜4C-L-tyrosine,and [â€˜23I]IMPare shown in Table 2. lodination and methylation ofthe tyrosine molecule increased the lipophilicity
to some extent, but the partition coefficient of â€˜231-L-AMT

50.0

was lower than that of [â€˜231]IMP,
which is a well known
lipophilic brain-seeking

amine (13,14). Little difference of

E
0
V

10.0

TABLE 1In Vivo Stability of lodinated Amino Acids*

5.0>

1251-L
i-D-MITS

1@@C-L-Tyr

V

01251LAMT
01530Time (mm)60

1Brain93.02 AMT-AMTFreel1251-L MIT-MIT Free

(2.65)1.08(0.78)Liver55.25
.88

3.87

(5.39)Kidney (7.05)1(2.90)66.25(1.34)1(1.42)(1.45)(4.55)(6.13)FIGURE 3. Clearanceof 125l-L-AMT,125l-L-MIT,1251-D-MIT,Urine94.93 93.09
4.79
3.81
94.21
and 14C-L-tyrosine
from the blood in mice. Eachpoint represents(2.45)2.21 (2.00)14.07 (1.52)75.07(1.19)*
the mean Â±s.d. of four to five animals. Carbon-i4-L-tyrosine
analysis
was determinedin plasmasample.(â€¢,125I-L-AMT;
0, 125l-L-MIT;(MeOH:AcOH = 1after
00:1).intravenousinjection,TLC
0, 1251-D-MIT;A, 14C-L-tyrosine).
Ten

Cerebral Amino Acid Transport â€¢
Kawai et al

minutes821

TABLE 2
Partition Coefflcients*
pH 7.0pH
7.41@l-L-AMTâ€”0.879

200(0.004)14C-L-tyrosineâ€”1(0.003)â€”0.911.98(0.02)â€”2.00(0.05)[1@l]lMP0.722(0.008)*log(n-Octanol/0.1

M

phosphate(0.026)0.940
buffer).

100E0125k-L-AMT

14C-L-tyrosmne

the partition coefficients between pH 7.0 and pH 7.4 wasobserved, in contrast with [â€˜231]IMP.
FIGURE 6. Inhibitionof 125l-L-AMTand 14C-L-tyrosine
accu
mulationin rat brain slices. Eachbar representsthe meanÂ±s.d.

Brain Uptake Index

Iodine-l25-L-AMT showed a high BUI of 62. 1 Â±4.3,

of five experiments. (Vertically striped bar, samples incubated forin contrast with the 34.2 Â±4.7 observed for â€˜4C-L-tyrosine 30 mm at 37Â°C;horizontallystriped bar, samples incubated at
4Â°C;open bar, samples loaded with 1 x 10@ M ouabain and(Fig. 5). In addition, the brain uptake of â€˜25I-L-AMTwas
preincubatedfor 20 mm; obliquely striped bar, L-tyrosine, andinhibited by the simultaneous injection ofcold L-AMT or
dotted bar,D-tyrosine,at 1 x 10@M were addedsimultaneously).

@

cold L-tyrosine, and a similar effect was detected with â€˜4C- * = p < 0.005,
L-tyrosine.

= p < 0.001.

In VftroAccumulationStudiesin Rat BrainSlices
The results of the accumulation and inhibition studies DISCUSSION
of 1251-L-AMTand â€˜4C-L-tyrosine
are shown in Figure 6.
Recent advances on PET brain studies have stimulated
With incubation at 37Â°Cfor 30 mm, â€˜251-L-AMT(158.4 Â±thesearch for radiopharmaceuticals for SPECT studies.
9.4%/g) showed a similar accumulation to â€˜4C-L-tyrosine
Tyrosineor its derivatives have been radioiodinated or(15 1.0 Â±l6.6%/g). With incubation at 4Â°C,the accumu
radiolabeledwith positron-emitting radionuclides, butlation of both labeled amino acids was significantly decreased. Inhibition of accumulation was also detected in
the presence of ouabain. In addition, stereoselective inhi
bition was detected only in the presence ofcold L-tyrosine.
These characteristics

they have been used mostly for studies of protein synthesisor elucidation ofbiochemical pathways in normal or pathologic state (15â€”17).
Studies of cerebral amino acid transportof â€˜251-L-AMT
were shared by â€˜4C-L-

are rare andonly basic research has been reported, particularly withtyrosine (8,18). At first, basic experimentation was carriedout with the radioiodinated tyrosine, MIT. The availabilityof radioiodinated MIT in its L- and D-form provided thepreliminary basis for this work. In vivo biodistribution
studies in mice showed high brain accumulation of the L
MIT, but not that of the D-MIT, a good indication of thewell known stereospecificity of the blood-brain barrier, inthe transport of neutral amino acids (8,18). However,tissue analysis revealed the metabolic unstability of L
MIT, a metabolic intermediate of thyroid hormones,
which is subjected to rapid enzymatic deiodination (19,tyrosine.

80

60
a)

V

0)
a

1..

20). Use of a radioiodinated tyrosine derivative for aminoacid transport studies requires an enzymatically stable
derivative of L-MIT.

20

Methylation of L-MIT was considered since alpha0125ILA@.J.

methylationâ€˜4C-L-tyrosmne

has been reported to bring metabolic stability

to the tyrosine molecule (21,22). Radioiodination of alpha-methyl

substituted

L-MIT was carried out and the

FIGURE5. Brainuptakeindexof 125l-L-AMT
andâ€œC-L-tyrometabolic stability of radiolabeled I-L-AMT needed for its
sine determinedin rats. Each bar representsthe meanÂ±s.d. of brain transport measurement was screened.
four to six animals. L-AMT and L-tyrosine were loaded at 1 x
io@M.(Vertically
stripedbar,controlBUI;openbar,L-tyrosine, In the early biodistribution stage, I-L-AMT showed
higher brain accumulation

than its non-methylated

L-MIT

and obliquely striped bar, L-AMT, at 1 x 1O@M were added
simultaneously). ; p < 0.005, @;p < 0.001.

and still higher, ifcompared with its parent â€˜4C-L-tyrosine;822

The Journalof NuclearMedicineâ€¢Vol. 32 â€¢
No. 5 â€¢May 1991

this difference

was assessed by the BUI. These results

indicated that not only methylation but the iodination of
the tyrosine molecule induced no interference in the transport affinity of L-tyrosine into the brain.
The most interesting findings were obtained in the post
injection analysis of tissue metabolites. As expected, thepresence of the methyl group in the alpha-position con

tributed to the stability of I-L-AMT against deiodination.
TLC analysis revealed only 1%â€”2%of free iodine com
pared with 65%â€”75%in the case of L-MIT. On the other
hand, a more systematic analysis of the brain homogenate

revealed the presence of more than 80% of the radioactiv
ity as unaltered

I-L-AMT with a lack of participationinprotein synthesis or other metabolic pathway, a distinctive
behavior from its parent â€˜4C-L-tyrosinecompound.

Thus,

the methylation in the alpha-position of the L-MIT might
have induced the loss of the tyrosine molecule affinity forthe metabolic pathway, but it kept the affinity for thetransport system. This concept is supported by the very

fast brain clearance of I-L-AMT observed 10â€”15mm
postinjection, while the brain accumulation of the parentâ€˜4C-L-tyrosine
was still increasing.
The data suggest that non-metabolizable I-L-AMT pro
vides one traceable characteristic of the parent L-tyrosine,
which is valuable for the measurement of amino acidtransport into the brain. To distinguish active transport
from simple diffusion, characterization ofl-L-AMT transport into the brain was performed. The in vivo as well as
in vitro studies revealed that I-L-AMT transport across the
blood-brain barrier is similar to its parent L-tyrosine (i.e.,saturable or carrier-dependent, temperature-dependent,
ouabain-inhibitable,
and cross-inhibitable only by L-tyrosine). Due to the unavailability of the methylated D-form,
no direct inhibition study could be performed, but the lackof inhibition with D-tyrosine might be considered as fur
nishing enough support for a stereospecific transport.

In

addition, the I-L-AMT n-octanol/phosphate buffer partition coefficient was too low for simple diffusion into thebrain to occur by its lipophilicity (21), although the higher
brain accumulation of I-L-AMT than its parent can betraced to the slightly higher value of its partition coeffi
cient.

The structural requirements for amino acid transport
into the brain are strict. The present methodical screeningof tyrosine derivatives paved the way for the selection of
I-L-AMT, as a radiopharmaceutical for brain tyrosine
transport. Although I-AMT has already been reported as
an imaging agent of the pancreas (24,25), melanoma (15,26â€”28),or brain tumors (29), the stereoselective blood
brain barrier transport property, independent from theamino acid metabolism, might serve as a tool not only forthe measurement oftyrosine transport in schizophrenia orother disease, but it also might be helpful in the building
up ofworkable amino acid tracer kinetic models. Recently,
human studies with 1231and â€˜24I-L-AMThave begun andgood quality of brain images has been reported (30). The

Cerebral Amino Acid Transport â€¢
Kawai et aIpresent study will provide an important basis for theevaluation of I-L-AMT accumulation in human brain.

ACKNOWLEDGMENT
The authors wish to thank Nihon Medi-Physics Co. Ltd. forthe generous supply of 123!-NaI.
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23. Levin VA. Relationship ofoctanol/water partition coefficient and molecular weight to rat brain capillary permeability. I Med Chem l980;23:682â€”
684.
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NuclMed 1979;20:973â€”976.
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SPECT. In: Cox PH, ed Progress in radiopharmacology, volume 3. Den
Haag Martinus Nijhoff; l982;97â€”107.
26. BockslaffH, Kloster G, StÃ¶cklin0, et al. Studies on L-3-['23IJiodo-methyl
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27. Bockslaff H, Kloster G, Dausch D, et al. First clinical results using L-3â€˜231-alpha-methyl
tyrosine for non-invasive detection of intraocular melanoma. Nuklearmedizin l981;(suppl 18):840â€”844.
28. Bockslaff H, Spitznas M, Hahn I, Kloster G. Noncontact detection ofexperimental amelanotic ocular melanoma with L-3-'23I-iodo-alpha-me
thyltyrosine. Albrecht v Graefes Arch K/in Ophihal 198I;2 17:255â€”266.
29. Biersack RI, Coenen HH, StOcklin G, et al. Imaging ofbrain tumors with
L-3-['23IIiodo-alpha-methyltyrosineand

SPECT. JNuclMed

l989;30: 110â€”112.
30. Langen K), Coenen HH, Roosen N, et al. SPECT studies ofbrain tumors
with L-3-['23IJiodo-alpha-methyltyrosine: comparison with PET, â€˜241MT.
and first clinical results. J Nuci Med 1990;3 1:281â€”286.

(continued from page 802)

SELF-STUDY TEST

Gastrointestinal Nuclear Medicine
A. Thereisevidenceforobstruction
oftheafferent(proximal) limb of the Billroth II reconstruction

B. Onthebasisoftheimagesalone,itcan be concluded that enterogastric reflux is responsible for the4patient's symptoms.

C. A calculatedpeakenterogastricrefluxindexof64%@t@:

indicates that the patient's symptoms are likely to be@4;t:;.;@.,

relieved by surgical diversion of bile with a 45-cm
Roux-en-Ylimb.

D. Thepatient'ssymptoms
arelikelyrelatedto post
operative gastroesophageal reflux.

E. Theabsenceof biliousvomitingmakesit unlikelythat the patient's symptoms are related to alkaline
reflux gastritis.

Figure 2B
I-

ITEM 1: NeonatalJaundiceANSWER: D

In infants less than 3 months of age, assessing the degree of hepatic

extractionmay aid in differentialdiagnosis.Good extractionwith a highTheinitialangiographicphasewithrapidsequentialimagingisa useful liver-to-heartactivity ratio at 5 minutes is suggestive of biliary atresia.
component of hepatobiliary scintigraphy, in that unsuspected Visually,there is rapid clearance from the blood pool with prominent
abnormalities,such as an arteriovenousmalformationinthe liveror renal hepaticuptake Evaluationofthetimeâ€”activity
curveswillconfirmprompt
inflammatory lesion, may occasionally be demonstrated. Avascular, uptake of tracer by the liver with either no washout over 60 minutesor

photon-deficientareaswithinthelivermaysuggestcyst@
dilatedbileducts a slightdecreaseafterreachingpeakactivity.Thisisinkeepingwiththe
asinCaroli'sdiseaseora choledochal
cyst.Thereisnospecificalteration relativelygood hepatocytefunction at this stage. Beyond the age of 3

in hepaticperfusionusefulfordistinguishinghepatocytedysfunctionfrom months,the effectofthe prolongedobstructionon liverfunctionbecomesbiliary atresia, however.
evident as hepatic extraction decreases.If the initial hepatic uptake is
The kidneys are the alternate route of excretion of the@Tc-lDA poor,then the patient is more likelyto have neonatalhepatitis(or somederivatives.Renal and bladder activity is prominent with either poor othercauseof hepatocellulardysfunction).Typically,the timeâ€”activity
hepaticuptakeand excretion(eg., hepatitis),or good hepaticextraction curve shows an early peak due to vascular activity.The shape of thebutnoexcretion(biliaryatresia).Normally,somerenalandbladderactivity curve parallelsthat ofthe cardiac blood pool, becausethere is minimal

is expectedbecaus@dependingon the specificiminodiaceticacid

derivative 5%-15% ofthe injecteddose will be excretedbythe kidneys.

activeuptakebytheliver.Withlessseverehepatitisthe extractionratio
isdecreased.Thecurvesshowdelaysduptakebythe liverwitha washout

The degree of renal excretioncannot be used to difterentiate rateequal to or slightly greater than the rate of decrease in blood-pool
hepatocellulardiseasefroman obstructiveprocess.
activity.lnthe latterinstance,excretionintothe bowelmay be anticipatedInthenewbornperiod,itisnotusualtoseegooddefinitionoftheintra in the delayedimages.Thus,an evaluationofthe earlyhepaticextraction
hepaticducts,andvisualizationofthe gallbladderis infrequent.When and washoutduring the first 60 minutesmay suggest the presence ofthe gallbladderis seen,however,intrahepaticbiliaryatresiacan be biliary atresiaor neonatalhepatitis, provided the patient is less than 3
excluded. Extrahepaticobstruction is still possible,but dilatationof themonths old.

bileductswilloftenbeevidentbyultrasonography.
Nonvisualizationof Rfrences
thegallbladderisusualwithimpairedhepatocytefunction
andprolonged 1. Gerhold JP@
KlingensmithWC II, KuniCC.et al. Diagnosisof biliary atresiawith
hepatictransitofthe radiopharmaceutical.Thus,nonvisualizationofthe
intrahepatic bile ducts and gallbladder may be seen with both hepatitis

and biliary atresia,and thesefeaturescannot serveto distinguishthese

disorders.

824

radionuclide hepatobiliary imaging. Radiology 1983;146:499-504.
2. Majd M, Reba AC. Altman AP Effect of phenobarbital on @mTc-lDA
scintigraphy in the evaluation of neonatal jaundice. Semin Nuci Med
1981;11:194-204.

(continued

on p. 829)

The Journal of Nuclear Medicine â€¢Vol. 32 â€¢
No. 5 â€¢May 1991