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K.P. Maresca et al. / Inorganic Chemistry Communications 10 (2007) 1409–1412
preliminary report we describe the synthesis of (3,5-dime-
thoxy-benzyl)-bis-pyridin-2-ylmethyl-amine (DPA) (3) and
bis-[1-(2,2-dimethoxy-ethyl)-1H-imidazol-2-ylmethyl]-(3,4,5-
trimethoxy- benzyl)-amine (DIA) (4), and the bromide salts
of the cationic rhenium complexes, [Re(CO)3{(C5H4N)-
CH2}2N(CH2 C6H3-3, 5-OCH3)]Br (5) and [Re(CO)3-
{(N-CH2CH(OCH3)2C3H2N2)CH2}2N(CH2- C6H2-3, 4,
5-OCH3)]Br (6). We also describe the biological distribu-
tion of the analogous 99mTc(I)-tricarbonyl complexes
complex is given in Table 1 and the data for Cardioliteꢁ
is presented for comparison. The octanol/water partition
coefficient and RP-HPLC retention of 7 and 8 demonstrate
these complexes exhibit lipophilicity similar to Cardioliteꢁ,
although protein binding appears to be somewhat greater
for both complexes.
Challenging the isolated, technetium complexes with
excess histidine or cysteine showed no loss of the metal
from the starting complex, even at elevated temperature
for 24 h. This is in keeping with previous results of our sin-
gle amino acid chelate constructs [14,15].
The biodistribution data of 7 (Fig. 2) shows retention in
the heart (0.84% ID/g at 5 min and 0.75% ID/g at
120 min), while steadily decreasing blood, liver and lung
levels resulting in improved signal-to-noise ratios, specifi-
cally heart-to-blood, liver and lung ratios over 120 min.
The activity decreased in all tissues as a function of time,
except in the GI tract (Table 2). Complex 8 demonstrated
similar clearance rates but with greater heart uptake and
accumulation, 2.31% ID/g at 30 min. The heart-to-blood
ratio increased to 90:1 at 2 h.
[
99mTc(CO)3{(C5H4N)CH2}2 N-(CH2C6H3-3, 5-OCH3)]+
(7) and [99mTc(CO)3{(N-CH2CH(OCH3)2- C3H2N2)CH2}2-
N(CH2C6 H2-3, 4, 5-OCH3)]+ (8) in normal rats.
The novel tridentate ether-derivatized ligands were
prepared from di(pyridylmethyl)amine (DPA) and di(imi-
dazolymethyl)amine (DIA) ligands. In the case of the
DPA ligand, lipophilicity was modulated through deriva-
tization of the bridge nitrogen. Structural modification
was then limited by the introduction of substituents at
one position. In contrast, the DIA ligand presented three
nitrogen functionalities for derivatization. This expanded
considerably both the number and type of derivatives
that could be potentially included in this ligand set.
Derivatization of the DPA ligand to give compound 3
was effected using an alkyl bromide as shown in
Fig. 1a [9]. The DIA was prepared by reductive alkyl-
ation as shown in Fig. 1b. Derivatization of DIA ligand
to provide compound 4 was effected using alkyl bromides
as shown in Fig. 1c. The symmetric ligands were selected
because of the ability to form robust complexes with a
cationic technetium(I) tricarbonyl core and the ease of
derivatization of the affected nitrogen. Another benefit
of the ligand set was the ability to vary the size and lipo-
philicity of the ligands without the formation of isomers.
The reaction pathways were straightforward with reason-
able yields resulting in easily purified products. The
resulting derivatized tridentate chelates were characterized
In conclusion, recent advances in the chemistry of tech-
netium cores have allowed us to use the novel Tc(I) chem-
istry developed by Alberto and coworkers, that exploits the
organometallic {99mTc(CO)3}+ core. The chemistry of the
{
99mTc(CO)3}+ core has been developed to the point where
commercial kits (Iso-link, Mallinckrodt) are available and
a practical alternative to technetium(V) is possible. The
precursor, [99mTc(CO)3(H2O)3]+, contains three tightly
bound carbonyls and provides three coordination sites
weakly coordinated with water, allowing for a large degree
of flexibility in the choice of ligands.
We have developed a unique series of tridentate ligands
that readily form stable complexes with the technetium tri-
carbonyl core [16]. These tridentate ligands possess a cen-
tral secondary amine, which links to substituents
containing aromatic nitrogens to produce an N3 ligand
donor set, which coordinates to the metal. The central
nitrogen atom provides a point of symmetry, while
enabling attachment for various aliphatic and aromatic
substituents. Such derivatization can be readily accom-
plished to provide large numbers of structurally varied
compounds without the generation of multiple isomers.
This organometallic core offers the possibility of creating
compact complexes, which may potentially enhance cellu-
lar diffusion, which will be critical for accurate assessment
of cardiac blood flow [16].
To summarize, a convenient simple method for the prep-
aration of a series of novel ether-containing ligands as
potential 99mTc(I) heart agents has been developed in rats
leading to two lead radiotracers, [99mTc(CO)3{(C5H4N)-
CH2}2 N(CH2C6H2-3, 5-OCH3)]+ (7) and [99mTc(CO)3-
{(N-CH2CH(OCH3)2- C3H2N2)CH2}2N- (CH2C6H2-3, 4,
5-OCH3)]+ (8). Preliminary data of the model di-pyridine
and di-imidazole complexes demonstrate an increasing
heart-to-blood ratio with a maximum at 90:1 at 120 min
for 8. While there is evidence indicating the potential
1
using both H NMR spectroscopy and GCMS. Further
details of the synthetic procedures are provided in the
Supplementary materials.
The periodic relationship between technetium and rhe-
nium indicates that 99mTc radiopharmaceuticals can be
structurally modeled with the analogous rhenium com-
plexes [10–12]. The rhenium complexes were easily
prepared by heating [NEt4]2[Re(CO)3Br3] and the appro-
priate ether ligand in methanol [13]. The 1H NMR
spectrum and ESMS of [Re(CO)3(3)]Br (5) and
[Re(CO)3(4)]Br (6) led to facile characterization of the rhe-
nium complexes. The rhenium complexes were used as
chromatographic standards for the analogous technetium
complexes (see Supplementary Figures S1 and S2).
The 99mTc analogues,
[
99mTc(CO)3(3)]+ (7) and
[
99mTc(CO)3(4)]+ (8) were prepared in excellent yields
(90%) after incubation of the free ligand with the techne-
tium tricarbonyl tri-aqua intermediate. Reverse phase
radio chromatographs showed the presence of a single spe-
cies that co-eluted with the corresponding rhenium com-
plexes. The log P and percent protein binding of each
Maresca, Kevin P.
