Journal of the American Chemical Society
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3
+
in the oxidized Mn ꢀJED complex. Fig 3C shows the same
phantoms as in 3A imaged with a 325 ms inversion preꢀpulse.
The inversion time was chosen to null signal in the untreated
sample, generating large positive contrast in the oxidized samꢀ
ple. Fig 3D shows the same inversion preꢀpulse sequence apꢀ
plied to the Gdꢀbisꢀ5HTꢀDTPA samples from Fig 3B. Regardꢀ
less of the scanning protocol, the contrast generated following
oxidation of the Mnꢀbased agent is much larger than that posꢀ
sible with the Gdꢀbased agent. Fig 3E compares percentage r1
change observed afer peroxidase oxidation of MnꢀJED and
Gdꢀbisꢀ5HTꢀDTPA at 4.7 T. The Mn agent undergoes 380% r1
change whereas the activatable Gdꢀbased agents experiences
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1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
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5
5
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0
1
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3
4
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7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
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1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
<
15% r change. At 1.4 T, the r change is also much greater
1
1
for the MnꢀJED system (790%) than for Gdꢀbisꢀ5HTꢀDTPA
60%). Images of phantoms prepared in human blood plasma
exhibit comparable contrast, Fig S15.
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To our knowledge, JED is the only chelator capable of staꢀ
bilizing both Mn and Mn in the physiological milieu, and
enables rapid and reversible biochemically mediated interconꢀ
version between Mn (low r ) and Mn (high r ). The bioꢀ
chemically mediated r change observed with MnꢀJED is the
largest of any activatable Gdꢀ or Mnꢀbased contrast agent.
Peroxidase mediated oxidation of Mn ꢀ to Mn ꢀJED provides
over an order of magnitude greater r change than the state of
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1
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000, 39, 747.
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+
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1
the art Gdꢀbased peroxidase sensor, and is achieved in minutes
at peroxidase concentrations 1000ꢀfold below what is seen in
vivo. MnꢀJED offers a promising new paradigm for activatable
MRI contrast agent development.
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Supporting Information. Experimental details, synthetic
procedures, compound characterization, structures not deꢀ
picted in manuscript text, additional spectra, HPLC traces,
and MRI acquisition parameters. The Supporting Inforꢀ
mation is available free of charge on the ACS Publications
website. (PDF)
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975.
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Notes
.
The authors declare no competing financial interests.
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(32) Caravan, P.; Farrar, C. T.; Frullano, L.; Uppal, R. Contrast Media.
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ACKNOWLEDGEMENTS
(33) Su, H. S.; Nahrendorf, M.; Panizzi, P.; Breckwoldt, M. O.;
Rodriguez, E.; Iwamoto, Y.; Aikawa, E.; Weissleder, R.; Chen, J. W.
Radiology 2012, 262, 181.
This work was supported by grants from the National
Heart, Lung, and Blood Institute (K25HL128899), the Naꢀ
tional Institute of Biomedical Imaging and Bioengineering
(R01EB009062, R21EB022804) and instrumentation fundꢀ
ed by the National Center for Research Resources and the
Office of the Director (P41RR14075, S10RR023385,
S10OD010650).
(34) Nahrendorf, M.; Sosnovik, D.; Chen, J. W.; Panizzi, P.; Figueiredo,
J.ꢀL.; Aikawa, E.; Libby, P.; Swirski, F. K.; Weissleder, R. Circulation
2008, 117, 1153.
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