Cationic [99mTcIII(DIARS)2(SR)2]+ complexes as potential myocardial perfusion imaging agents (DIARS = o-phenylenebis(dimethylarsine);SR- = thiolate).

Article abstract of DOI:10.1021/jm9507789

Reduction-substitution reactions on [99mTcO4]- with both o-phenylenebis(dimethylarsine) (DIARS) and various thiols produce a series of monocationic [99Tc(DIARS)2(SR)2]+ complexes. Addition of [99gTcO4]- to the above reaction mixtures allows the characterization of the "carrier-added" complexes by means of reverse-phase high-performance liquid chromatography with radiometric and optical detection systems. The identity of the [99mTc(DIARS)2(SR)2]+ complexes is confirmed by fast atom bombardment mass spectroscopy; equivalence of the [99gTc(DIARS)2-(SR)2]+ and [99mTc(DIARS)2(SR)2]+ species is demonstrated by identical HPLC retention times. All the [99mTc(DIARS)2(SR)2]+ complexes tested accumulate in the myocardium of Sprague-Dawley rats with an average uptake of 1.5-2.0% of injected dose/g at 30 min. Thus, as designed, these nonreducible Tc(III) complexes do not exhibit the rapid myocardial washout observed for reducible Tc(III) complexes. These [99mTc(DIARS)2(SR)2]+ complexes also exhibit an initially high liver uptake, but the presence of ether groups within the thiolate ligands causes this liver uptake to decrease over time without affecting the heart uptake, thereby improving the heart/liver ratio.

Full text of DOI:10.1021/jm9507789

J . Med. Chem. 1996, 39, 1253-1261
1253
Ca tion ic [99m TcIII(DIARS)2(SR)2]+ Com p lexes a s P oten tia l Myoca r d ia l P er fu sion
Im a gin g Agen ts (DIARS ) o-p h en ylen ebis(d im eth yla r sin e); SR- ) th iola te)
Francesco Tisato,† Theodosia Maina, Li-Ren Shao,‡ Mary J ane Heeg,* and Edward Deutsch§
Istituto di Chimica e Tecnologie Inorganiche e dei Materiali Avanzati, Corso Stati Uniti 4, 35020 Padova, Italy, and
Mallinckrodt Medical, Inc., 675 McDonnell Boulevard, St. Louis, Missouri 63134-0840
Received October 18, 1995X
Reduction-substitution reactions on [99mTcO4]- with both o-phenylenebis(dimethylarsine)
(DIARS) and various thiols produce a series of monocationic [99mTc(DIARS)2(SR)2]+ complexes.
Addition of [99gTcO4]- to the above reaction mixtures allows the characterization of the “carrier-
added” complexes by means of reverse-phase high-performance liquid chromatography with
radiometric and optical detection systems. The identity of the [99gTc(DIARS)2(SR)2]+ complexes
is confirmed by fast atom bombardment mass spectroscopy; equivalence of the [99gTc(DIARS)2-
(SR)2]+ and [99mTc(DIARS)2(SR)2]+ species is demonstrated by identical HPLC retention times.
All the [99mTc(DIARS)2(SR)2]+ complexes tested accumulate in the myocardium of Sprague-
Dawley rats with an average uptake of 1.5-2.0% of injected dose/g at 30 min. Thus, as designed,
these nonreducible Tc(III) complexes do not exhibit the rapid myocardial washout observed
for reducible Tc(III) complexes. These [99mTc(DIARS)2(SR)2]+ complexes also exhibit an initially
high liver uptake, but the presence of ether groups within the thiolate ligands causes this
liver uptake to decrease over time without affecting the heart uptake, thereby improving the
heart/liver ratio.
In tr od u ction
[TcIII/IID2(SR)2]+/0 species is crucial in determining
whether the parental Tc(III) complex remains cationic
in vivo or whether it undergoes in vivo reduction to
Tc(II) which will lead to myocardial washout.11 It has
been observed that [TcIII(DMPE)2(SR)2]+ complexes are
much more resistant to reduction to TcII than their
dihalo [TcIII(DMPE)2X2]+ analogues;10,12 in other words,
thiolato ligands enhance the redox stability of these
trans-[TcIII/IID2X2]+/0 complexes, where D represents
a tertiary diphosphine or diarsine and X represents a
halide or thiocyanate,1-3 have received considerable
attention in the last decade because (i) they were among
the very first technetium complexes to be fully charac-
terized utilizing macroscopic amounts of 99gTc2 and (ii)
their 99mTc analogues exhibit important biological prop-
erties.3 In fact, trans-[TcIII(DMPE)2Cl2]+ (where DMPE
) 1,2-bis(dimethylphosphino)ethane) was the first cat-
ionic 99mTc complex to be evaluated as a myocardial
perfusion imaging agent in humans.4 Unfortunately,
it suffers in vivo reduction to the neutral trans-
Tc(III) complexes. Similarly, while dihalo [TcIII
-
(DIARS)2X2]+ (where DIARS ) o-phenylenebis(dimeth-
ylarsine)) complexes are easier to reduce than the
corresponding DMPE derivatives because of the in-
creased π-acidity of the As-based backbones, the addi-
tion of strong σ-donating alkylthiolato ligands brings
[TcIII(DIARS)2(SR)2]+ complexes out of the range of
biologically accessible reduction.10d,12 Therefore, in vivo
reduction of [TcIII(DIARS)2(SR)2]+ to its Tc(II) form is
not possible, and myocardial washout should be blocked.
In addition, variations in the R group of the thiolato
ligand allow important properties (e.g., lipophilicity) of
the [99mTc(DIARS)2(SR)2]+ complexes to be subtly var-
ied, and in this way the overall biodistribution of the
complexes can be controlled.
[
99mTcII(DMPE)2Cl2]0 form, which washes out of the
heart and accumulates in the liver.5 Even though this
initial candidate technetium cation did not succeed as
a myocardial imaging agent,6 the general approach of
using cationic technetium complexes has generated
several successful examples (Figure 1).
Among these, 99mTc-MIBI (Cardiolite),7 hexakis-
(methoxybutylisonitrile)technetium(I), has been ap-
proved by the FDA for myocardial infarct imaging, and
at least two other cationic tracers are in clinical trials
99mTc-Q12, a mixed N2O2-donor Schiff base/phosphine
In this paper we report on the reduction-substitution
reactions of “no carrier-added” [99mTcO4]- with both
DIARS and a series of thiols (n-propanethiol, 1; 2-meth-
oxyethanethiol, 2; 2,3-dimethoxypropanethiol, 3; 2,2-
dimethyl-4-(mercaptomethyl)-1,3-dioxolane, 4; 2-(2-
mercaptoethyl)-1,3-dioxane, 5; and 1-methoxy-2-(meth-
oxymethylene)pentane-5-thiol, 6; see Figure 2) to yield
a group of new monocationic [99mTcIII(DIARS)2(SR)2]+
complexes. Also reported are the chemical character-
izations of these new thiolato Tc(III) complexes, as well
as their biodistributions in Sprague-Dawley rats.
(
Tc(III) cation,8 and 99mTc-P53, a trans-dioxobis(diphos-
phine) Tc(V) cation9).
Synthetic strategies in the development of new
[TcIII/IID2X2]+/0 complexes include the replacement of the
X ligands by thiolato groups (SR-).10 In this strategy,
the organic R substitutent can be systematically and
subtly varied to create Tc complexes which have incor-
porated carefully controlled properties. Among these
properties, the Tc(III/II) redox potential of the
* To whom correspondence should be addressed at the Department
of Chemistry, Wayne State University, Detroit, MI 48202-3489.
† ICTIMA.
Resu lts a n d Discu ssion
‡ Current address: Isotec, Inc., 3858 Benner Rd., Miamisburg, OH
45342.
Liga n d P r ep a r a tion . Thiols 1 and 7 are com-
mercially available. The preparation of thiols 2-6 is
outlined in Scheme 1. Thiol 2 is made by reacting
§ Mallinckrodt Medical, Inc.
X Abstract published in Advance ACS Abstracts, February 1, 1996.
0022-2623/96/1839-1253$12.00/0 © 1996 American Chemical Society

1254 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 6
Tisato et al.
F igu r e 1. Cationic 99mTc complexes developed as possible myocardial imaging agents.
pressure, mass spectrometry, and 1H and 13C NMR
spectroscopy. Elemental analyses are also reported for
thiols 2 and 5. The physical data are reported in the
Experimental Section. In general, the proton NMR
spectra of all free thiols show a sharp triplet at ∼1.50
ppm, characteristic of the S-H proton coupled with the
vicinal methylene system. The complete assignment of
the other proton signals can be made from the relative
integrations, spin-spin splittings, homonuclear decoup-
ling, and two-dimensional homonuclear shift correla-
tions (2D-COSY).13 A typical 2D-COSY contour plot is
shown in Figure 3.
The synthesis of [99mTc(DIARS)2(SR)2]+ complexes
requires both high temperature and acid conditions (1
M CF3SO3H; pH range 1.5-3.5). Consequently, the
stability of each free thiol is tested in hot, acidic media
by proton NMR to mimic the ethanolic solutions em-
ployed during the radiolabeling procedures. Stability
tests are conducted in 50/50 D2O/C2D5OD-d6 mixtures,
adjusting the pH with D3PO4. Thiols 1-3 and 6, as well
as the DIARS ligand, prove stable for 1 h at pH 1.5, 80
°C. Conversely, thiol 4 hydrolyzes completely within a
few seconds under these conditions, to yield acetone and
3-mercapto-1,2-propanediol as hydrolysis products.
Therefore, thiol 4 was not utilized for labeling. The
acetal ring of thiol 5 hydrolizes within 15 min at pH
1.5 and 80 °C, producing a characteristic aldehyde
proton signal of the 2-thiopropionaldehyde at 9.50 ppm
and two related multiplets of 1,3-propanediol at 3.70
and 1.70 ppm, respectively. Under less stringent condi-
tions (i.e., 80 °C and pH 3.5) the observed hydrolysis is
greatly reduced and more than 90% of the free thiol 5
remains intact after 15 min, allowing the radiolabeling
reaction to proceed.
F igu r e 2. Thiols used in the synthesis of [TcIII(DIARS)2(SR)2]+
complexes.
1-chloro-2-methoxyethane with thiourea in refluxing
95% ethanol. The resulting S-alkylisothiouronium salt
can be hydrolyzed in a sodium hydroxide solution to
yield the desired thiol as a separate oil layer. Thiols
3-6 are synthesized by the reaction of freshly prepared
aqueous sodium thiocarbonate with an alcoholic solution
of the appropriate parental halide as detailed in Scheme
1. The resulting mixtures are then acidified with HCl
and the target thiols extracted in ether.
Ch a r a ct er iza t ion of [99m TcIII(DIAR S)2(SR )2]+
Agen ts. The reduction-substitution reaction of [TcO4]-
with thiols and either diphosphines or diarsines (D) is
a well-documented route of synthesis for [TcIII/IID2(SR)2]+/0
complexes.10 The thorough characterization of these
compounds utilizing macroscopic amounts of the long-
Liga n d Ch a r a cter iza tion a n d p H Sta bility. Thi-
ols 2-6 are characterized by boiling point at reduced

[
99mTcIII(DIARS)2(SR)2]+ for Myocardial Perfusion Imaging
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 6 1255
Sch em e 1
lived isotope 99gTc has established their structural,
spectroscopic, and electrochemical properties. The re-
dox properties of [99gTcIII(DIARS)2(SR)2]+ 10d complexes
confirm that they are incapable of undergoing reduction
in vivo. Therefore, we have prepared a series of [99mTcIII-
(DIARS)2(SR)2]+ analogues at the “no carrier-added”
level in order to investigate both their ability to ac-
cumulate in the myocardium and their resistance to
myocardial washout which is hypothesized to result
from in vivo reduction of Tc(III) to Tc(II).
The 99mTc labeling procedure mimics the reduction-
substitution method utilized in the macroscopic 99gTc
syntheses. Commercially available sodium 99m-pertech-
netate, metathesized to the organically soluble tetrabu-
tylammonium salt, is brought into reaction with a
solution of DIARS and the appropriate neat thiol in
acidic ethanol. The reaction produces low-valence cat-
ionic species which are monitored by liquid chromatog-
raphy coupled with radiometric detection. The reduc-
tion-substitution reaction is accomplished via either a
one-step procedure (addition of both DIARS and thiol
followed by heating) or a two-step procedure (addition
of DIARS first followed by heating/cooling and subse-
quent addition of the neat thiol with further heating)
depending on the thiol employed. The two-step reaction
allows the generation of an intermediate species pre-
sumed to be a Tc(V) complex such as [TcV
O2(DIARS)2]+.2b
Two representative chromatograms are illustrated in
Figure 4. They show the different retention times
exhibited by the DIARS-containing Tc(V) intermediate
and the mixed DIARS-thiol Tc(III) product under
identical chromatographic conditions. The Tc(V) com-
plex elutes first, tracing as a broad peak which char-
acteristically results from interactions of oxo groups
with the silica-based stationary phase of the column.
The unambiguous identification of the Tc(III) product
is obtained by “carrier-added” experiments, wherein
both 99mTc and 99gTc radionuclides are present in the
reaction mixture. The reaction mixture is assayed by
HPLC simultaneously monitored by radiometric and
optical detection systems. The peaks arising from the
radiolabeled species in the radiometric trace show the
same retention times as those exhibited by the corre-
sponding species in the UV-vis trace. In addition, the
99gTc(III) species show an intense absorption in the
visible region around 600 nm, typical of all the blue
[
99gTcD2(SR)2]+ complexes previously characterized at
the macroscopic level.10 Conclusive characterization of

1256 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 6
Tisato et al.
Ta ble 1. Retention Times in Reverse-Phase HPLC of Related
99mTc Complexesa
complex
tR (min)
[TcVIIO4]-
2.5
7.0
[TcVO2(DIARS)2]+
[TcIII(DIARS)2(SR1)2]+
[TcIII(DIARS)2(SR2)2]+
[TcIII(DIARS)2(SR3)2]+
[TcIII(DIARS)2(SR5)2]+
[TcIII(DIARS)2(SR6)2]+
[TcIII(DIARS)2(SR7)2]+
15.0
10.0
8.5
9.7
10.1
5.6
a
The thiolates represented by SR1-SR7 are diagrammed in
Figure 2. Chromatographic conditions are described as MP2 in
the text. In this chromatographic system, it is usually assumed
that lipophilicity increases with increasing retention time. Thus,
thiol 1 gives the most lipophilic complex, while thiol 7 gives the
least lipophilic complex.
retention times (tR) are summarized in Table 1.
A
hydrophilic thiol derivative, 2-mercaptoethanol (thiol 7),
is included in the study for comparison purposes. As
expected, [99mTcO4]- elutes at the solvent front at tR
)
2.5 min, whereas the Tc(V) species, [99mTcO2(DIARS)2]+,
follows at 7 min. All the mixed DIARS-thiolato 99mTc-
(III) complexes considered herein for biological studies
elute after 8 min with the complexes containing thiols
2, 5, and 6 exhibiting practically identical retention
times around 10 min. The complex with thiol 1, which
bears no ether functionalities in the thiolato organic R
group, elutes much later at 15 min. Interestingly, the
complex of thiol 7 shows surprisingly high hydrophilic
character for a Tc(III) species, eluting even before the
Tc(V) complex.
F igu r e 3. 2D-COSY90 1H NMR (250-MHz) contour plot of
thiol 5. The cross peaks outside of the diagonal account for
the scalar couplings of vicinal protons. The couplings of the
alkyl chain protons are connected with a solid line. The other
spots on the diagonal and related cross peaks belong to the
methylene system of the 1,3-dioxane ring.
Biodistr ibu tion . The biodistributions of the [99mTcIII-
(DIARS)2(SR)2]+ complexes reported herein are evalu-
ated in female Sprague-Dawley rats. Purification of
the radiolabeled product before injection is necessary
in order to remove excess ligand as well as any radio-
chemical impurity formed during the labeling procedure.
For this purpose, the radiolabeled reaction mixture is
usually diluted with water and loaded onto a Sep-Pak
C18 cartridge previously activated with 10% ethanol.
The cartridge is then rinsed with water, ethanol/water,
and ethanol solutions, and finally, the radiolabled
product is eluted with lithium trifluoromethanesulfonate
in ethanol. However, one complex, [99mTc(DIARS)2-
(SR6)2]+, had to be further purified by HPLC due to
heavy loss of activity when the cartridge method was
followed. The radiochemical purity and stability of the
resulting purified product is verified prior to in vivo
administration, as well as during the use period, by
HPLC, to guarantee >95% purity of the injected ra-
diopharmaceutical. This purified product is adminis-
tered to the animals through the jugular vein. Groups
of at least three rats are sacrificed at time intervals of
5, 15, 30, 60, and 120 min postinjection (pi). Cumulative
biodistribution data, calculated as percent injected dose
per gram (% ID/g), are shown in Table 2. All complexes
are found to be stable with respect to conversion to
pertechnetate in vivo, as indicated by the low amounts
of radioactivity detected in the stomach (these results
are not shown). All complexes exhibit low initial activity
in the blood followed by a very rapid blood clearance
(ca. 0.3% ID/g at 30 min pi). Activity is eliminated from
the body through both the hepatobiliary system and the
urinary tract. No brain uptake is found, as expected
from the overall +1 charge of the complexes. Lung
uptake is low, thus offering the possibility of a clear
F igu r e 4. HPLC chromatograms (radiometric traces) under
chromatographic conditions MP1 (see Experimental Section)
of (a) [99mTcVO2(DIARS)2]+ (tR ) 3.65 min) containing unreacted
[
99mTcO4]- (tR ) 1.86 min) and (b) [99mTcIII(DIARS)2(SR2)2]+ (tR
) 6.79 min). Numbers labeling the peaks represent retention
times in minutes. Integrated areas under the peaks represent
(a) 25.6% of concentration at 1.86 min, 71.2% at 3.65 min, and
(b) 93.0% at 6.79 min.
this colored species comes from positive ion FAB-MS,
which shows a parent ion consistent with the [99gTc-
(DIARS)2(SR)2]+ formulation.
The incorporation of one or more ether functionalities
in the thiolato R group (as in thiols 2-6) does not affect
the stoichiometry or net charge of the resulting Tc
complexes but is expected to influence their biological
properties as a function of relative stability and lipo-
philicity. Relative lipophilicity orderings are derived
from the comparison of reverse-phase HPLC retention
times under identical chromatographic conditions. The

[
99mTcIII(DIARS)2(SR)2]+ for Myocardial Perfusion Imaging
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 6 1257
Ta ble 3. Heart/Blood and Heart/Liver Ratios for
Ta ble 2. Biodistribution of [99mTcIII(DIARS)2(SR)2]+ Complexes
in Sprague-Dawley Ratsa
[
99mTcIII(DIARS)2(SR)2]+ Complexesa
time
complex
time (min) heart/blood heart/liver
(min) blood
liver
spleen
kidney
heart
lung
[
99mTcIII(DIARS)2(SR1)2]+
5
15
30
60
120
5
2.01(9)
0.08(4)
0.07(1)
0.06(8)
0.07(8)
0.06(5)
0.19(3)
0.16(4)
0.36(14)
0.69(7)
0.83(12)
0.25(4)
0.29(3)
0.39(7)
0.60(5)
0.60(5)
0.24(6)
0.34(10)
0.38(2)
0.53(16)
0.66(3)
0.40(6)
0.47(3)
0.51(4)
0.52(4)
0.64(11)
[
99mTcIII(DIARS)2(SR1)2]+
2.47(15)
3.32(13)
5.78(18)
6.63(21)
2.64(96)
4.82(1.35)
6.88(1.12)
8.48(90)
8.75(1.22)
5.29(52)
4.56(47)
6.17(71)
8.09(20)
5.81(1.38)
2.40(77)
5.08(71)
4.74(36)
5.83(58)
6.66(48)
2.36(34)
3.42(31)
3.80(30)
4.77(29)
6.71(1.46)
5
0.59(7) 15.43(1.43)
4.35(30) 1.19(10)
3.29(51) 0.91(11)
3.79(43) 0.95(9)
3.76(23) 1.00(25)
3.58(70) 0.88(27)
15 0.37(2) 13.72(5)
30 0.29(4) 15.96(1.08)
60 0.17(3) 13.95(2.72)
120 0.13(4) 13.76(81)
[
[
[
[
99mTcIII(DIARS)2(SR2)2]+
99mTcIII(DIARS)2(SR3)2]+
99mTcIII(DIARS)2(SR5)2]+
99mTcIII(DIARS)2(SR6)2]+
15
30
60
120
5
15
30
60
120
5
[
99mTcIII(DIARS)2(SR2)2]+
1.08(4) 13.04(12) 7.64(1.60) 22.56(1.11) 2.43(38) 2.54(10)
15 0.42(10) 12.66(93) 5.24(34) 16.41(1.77) 1.93(33) 2.22(12)
5
30 0.31(3)
60 0.22(3)
120 0.24(2)
6.24(72) 5.19(79) 18.71(1.87) 2.17(54) 1.94(9)
2.68(21) 2.57(47) 15.98(37) 1.87(32) 1.75(14)
2.50(27) 2.35(7)
99mTcIII(DIARS)2(SR3)2]+
7.40(1.07) 3.05(21) 10.07(1.02) 1.78(8) 1.42(8)
16.92(80) 2.03(8) 1.59(11)
[
5
0.34(6)
15 0.34(6)
30 0.24(1)
60 0.17(1)
120 0.20(5)
5.41(29) 1.90(31)
3.85(47) 2.06(22)
2.36(14) 1.71(11)
1.85(12) 1.26(8)
8.73(48) 1.59(12) 1.02(8)
6.33(49) 1.45(7) 0.92(5)
4.59(39) 1.40(6) 0.79(3)
3.20(11) 1.10(4) 0.79(1)
15
30
60
120
5
15
30
60
120
[
99mTcIII(DIARS)2(SR5)2]+
0.68(11) 6.78(1.29) 5.81(1.61) 8.39(57) 1.58(25) 2.74(8)
5
15 0.35(2)
30 0.27(2)
60 0.22(2)
120 0.16(1)
5.31(82) 3.97(68)
3.46(47) 3.63(71)
2.49(47) 2.49(34)
1.59(10) 1.31(23)
9.82(2.19) 1.78(35) 2.56(19)
6.21(1.00) 1.30(13) 2.31(29)
7.12(79) 1.28(20) 0.78(8)
5.92(61) 1.06(7) 0.54(14)
99mTcIII(DIARS)2(SR6)2]+
a
[
Standard deviations of last significant digits(s) are given in
5
0.62(8)
3.71(54) 1.21(25)
2.59(11) 1.11(9)
2.53(28) 1.28(11)
2.39(35) 1.37(15)
1.63(26) 1.02(14)
7.45(1.08) 1.45(20) 4.66(1.52)
6.31(1.24) 1.27(13) 3.28(80)
5.05(77) 1.30(16) 3.71(96)
5.54(49) 1.24(17) 2.38(78)
4.36(21) 1.02(5) 1.34(14)
parentheses.
15 0.37(0)
30 0.34(2)
60 0.26(2)
120 0.16(4)
contains one ether group per thiol at 13.04% at 5 min
pi and [99mTc(DIARS)2(SR6)2]+ which contains two ether
groups per thiol at 3.71% at 5 min pi). For thiol 6, a
greater number of hydroxy groups may be “unmasked”
in the liver resulting in a higher hydrophilicity and
therefore greater washout. The fast liver clearance and
constant % ID/g uptake values for the heart for [99mTc-
(DIARS)2(SR2)2]+ and [99mTc(DIARS)2(SR6)2]+ result in
increasing heart/liver ratios with time (see Table 3).
For the complexes of thiols 3, 5, and 6, wherein there
are two ether linkages per R group, a slow myocardial
washout is observed. Since the complexes of thiols 1
and 2 do not exhibit this washout, it is tempting to
presume that it is the multiple ether functionalities of
thiols 3, 5, and 6 which underlie the myocardial washout
phenomenon. If so, this may provide a means of using
99mTc complexes to monitor a myocardial metabolic
function. Further studies may determine if it is feasible
to establish bench-mark values for how rapidly these
multiple ether complexes are metabolized and then
cleared from the myocardium in normal, healthy indi-
viduals. This information could be used as a base line
against which to measure the clearance rate of these
complexes as an early predictor of impaired cardiovas-
cular function.
a
Data are presented as average percent injected dose/gram (%
ID/g). Standard deviations of last significant digits(s) are given
in parentheses.
visualization of the heart. Rapid heart uptake is
observed for all derivatives at 5 min pi (∼1.5-2.0% ID/
g), and for the prototypical thiols 1 and 2, this uptake
remains relatively constant up to 2 h pi. This rapid
heart uptake in combination with the rapid blood
clearance results in high heart/blood ratios that increase
with time (i.e., for [99mTc(DIARS)2(SR2)2]+ the initial
heart/blood ratio at 5 min is 2.6 and increases to 8.7 at
2 h pi; see Table 3). Interestingly, the more function-
alized complexes derived from thiols 2, 5, and 6 exhibit
a slow myocardial washout.
Of particular interest is the comparison of the liver
uptake and washout between the lipophilic [99mTc-
(DIARS)2(SR1)2]+ complex (SR1 ) CH3CH2CH2S-) and
the rest of the group studied. Whereas [99mTc(DIARS)2-
(SR1)2]+ has a relatively high liver uptake (15.4% ID/g
at 5 min pi) that remains practically constant up to 2 h
pi, the rest of the compounds show lower initial liver
uptake and by far more rapid liver clearance (cf. [99mTc-
(DIARS)2(SR3)2]+ exhibits an initial liver uptake of 7.4%
ID/g at 5 min pi which decreases to 1.8% ID/g at 2 h
pi). The fast liver washout of these complexes can be
attributed to the ether functionalities incorporated into
the thiolato ligand. These groups may undergo hy-
drolysis in the liver, thus giving rise to the correspond-
ing hydroxy derivatives which are very hydrophilic (see
Table 1, compound [99mTc(DIARS)2(SR7)2]+). As a con-
sequence, these agents are then rapidly washed out of
the liver, yielding a high heart/liver ratio. The fact that
multiple ether functionalities in the thiolate ligand
decrease liver uptake and enhance liver clearance
further supports this hypothesis (compare liver uptake
and washout between [99mTc(DIARS)2(SR2)2]+ which
Non r edu cible Tc(III) Myocar dial Im agin g Agen ts.
The synthetic design strategy pursued herein stems
from the results of biodistribution experiments which
compared analogous 99mTc and 186Re complexes. Al-
though the biological milieu cannot distinguish between
[
[
99mTcI(DMPE)3]+ and [186ReI(DMPE)3]+ complexes, when
99mTcIII(DMPE)2Cl2]+ and [186ReIII(DMPE)2Cl2]+ are
coinjected into rats the chemical processes of the
biological milieu readily reduce the 99mTc(III) complex
but not the 186Re(III) complex.5 The difference in
reduction potential between [99gTcIII(DMPE)2Cl2]+ and
[ReIII(DMPE)2Cl2]+ is 190 mV under laboratory condi-
tions. The cationic nature of the [99mTcIII(DMPE)2Cl2]+
complex encourages initial myocardial uptake. How-

1258 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 6
Tisato et al.
samples were counted on an LKB Wallace 1282 Compugamma
Universal gamma counter.
ever, as the positive charge is lost in the Tc(III) f Tc-
(II) reduction, the neutral 99mTc complex is transported
out of the heart and processed through the liver. These
observations imply that useful heart imaging agents
could be built upon the [99mTc-”mixed-ligand”]+ template
if in vivo reduction could be avoided. There are a
number of ways to modify [99mTcIII(DMPE)2Cl2]+ so that
it becomes more difficult to reduce. One successful
approach has been to reduce the number of phosphine
ligands, which are characterized by their ability to
accept π-density from the central metal, making it more
susceptible to chemical reduction. The “Q” series of
technetium complexes8 were designed on this principle
and contain an N2O2P2 donor set, as opposed to the
Cl2P4 donor set of [99mTcIII(DMPE)2Cl2]+. Clinical stud-
ies have demonstrated the effectiveness of more than
one “Q” example as myocardial imaging agents. It is
expected that one such complex, “Q12”, will be approved
for commercial distribution in the United States and
Europe (see Figure 1). The success of this strategy to
design cationic, mixed-ligand, nonreducible 99mTc com-
plexes is completely applicable to the [99mTc(DIARS)2-
(SR)2]+ complexes evaluated herein. They are suf-
ficiently robust as cations to resist reduction to Tc(II),
and they exhibit significant initial myocardial uptake.
Yet some interesting biological processing occurs when
multiple etheric groups are attached to each thiolato
ligand, and this processing may be capitalized on in the
future. It is possible that the judicious choice of R group
in this series of [99mTc(DIARS)2(SR)2]+ complexes will
produce myocardial imaging agents which produce
unique clinical utility.
Syn th eses: 2-Meth oxyeth a n eth iol (Th iol 2). A mixture
of 1-chloro-2-methoxyethane (49 g, 0.52 mol), thiourea (39.45
g, 0.52 mol), and 95% ethanol (250 mL) was refluxed on a
steam cone for 24 h. A solution of sodium hydroxide (30 g,
0.75 mol) in water (300 mL) was added, and the mixture was
further refluxed for 2 h. During this period the desired thiol
separated as an oil. The layers were separated, and the
aqueous phase was acidified with dilute sulfuric acid (7 mL of
concentrated H2SO4 in 50 mL water) and then extracted with
one 75 mL portion of diethyl ether. The organic phase was
added to the crude thiol layer and dried over anhydrous
sodium sulfate (43%): bp 108-110 °C; mass calcd for C3H8OS
(M+) m/z 92.0296, found 92.03. 1H NMR δ (ppm): 1.56 (t, 1H,
S-H), 2.68 (dt, 2H, CH2-SH), 3.51 (t, 2H, CH2-OCH3), 3.36 (s,
3H, O-CH3). 13C NMR δ (ppm): 24.2, 58.6, 74.1. Anal. Calcd
for (C3H8OS): C, 39.1; H, 8.8; S, 34.8. Found: C, 39.8; H, 8.95;
S, 34.66.
1-Ch lor o-2,3-d im eth oxyp r op a n e (3a ). 3-Chloro-1,2-pro-
panediol was dissolved in iodomethane and methylated in the
usual manner14 by addition of silver oxide. The spontaneous
reaction was sustained by warming in a water bath; an
additional amount of iodomethane was added when the
mixture became pasty. The reaction mixture was extracted
three times with diethyl ether and the organic solution
evaporated to give a clear colorless liquid (54%): bp 156 °C;
mass calcd for C5H11O2Cl (M+) m/z 138.0447, found 138.04.
2,3-Dim et h oxyp r op a n et h iol (Th iol 3). 1-Chloro-2,3-
dimethoxypropane (3a ) (14.52 g, 0.105 mol) was added within
25 min to 33% aqueous sodium thiocarbonate15 (70.88 mL, 0.15
mol) at room temperature. The reaction mixture was then
heated at 60 °C and stirred for 5 h (no CS2 evolution was
observed). The basic mixture was treated with diethyl ether
and the separated aqueous layer acidified with concentrated
HCl, thus promoting the evolution of CS2. The gas was totally
removed by evaporation under reduced pressure. The acidic
aqueous layer was treated three times with diethyl ether, and
the combined organic extracts were washed with H2O, dried
over anhydrous magnesium sulfate, and evaporated at reduced
pressure to give 10 g (70%) of the desired 2,3-dimethoxy-
propanethiol: bp 88-90 °C at 44 mmHg; mass calcd for
C5H11O2S (M+) m/z 136.0559, found 136.05. 1H NMR δ
(ppm): 1.52 (t, 1H, S-H), 2.70 (m, 2H, CH2-SH), 3.42 (m, CH-
OCH3), 3.52 (d, 2H, CH2-OCH3), 3.38 (s, 3H, CH2-OCH3), 3.44
(s, 3H, CH-OCH3). 13C NMR δ (ppm): 25.6, 58.1, 59.7, 72.9,
81.2.
2,2-Dim eth yl-4-(ch lor om eth yl)-1,3-d ioxola n e (4a ). Ac-
etone (150 mL, 2.05 mol), 3-chloro-1,2-propanediol (60 g, 0.55
mol), low-boiling petroleum ether (1.30 mL), and p-toluene-
sulfonic acid (1.5 g, 0.009 mol) were placed in a 500 mL three-
necked flask equipped with a magnetic stirrer and a fraction-
ating column (2 × 45 cm, packed with glass helices) attached
to a reflux phase separating head. The mixture was heated
under stirring so that the petroleum ether refluxed as rapidly
as the column allowed. The stirring and refluxing were
continued for 25 h until no more H2O was collected in the
separating head trap. The mixture was cooled to room
temperature, and sodium acetate (1.5 g) was added. The
resulting mixture was filtered, and the remaining petroleum
ether and acetone were removed from the filtrate by evapora-
tion under reduced pressure. The solution was then distilled
and the fraction boiling at 156-158 °C was collected, affording
127.5 g (85%) of the desired product: mass calcd for C6H11O2-
Cl (M+) m/z 150.0448, found 150.05.
2,2-Dim eth yl-4-(m er ca p tom eth yl)-1,3-d ioxola n e (Th iol
4). Compound 4a (13 g, 0.086 mol) was added dropwise within
25 min to a 33% aqueous sodium thiocarbonate solution (57
mL, 0.12 mol) at room temperature. The mixture was heated
under stirring at 60 °C for 5 h, and the resulting alkaline
solution was treated once with diethyl ether. The separated
layer was acidified with sulfuric acid and then extracted three
times with diethyl ether. The combined organic extracts were
washed with H2O, dried over anhydrous magnesium sulfate,
and evaporated at reduced pressure to give 7.77 g (61%) of
the desired thiol: bp 90-93 °C at 38 mmHg; mass calcd for
Exp er im en ta l Section
Rea gen ts. Unless otherwise noted, all chemicals were of
reagent grade. o-Phenylenebis(dimethylarsine) (DIARS) was
purchased from Strem Chemicals Co., checked before use by
proton NMR spectroscopy, and employed as a 1% ethanolic
solution. n-Propanethiol (thiol 1) and 2-mercaptoethanol (thiol
7) were purchased from Aldrich and used without further
purification. 99mTc was eluted as Na[99mTcO4] from a 99Mo/
99mTc commercial generator (Mallinckrodt Medical, Inc.) in
0.9% aqueous NaCl solution. Commercially available K[99gTcO4]
(Oak Ridge National Laboratory) was purified from a black
contaminant (99gTcO2‚nH2O) by addition of H2O2 and NH4OH
solutions followed by recrystallization as NH4[99gTcO4] from
hot water. The tetraalkylammonium salt was prepared by
addition of aqueous n-Bu4NCl to a suspension of NH4[99gTcO4]
in water. The white flocculent precipitate of the desired
n-Bu4N[99gTcO4] salt was removed by filtration and washed
with water and a few drops of Et2O.
Ap p a r a tu s. Elemental analyses were performed on a
Fisons model EA-1108 elemental analyzer. Proton and 13C
NMR measurements were performed on a Bruker NR-80 or
Bruker WM-250 instrument in CDCl3 using TMS as the
internal standard. High-resolution gas-mass spectra were
obtained on a Kratos MS-80 mass spectrometer. Positive ion
FAB-MS were recorded by using a glycerol matrix on a VG
30-250 spectrometer at ambient temperatures. A Beckman
model 114M liquid chromatograph equipped with a Beckman
170 radioactive detector was used to monitor “carrier free”
preparations. An ISCO liquid chromatograph equipped with
both an HP 1040 photodiode array detector and a Beckman
170 radioactive detector was employed to follow “carrier-added”
preparations. Reverse-phase C8 columns (27.5 × 0.5 cm from
Hamilton Co.) and guard columns filled with 10 µm size RP-
C8 packing material were utilized for all experimental prepa-
rations. Reverse-phase RP-C18 Sep-Pak cartridges (Waters
Assoc.) were used for both the production of n-Bu4N[99gTcO4]
and the purification of the radiolabeled species. Biological

[
99mTcIII(DIARS)2(SR)2]+ for Myocardial Perfusion Imaging
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 6 1259
C6H12O2S (M+) m/z 148.0558, found 148.05. 1H NMR δ
(ppm): 1.47 (t, 1H, S-H), 2.68 (m, 2H, CH2-SH), 4.21 (quintet,
1H, CH2-CH-CH2), 3.77 (dd, 1H, CH2(eq)-O), 4.11 (dd, 1H, CH2-
(ax)-O), 1.36 (s, 3H, C-CH3), 1.44 (s, 3H, C-CH3′). 13C NMR δ
(ppm): 25.5, 26.9, 27.6, 68.3, 109.7.
added. The vial was quickly capped and placed into an oil
bath at 85 °C for 15 min.16 The reaction mixture was left to
cool at ambient temperature, the vial was then opened, and
aliquots of the reaction mixture were analyzed by HPLC. The
desired thiol (40 µL) was then added to the cooled mixture,
and again the capped vial was placed into the oil bath at 85
°C for 10 min. The vial was left to cool at ambient tempera-
ture, and aliquots of the reaction mixture were once again
tested by HPLC (second step). The two-step reaction proce-
dure was necessary to optimize the yield when thiol 3 was
used, whereas in all other cases, both DIARS and thiol were
added together in one step to the degassed radioactive solution.
The capped vial was placed into the oil bath at 85 °C for 15
min. The reaction mixture was then left to cool at room
temperature, and aliquots were again analyzed by HPLC.
P r ep a r a tion of “Ca r r ier -Ad d ed ” Rea ction Mixtu r es.
A 5 mL borosilicate vial containing an ethanolic solution of
n-Bu4N[99mTcO4] (0.5 mL, 1-5 mCi) and a 0.02 M ethanolic
solution of n-Bu4N[99gTcO4] (56 µL) was prepared as described
above; then 1 M aqueous CF3SO3H (10 µL) was added. The
reaction mixture was degassed for 5 min, and while degassing,
the appropriate thiol (50 µL) and a 1% DIARS ethanolic
solution (120 µL) were added. The vial was quickly capped
and placed in an oil bath at 85 °C for 15 min. An intensive
blue-violet color always appeared at the end of the reaction.
The mixture was left to cool, and aliquots were subjected to
HPLC analyses using both radioactive and optical detection
modes. The HPLC fraction exhibiting both the correct reten-
tion time and the blue absorption was collected, its volume
was reduced by rotary evaporation, and finally it was submit-
ted for characterization by positive ion FAB-MS.
2-(2-Mer ca p toeth yl)-1,3-d ioxa n e (Th iol 5). 2-(2-Bromo-
ethyl)-1,3-dioxane (25 g, 0.128 mol) in methanol (20 mL) was
added dropwise within 1 h to a 33% aqueous sodium thiocar-
bonate solution (85 mL, 0.182 mol) in methanol (60 mL) under
stirring at room temperature. The mixture was allowed to stir
for 5 h, during which time essentially no CS2 formation was
observed. The basic reaction mixture was extracted with
diethyl ether and the aqueous layer acidified with concentrated
HCl, thus promoting the evolution of CS2 which was removed
by evaporation at reduced pressure. The acidic residue was
then extracted three times with diethyl ether. The combined
ether extract was washed with water, dried over magnesium
sulfate, and distilled under reduced pressure to give 10 g (56%)
of the desired thiol: bp 60-63 °C at 13 mmHg; mass calcd for
C6H12O2S (M+) m/z 148.0558, found 148.05. 1H NMR δ
(ppm): 1.39 (t, 1H, S-H), 2.62 (dt, 2H, CH2-SH), 1.90 (m, 2H,
CH2-CH2-CH), 4.68 (t, 1H, CH2-CH), 3.76 (m, 2H, O-CH2), 4.10
(m, 2H, O-CH2′), 1.33 (m, 1H, CH2-CH2(eq)-CH2), 2.07 (m, 1H,
CH2-CH2(ax)-CH2). 13C NMR δ (ppm): 19.2, 25.7, 39.2, 66.8,
100.4, 187.7. Anal. Calcd for (C6H12O2S): C, 48.6; H, 8.2; S,
21.6. Found: C, 49.2; H, 8.3; S, 22.0.
2-(3-Ch lor op r op yl)p r op a n e-1,3-d iol (6a ). To a refluxing
solution containing diethyl (3-chloropropyl)malonate (42 g, 0.18
mol) and sodium hydroxide (11.09 g, 0.18 mol) in tert-butyl
alcohol (224 mL) was added methanol (14 mL) in three aliquots
over 30 min. The resulting mixture was refluxed for 30 min
further and then allowed to cool to room temperature. HCl
(5 M) was added with care until the solution became neutral.
It was then filtered, and the filtrate was extracted with 2 ×
100 mL of ethanol. The ethanolic fractions were combined,
and the solvent was removed by rotary evaporation. The
residue was extracted again with ethanol (60 mL) and filtered.
The solvent was removed to afford 25 g (92%) of the desired
product as a colorless liquid.
1-Ch lor o-4,4-bis(m eth oxym eth yl)bu ta n e (6b). Dry sil-
ver oxide (153 g, 0.66 mol) was added gradually under
mechanical stirring to 6a (25 g, 0.166 mol) dissolved in
iodomethane (188 g, 1.32 mol) and the mixture refluxed for 6
h. Then additional iodomethane (90 g, 0.634 mol) was added
and the solution refluxed for another 18 h. After standing at
40 °C overnight, dry diethyl ether was added. The precipitate
was filtered off and the filtrate evaporated. The residual oil
was distilled to give the desired product (75%): bp 110-115
°C at 12 mmHg.
1-Meth oxy-2-(m eth oxym eth ylen e)pen tan e-5-th iol (Th i-
ol 6). To a 33% aqueous solution of sodium thiocarbonate (25
mL, 0.053 mol) was added 6b (6.73 g, 0.037 mol) in methanol
(5 mL) dropwise within 1 h with stirring at room temperature.
The reaction mixture was heated at 60 °C for 5 h. The cooled
solution was acidified with concentrated HCl and extracted
three times with diethyl ether. The combined organic fractions
were washed with water, dried over anhydrous magnesium
sulfate, and distilled to give 4 g (61%) of the desired thiol: bp
105-108 °C at 3 mmHg; mass calcd for C8H18O2S (M+) m/z
178.1028, found 178.1031. 1H NMR δ (ppm): 1.36 (t, 1H, S-H),
2.52 (dt, 2H, CH2-SH), 1.65 (m, 2H, CH2-CH2-CH2), 1.44 (m,
2H, CH2-CH2-CH), 1.82 (quintet, 1H, C-H), 3.36 (m, 4H, CH-
CH2-O), 3.33 (s, 6H, O-CH3). 13C NMR δ (ppm): 24.8, 27.6,
31.7, 38.9, 58.9, 73.3.
Ch r om a togr a p h y Con d ition s. Quality control tests were
performed using RP-C8 columns. All HPLC chromatograms
were obtained under isocratic conditions using the following
mobile phases: (i) 85/15 methanol/water solution containing
0.01 M sodium heptanesulfonate in total volume at a flow rate
of 1.5 mL/min (MP1) and (ii) 78/22 ethanol/water solution
containing 0.01 M ammonium acetate in total volume at a flow
rate of 1.5 mL/min (MP2).
Com p a r a tive Lip op h ilicity Stu d y. All 99mTc chelates
were subjected to HPLC analysis under identical chromato-
graphic conditions. The MP2 conditions outlined above were
selected for this experiment.
P u r ification P r ocedu r es: [99mTc(DIARS)2(SR1)2]+. Three
milliliters of water was added to the “carrier free” reaction
mixture (ca. 1 mL in ethanol) and the content of the vial loaded
onto a reverse-phase Sep-Pak C18 cartridge (Waters Assoc.)
previously activated with 10% ethanol (10 mL). The cartridge
was washed with water (5 mL), 1/2 ethanol/water (20 mL),
1/1 ethanol/water (10 mL), and ethanol (1 mL). The desired
cationic complex eluted with 0.13 M lithium trifluoromethane-
sulfonate in ethanol (1 mL). The filtrate was diluted with
physiological saline (9 mL) resulting in a final 10% ethanolic
solution suitable for iv injection.
[
99m Tc(DIARS)2(SR2)2]+. Nine milliliters of saline was
added to the “carrier free” preparation, and the content of the
vial was loaded onto a reverse-phase Sep-Pak C18 cartridge
(Waters Assoc.) previously activated with 10% ethanol (5 mL).
The cartridge was rinsed with water (10 mL) followed by 50%
ethanol (10 mL) and ethanol (2 mL). The desired 99mTc species
eluted with 0.13 M lithium trifluoromethanesulfonate in
ethanol (1 mL). The activity was diluted with physiological
saline (9 mL) to give a 10% ethanolic solution ready for
injection.
[
99m Tc(DIARS)2(SR3)2]+. A reverse-phase Sep-Pak C18
P r ep a r a tion of “Ca r r ier -F r ee” 99m Tc Rea ction Mix-
tu r es. A solution containing a mixture of Na[99mTcO4] (1 mL,
5-20 mCi) and 0.01 M n-Bu4NBr (1 mL) was loaded onto an
RP-C18 Sep-Pak cartridge previously activated with 95%
ethanol (3 mL) followed by 0.01 M n-Bu4NBr (3 mL). The
cartridge was rinsed with water (20 mL) and the activity
collected as n-Bu4N[99mTcO4] in ethanol (0.5-1.0 mL) (yield
90-95%). To this ethanolic solution was added 1 M CF3SO3H
(20-30 µL) (pH ) 1-3) in a 5 mL borosilicate vial. The
mixture was degassed for 5 min under an Ar stream, and while
degassing, a 1% ethanolic DIARS solution (30-50 µL) was
cartridge (Waters Assoc.) was activated with 10% ethanol (10
mL), and the activity from the “carrier free” preparation
previously diluted with physiological saline (9 mL) was loaded
onto it. The cartridge was washed with water (10 mL), 50%
ethanol (7 mL), and ethanol (2 mL). The 99mTc complex was
collected with 0.13 M lithium trifluoromethanesulfonate in
ethanol (1 mL). The filtrate was diluted with physiological
saline (9 mL) to obtain a 10% ethanolic solution suitable for
injection.
[
99m Tc(DIARS)2(SR5)2]+. A reverse-phase Sep-Pak C18
cartridge (Waters Assoc.) was activated by passing 10%

1260 J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 6
Tisato et al.
Biodistribution of Cationic Tc-99m Complexes. Nucl. Med. Biol.
1989, 16, 191-232.
ethanol (5 mL). To the radiolabeled mixture (1 mL) was added
physiological saline (9 mL), and the result was loaded onto
the cartridge. After rinsing with water (10 mL) and 50%
ethanol (5 mL), the activity was collected by eluting 0.13 M
lithium trifluoromethanesulfonate in ethanol (1 mL) through
the cartridge. The filtrate was then diluted with physiological
saline (9 mL) to obtain a 10% ethanolic solution ready for
injection.
(7) (a) J ones, A. G.; Abrams, M. J .; Davison, A.; Brodack, J . W.;
Toothaker, A. K.; Adelstein, S. J .; Kassis, A. I. Biological Studies
of a New Class of Technetium Complexes: the Hexakis(alkyl-
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[
99m Tc(DIARS)2(SR6)2]+. This 99mTc species was purified
before injection by HPLC (chromatographic conditions MP2
specified above). The isolated fraction containing [99mTc-
(DIARS)2(SR6)2]+ was concentrated by rotary evaporation and
the residue brought to the desired volume by adding physi-
ological saline to obtain a final 10% ehanolic solution.
An im a l Stu d ies. Female Sprague-Dawley rats (200 ( 20
g), anesthetized under metophan inhalation, were injected
intravenously (via the jugular vein) with 0.15 mL of a purified
99mTc complex (30-50 µCi) in 10% ethanol. At 5, 15, and 30
min after injection, groups of at least three rats were sacrificed
by cervical dislocation. At 60 and 120 min after injection,
additional groups of animals were sacrificed by CO2 asphixi-
ation. Immediately after death, a blood sample (ca. 1 mL) was
withdrawn from the heart. The organs of interest were
subsequently excised, weighed, and assayed for 99mTc content
relative to appropriate blank samples and standards. The
heart/blood and heart/liver ratios were calculated from the
respective percent dose/gram values.
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Tomography Using Technetium-99m-Tetrofosmin to Evaluate
Coronary Artery Disease. J . Nucl. Med. 1994, 35, 594-600.
(10) (a) Konno, T.; Kirchhoff, J . R.; Heineman, W. R.; Deutsch, E.
Thiolato-Technetium Complexes. 2. Synthesis, Characterization,
Electrochemistry and Spectroelectrochemistry of the Techne-
tium(III) Complexes trans-[Tc(SR)2(DMPE)2]+, Where R is an
Alkyl or Benzyl Group and DMPE is 1,2-Bis(dimethylphosphi-
no)ethane. Inorg. Chem. 1989, 28, 1174-1179. (b) Konno, T.;
Heeg, M. J .; Deutsch, E. Thiolato-Technetium Complexes. 3.
Synthesis and X-Ray Structural Studies on the Geometrical
Isomers cis- and trans-bis(p-chlorobenzenethiolato)-bis(1,2-bis-
(dimethylphosphino)ethane)techentium(II). Inorg. Chem. 1989,
28, 1694-1700. (c) Konno, T.; Seeber, R.; Kirchhoff, J . R.;
Heineman, W. R.; Deutsch, E. Thiolato-Technetium Complexes.
4. Synthesis, Characterization and Electrochemical Properties
of bis(1,2-bis(dimethylphosphino)ethane)technetium(III) Com-
plexes with Arene-Thiolato Ligands. Transition Met. Chem.
(London) 1993, 18, 209-217. (d) Konno, T.; Heeg, M. J .; Stuckey,
J . A.; Kirchhoff, J . R.; Heineman, W. R.; Deutsch, E. Thiolato-
Technetium Complexes. 5. Synthesis, Characterization, and
Electrochemical Properties of Bis(o-phenylenebis(dimethylars-
ine))technetium(II) and -technetium(III) Complexes with Thi-
olato Ligands. Single Crystal Structural Analyses of trans-
Ack n ow led gm en t. T.M. thanks the IAEA, Vienna,
Austria, for financial support, Grant No. C6/GRE/8804P.
Refer en ces
(1) Deutsch, E.; Bushong, W.; Glavan, K. A.; Elder, R. C.; Sodd, V.
J .; Scholz, K. S.; Fortman, D. L.; Lukes, S. J . Heart Imaging
with Cationic Complexes of Technetium. Science (Washington,
D.C.) 1981, 214, 85-86.
(2) (a) Hurst, R. V.; Heineman, W. R.; Deutsch, E. Technetium
Electrochemistry. I. Spectroelectrochemical Studies of Halogen,
DIARS and DIPHOS Complexes of Technetium in Non-Aqueous
Media. Inorg. Chem. 1981, 20, 3298-3303. (b) Vanderheyden,
J .-L.; Ketring, A. R.; Libson, K.; Heeg, M. J .; Roecker, L.; Motz,
P.; Whittle, R.; Elder, R. C.; Deutsch, E. Synthesis and Char-
acterization of Cationic Technetium Complexes of 1,2-bis(di-
methylphosphino)ethane (DMPE). Structure Determinations of
trans-[TcV(DMPE)2(OH)(O)](F3CSO3)2, trans-[TcIII(DMPE)2Cl2]F3-
CSO3, and [TcI(DMPE)3]+ using X-Ray Diffraction, EXAFS and
Technetium-99 NMR. Inorg. Chem. 1984, 23, 3184-3191. (c)
Ichimura, A.; Heineman, W. R.; Vanderheyden, J .-L.; Deutsch,
E. Technetium Electrochemistry. 2. Electrochemical and Spec-
troelectrochemical Studies of the Bis(tertiaryphosphine) (D)
Complexes trans-[TcIIID2X2]+ (X ) Cl or Br). Inorg. Chem. 1984,
23, 1272-1278.
(3) (a) Deutsch, E.; Glavan, K. A.; Sodd, V. J .; Nishiyama, H.;
Ferguson, D. L.; Lukes, S. J . Cationic Tc-99m Complexes as
Potential Myocardial Imaging Agents. J . Nucl. Med. 1981, 22,
897-907. (b) Nishiyama, H.; Adolph, R. J .; Deutsch, E.; Sodd,
V. J .; Libson, K.; Gerson, M. C.; Saenger, E. L.; Lukes, S. J .;
Gabel, M.; Vanderheyden, J .-L.; Fortman, D. L. Effect of
Coronary Blood Flow on Uptake and Washout of Technetium-
99m-Labeled DMPE and Thallium-201. J . Nucl. Med. 1982, 23,
1102-1110. (c) Nishiyama, H.; Deutsch, E.; Adolph, R. J .; Sodd,
V. J .; Libson, K.; Saenger, E. L.; Gerson, M. C.; Gabel, M.; Lukes,
S. J .; Vanderheyden, J .-L.; Fortman, D. L.; Scholz, K. L.;
Grossman, L. W.; Williams, C. C. Basal Kinetic Studies of
Technetium-99m-Labeled DMPE as a Myocardial Imaging Agent
in Dog. J . Nucl. Med. 1982, 23, 1093-1101. (d) Neves, M.;
Libson, K.; Deutsch, E. Neutral Technetium(II)-99m Complexes
as Potential Brain Perfusion Imaging Agents. Nucl. Med. Biol.
1987, 14, 503-510.
(4) Gerson, M. C.; Deutsch, E. A.; Nishiyama, H.; Libson, K. F.;
Adolph, R. J .; Grossman, L. W.; Sodd, V. J .; Fortman, D. L.;
Vanderheyden, J .-L.; Williams, C. C.; Saenger, E. L. Myocardial
Perfusion Imaging with 99mTc-DMPE in Man. Eur. J . Nucl. Med.
1983, 8, 371-374.
(5) Vanderheyden, J .-L.; Heeg, M. J .; Deutsch, E. Comparison of
the Chemical and Biologial Properties of trans-[Tc(DMPE)2Cl2]+
and trans-[Re(DMPE)2Cl2]+, where DMPE ) 1,2-bis(dimeth-
ylphosphino)ethane. Single Crystal Structural Analysis of trans-
[Re(DMPE)2Cl2]PF6. Inorg. Chem. 1985, 24, 1666-1673.
(6) Deutsch, E.; Ketring, A. R.; Libson, K.; Vanderheyden, J .-L.;
Hirth, W. The Noah’s Ark Experiment: Species Dependent

[
99mTcIII(DIARS)2(SR)2]+ for Myocardial Perfusion Imaging
J ournal of Medicinal Chemistry, 1996, Vol. 39, No. 6 1261
[Tc(SCH3)2(DIARS)2]PF6 and trans-[Tc(SC6H5)2(DIARS)2]o. Inorg.
Chem. 1992, 31, 1173-1181.
(11) Deutsch, E.; Hirth, W. In Vivo Inorganic Chemistry of Techne-
N-R-methylbenzylamido]nickel(II). Angew. Chem., Int. Ed. Engl.
1985, 24, 231-233.
(14) Fairbourne, A.; Gibson, G. P.; Stephens, W. The Partial Esteri-
fication of Polyhydric Alcohols. Part XI. The Five Methyl Esters
of Glycerol and Related Compounds. J . Chem. Soc. 1931, 445-
458.
(15) Na2CS3 was prepared by adding CS2 to a warmed aqueous
solution of sodium sulfide (Na2S). The unreacted CS2 was
removed by evaporation at reduced pressure, and the resulting
deep red liquid was diluted to give a 33% aqueous solution that
can be used within 1 week when stored at room temperature.
(16) The temperature must be strictly controlled. In fact, higher
temperatures cause formation of a stable chemical impurity
having a longer retention time with respect to both Tc(V) and
Tc(III) species and is tentatively assigned to be [TcI(DIARS)3]+.
See ref 2b.
tium Cations. J . Nucl. Med. 1987, 28, 1491-1500.
(12) (a) Hurst, R. W.; Heineman, W. R.; Deutsch, E. Technetium
Electrochemistry. 1. Spectroelectrochemical Studies of Halogen,
Diars and Diphos Complexes of Technetium in Nonaqueous
Media. Inorg. Chem. 1981, 20, 3298-3303. (b) Ichimura, A.;
Heineman, W. R.; Vanderheyden, J .-L.; Deutsch, E. Technetium
Electrochemistry. 2. ELectrochemical and Spectroelectrochemi-
cal Studies of the Bis(tertiary phosphine) (D) Complexes trans-
[TcIIID2X2]+ (X ) Cl, Br) and [TcID3]+. Inorg. Chem. 1984, 23,
1272-1278.
(13) Peters, W.; Fuchs, M.; Sicius, H.; Kuchen, W. The First Applica-
tion of 2D-NMR to the Spectral Analysis of a Paramagnetic
Complex. Example: Bis[R-(+)-P,P-diethylthiophosphinic acid-
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