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X. Chen et al. / Bioorg. Med. Chem. Lett. 18 (2008) 1442–1445
Table 1. Biodistribution of radioactivity measured after the administration of complex 6a in normal micea
Organ
2 min
30 min
60 min
120 min
Blood
Heart
Lung
6.14 0.47
17.49 0.70
10.38 0.87
25.94 2.24
4.60 1.23
15.88 1.58
1.34 0.16
3.88 0.19
5.31 0.30
5.03 0.40
34.51 4.28
4.50 0.86
8.92 0.44
0.99 0.08
4.43 0.56
5.09 0.75
4.38 0.39
34.62 5.98
3.51 0.66
6.98 1.33
0.65 0.10
4.71 1.24
3.75 0.77
3.34 0.62
32.45 4.27
2.89 0.49
5.10 0.73
0.44 0.04
Liver
Spleen
Kidney
Brain
a All data are the mean percentage (n = 3) of the injected dose per gram of wet tissue (% ID/g) the standard deviation of the mean.
the normal mice brain. The high blood background,
which may be due to the high hydrophobicity, is unfa-
vorable for imaging application.
References and notes
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The lipophilicity plays an important role in BBB penetra-
tion. Hansch and Leo found that blood–brain barrier
penetration is optimal when the logP values are in the
range of 1.5–2.7, with the mean value of 2.1.30 The ligands
that can bind to Ab aggregates are very hydrophobic and
the hydrophobic interaction contributes to the binding.
However, compounds with high logP value may bind to
the proteins in the blood leading to high blood back-
ground. This contradiction seems not easy to be compro-
mised. The less lipophilic MAMA ligand was chosen to
adjust the lipophilicity of final compound. Former studies
conjugating BTA with bisaminoethanethiol ligand
showed lower brain uptake of the Tc-99m labeled com-
pound.21,24 And 6-Me-BTA lost its binding affinity after
chelation with 99mTcðCOÞ .22 The choice of suitable con-
3
jugation method is critical for the binding affinity and
brain uptake. Further experiments will be optimizing
the pharmacokinetics while keeping its binding affinity.
Introducing hydroxyl group to increase its solubility
may improve the pharmacokinetics.
In conclusion, the isostructural 99mTc and Re complexes
6a and 6b were successfully synthesized and their preli-
minary evaluation results demonstrated the binding of
6b to Ab aggregates in the brain slices of transgenic
mouse and AD patient. In addition, complex 6a can
penetrate BBB with high initial brain uptake and med-
ium wash-out. These results are encouraging for further
exploration of their derivatives as imaging agents for Ab
plaques in the brain.
Acknowledgment
The work was financially supported by NSFC
(20471011).
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Supplementary data
Synthetic procedures and HPLC analysis for 6a and 6b,
fluorescent staining of brain sections with 6b, partition
coefficient determination and biodistribution of 6a in
normal mice are available in supporting information.
Supplementary data associated with this article can be