A new single-photon emission computed tomography imaging agent for serotonin transporters: [123I]IDAM, 5-Iodo-2-((2- ((dimethylamino)methyl)phenyl)thio)benzyl alcohol

Full text of DOI:10.1021/jm9806751

© Copyright 1999 by the American Chemical Society
Volume 42, Number 3
February 11, 1999
Communications to the Editor
transporters: Ki ) 23.5 and 1.82 nM, respectively).
A New Sin gle-P h oton Em ission
Since SPECT is more widely available than PET, there
is a strong impetus to develop clinically useful SPECT
ligands for imaging SERT. Several radioiodinated trac-
ers designed for SPECT imaging have been tested
unsuccessfully, including 4-iodotomoxetine reported
previously from this laboratory.6 Only [123I]5-iodo-6-
nitroquipazine7-9 showed promising properties as an in
vivo tracer for imaging SERT sites in monkey’s brain.
However, no human study of this agent using SPECT
imaging has been reported. It has been widely suggested
that [123I]â-CIT (2â-carbomethoxy-3â-(4-iodophenyl)-
tropane), a SPECT imaging agent that binds to both
DAT and SERT, will be able to clarify pathological
changes in both dopaminergic and serotonergic systems.
However, differential kinetics of [123I]â-CIT binding to
DAT and SERT were observed.10-12 The effect of a
selective serotonin uptake inhibitor in human brain in
vivo has been directly measured by [123I]â-CIT/SPECT
imaging of SERT sites in depressed patients undergoing
treatment with citalopram.13 A more selective series of
compounds, nor-â-CIT (N-demethylated analogue of
â-CIT)14 and its related derivatives,15 has recently been
reported as improved SPECT imaging agents for SERT.
It is suggested that [123I]nor-â-CIT might be a suitable
alternative tracer for visualization of SERT sites in the
human brain with SPECT.14,16 However, [123I]nor-â-CIT
binds to both DAT and SERT, and the selectivity is not
sufficient to distinguish between these two monoamine
transporter sites. There is a strong impetus to find more
selective tracers for imaging SERT in the brain.
Com p u ted Tom ogr a p h y Im a gin g Agen t
for Ser oton in Tr a n sp or ter s: [123I]IDAM,
5-Iod o-2-((2-((d im eth yla m in o)m eth yl)-
p h en yl)th io)ben zyl Alcoh ol
Shunichi Oya,† Mei-Ping Kung,† Paul D. Acton,†
Mu Mu,† Catherine Hou,† and Hank F. Kung*,†,‡
Departments of Radiology and Pharmacology, University of
Pennsylvania, Philadelphia, Pennsylvania 19104
Received December 3, 1998
The serotonin reuptake or transporter sites (SERT)
are located specifically on the terminals and cell bodies
of the serotonergic neurotransmission system in the
brain. They are the primary binding sites for selective
serotonin reuptake inhibitors (SSRI)scommon antide-
pressant drugs such as fluoxetine, sertraline, and par-
oxetine.1,2 Imaging of SERT in humans would provide
a useful tool to understand how alterations of this
system are related to depressive illness and other
psychiatric disorders. In addition, the saturation of
SERT and its clinical consequences can be evaluated
by a direct measurement of SERT binding in patients
undergoing various drug treatments targeting these
sites. In the past few years, development of specific
tracers for in vivo PET (positron emission tomography)
or SPECT (single-photon emission computed tomogra-
phy) imaging of SERT has only met with a limited
success. The most successful PET ligand for imaging
SERT is [11C](+)McN5652 (trans-1,2,3,5,6,10â-hexa-
hydro-6-[4-(methylthio)phenyl]pyrrolo[2,1-R]isoquino-
lone),3-5 which showed excellent inhibition of 5-HT
reuptake in rat brain synaptosomes (Ki ) 0.40 nM) and
moderate selectivity toward other monoamine trans-
porters (DAT (dopamine) and NET (norepinephrine)
A chlorinated compound, 5-chloro-2-((2-((dimethy-
lamino)methyl)phenyl)thio)benzyl alcohol (403U76), was
reported as an inhibitor of serotonin uptake and nore-
pinephrine uptake in rat brain synaptosomes (Ki ) 2.1
and 55 nM, respectively).17-20 To develop a new SERT
selective imaging agent, a radioiodinated analogue,
5-iodo-2-((2-((dim et h yla m in o)m et h yl)ph en yl)t h io)-
benzyl alcohol (IDAM), has been synthesized in our
laboratory. The synthesis of IDAM (6) and its bromo
derivative 4 was achieved by a reaction sequence
outlined in Scheme 1. The direct coupling of 2,5-dibromo-
* Corresponding author: Hank F. Kung, Ph.D., Department of
Radiology, University of Pennsylvania, 3700 Market St, Rm 305,
Philadelphia, PA 19104. Tel: (215)662-3096. Fax: (215)349-5035.
E-mail: kunghf@sunmac.spect.upenn.edu.
† Department of Radiology.
‡ Department of Pharmacology.
10.1021/jm9806751 CCC: $18.00 © 1999 American Chemical Society
Published on Web 01/27/1999

334 J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 3
Communications to the Editor
Sch em e 1
benzoic acid (1) or 2,5-diiodobenzoic acid (7) with 2-thio-
N,N-dimethylbenzamide (2) was carried out in N,N-
dimethylacetamide (DMAC) with sodium methoxide to
give the desired compounds in good yield (59% and 44%
for 3 and 8, respectively). Only when 2-thio-N,N-
dimethylbenzamide (2) was freshly prepared was a good
coupling yield achieved. This may due to the fact that
the free thiol 2 was not stable upon prolonged standing
at room temperature. Compound 3 was reduced suc-
cessfully with BH3-THF. The bromo compound 4 was
converted to the corresponding tri-n-butyltin derivative
5 by a tetrakis(triphenylphosphine)palladium(0)-cata-
lyzed reaction with good yield (66%). The tin derivative
5 was successfully converted to IDAM (6) with excellent
yield (97%), or alternatively, 2-((4-iodo-2-carboxyphe-
nyl)thio)-N,N-dimethylbenzamide (8) was reduced to
IDAM (6) with 66% yield.21 Radioiodination was carried
out by an iododestannylation reaction; 5 was reacted
with radioactive sodium iodide (I-125 or I-123) in the
presence of hydrogen peroxide. The final no-carrier-
added [125I or 123I]IDAM (6) was purified using an HPLC
method (purity > 99%, tR ) 11.38 min, PRP-1 column
eluted, 1 mL/min, with a 80:20 mixture of acetonitrile
and 3,3-dimethylglutaric acid buffer, pH 7.4) as reported
previously.6
F igu r e 1. Comparison of MRI images (anatomy) and SPECT
images23 of [123I]IDAM (6) (SERT localization) presented in
transaxial, sagittal, and coronal views (between 60 and 120
min post iv injection). [123I]IDAM ([123I]6) localized with high
concentration in midbrain (MB) (raphe nucleus, substantia
nigra, hypothalamus), where the SERT concentration is high;
it displayed no specific uptake in cerebellum (CER) (area
lacking SERT). Ratio of MB/CER at 120 min was 2.4.
In vitro binding studies were performed using mem-
brane preparation from LLC-PK1 cells individually
expressing monoamine transporters (kindly provided by
Dr. Rudnick, Yale University22). IDAM (6) displayed a
high binding affinity to SERT (Ki ) 0.097 nM). The
binding affinity to the other two monoamine transport-
ers is much lower (Ki ) >10 000 and 234 nM for DAT
and NET, respectively). The bromo derivative 4 dis-
played a lower binding affinity for SERT and lower
SERT/NET selectivity (Ki ) 0.52, >10 000, and 35 nM,
for SERT, DAT, and NET, respectively, while (+)-
McN5652 showed Ki ) 0.01, 112, and 11.3 nM under
the same conditions). It appears that IDAM (6) dis-
played a superior binding affinity for SERT and higher
SERT/DAT and SERT/NET selectivity than 4 and (+)-
McN5652. It is interesting to note that by changing the
substitution group from the chloro of 403U76 to the iodo
group as in IDAM (6) the selectivity for SERT binding
is dramatically improved: Ki(NET)/Ki(SERT) > 1000.
Initial biodistribution study in rats (iv injection) showed
a rapid brain uptake and washout (2.78%, 1.17%, 0.50%,
and 0.17% dose/organ at 2, 30, 60, and 120 min,
respectively). More importantly the hypothalamus re-
gion where the serotonin neurons are located exhibited
a high specific uptake. Hypothalamus/cerebellum ratio
based on %dose/g of these two regions showed a value
of 1.29, 2.21, 2.76, and 2.68 at 2, 30, 60, and 120 min,
post iv injection, respectively. Preliminary imaging
study of [123I]IDAM ([123I]6) in the brain of a baboon by

Communications to the Editor
J ournal of Medicinal Chemistry, 1999, Vol. 42, No. 3 335
SPECT23 at 60-120 min post iv injection showed an
excellent contrast in midbrain area where SERT are
found with a high density (Figure 1). The specific uptake
in the midbrain region in the brain of baboons can be
displaced by a chasing dose of (+)McN5652, a SERT
ligand, but not with nisoxetine, a selective NET ligand
(data not shown). The biological properties of [123I]IDAM
(6) show promise to be a superior SPECT imaging agent
for in vivo evaluation of this important serotonin bind-
ing site in the brain.
In conclusion, a new iodinated SERT ligand, 5-iodo-
2-((2-((dimethylamino)methyl)phenyl)thio)benzyl alcohol
(IDAM) (6), was developed. This novel ligand showed
excellent binding affinity and selectivity, and it may be
useful as an in vitro and in vivo tool for studying the
SERT binding sites.
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Ack n ow led gm en t. This work was supported by
grants awarded by the National Institutes of Health (NS
35120 and MH-48125).
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-
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C
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(23) The SPECT images were obtained by a triple-head gamma
camera equipped with ultra-high-resolution fan-beam collima-
tors (Picker Prism 3000). The acquisition parameters comprised
a rotational radius of 14 cm, a 15% energy window centered on
159 keV, 120 projection angles over 360°, and a 128 × 128 matrix
with a pixel width of 2.11 mm in the projection domain. Data
collection started immediately after iv injection of 555 MBq (15
mCi) of [123I]IDAM. Forty-eight 5-min scans were carried out
over a total time period of 240 min. The projection images were
reconstructed by filtered-back projection. Then, a 3D low-pass
Butterworth filter was applied. For uniform attenuation correc-
tion, Chang’s first-order method was used. The MRI scans were
acquired on a 1.5-T instrument (GE Medical Systems, Milwau-
kee, WI) with a spoiled GRAS sequence that produces 0.97- ×
0.97- × 1-mm voxels. The MRI scans were resized and resliced
in planes parallel to the one containing the anterior and posterior
commissures.
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the living human brain. Eur. J . Nucl. Med. 1995, 22, 346-350.
J M9806751