The Development of Novel
Contrast
Agents
Robert E. Lenkinski PhD
Department of Radiology
Bench Meets Bedside
Topics
Non-targeted agents
Activatable agents
Targeted and responsive agents
Non Targeted Contrast Agents
•  FDA approved agents are widely used clinically
in CT and MRI
•  Micro-bubbles are less widely used in US
“Gadolinium” is widely used to delineate
tumor borders
MRI contrast agents rely upon rapid exchange
of Gd3+-bound water with bulk water
60
τR = 30 ns
-1
Relaxivity, mM s
-1
50
40
τR = 3 ns
30
20
τR = 0.3 ns
10
0
-12
For Gd(H2O)93+, tauM= 1.24 ns
GdDTPA2-
ταυM = 303 ns
-10
-8
log τ M
-6
-4
The optimal inner-sphere water
lifetime is ~20-30 ns
GdDOTA-
tauM = 244 ns
Relaxivity
units: sec-1 mM-1at 20 MHz
a relaxivity of 5 means that
1 mM of the agent shortens the T1 to
200 ms
5 is typical of the current relaxivities
of Gd based contrast agents
we can probably detect a 10% change in T1
Starting T1 of 1 sec, lowest detection limit
20 micromolar.
Activatable agents
Optical (fluorescence)
MRI/MRS based agents
Schematic of some key steps involved in a molecular imaging study.
Michelle L. James, and Sanjiv S. Gambhir Physiol Rev
2012;92:897-965
©2012 by American Physiological Society
Key molecular imaging modalities used for preclinical and/or clinical applications.
http://www.utsouthwestern.edu/research/
core-facilities/sair/index.html
Michelle L. James, and Sanjiv S. Gambhir Physiol Rev
2012;92:897-965
©2012 by American Physiological Society
Schematic diagram of the synthesis (a) and activation (b) of the developed reporter probe.
Ching-Hsuan Tung et al. Cancer Res 2000;60:4953-4958
©2000 by American Association for Cancer Research
Representative optical images of the lower abdomen of a nude mouse implanted with a CaD+
(red arrow) and CaD− (blue arrow) tumor. a, white light image 24 h after i.v. injection of the
reporter probe. b, identical imaging set-up as in a, except that NIRF flu...
Ching-Hsuan Tung et al. Cancer Res 2000;60:4953-4958
©2000 by American Association for Cancer Research
Contrast Agent Development
for the Visualization of Microcalcifications
Robert E. Lenkinski , John V. Frangioni, and
Elena Vinogradov
Departments of Radiology and Medicine
Beth Israel Deaconess Medical Center
Harvard Medical School
Synthesis of a Near-Infrared Fluorescent Bisphosphonate
Na+ -O
Na+
O
OH O
P
P
O-
O-
O- Na+
Na+
H2N
Na+
Pamidronate
-O
Na+
O
OH O
P
P
O-
O-
M.W. 323
O
O-
Na+
Na+
NH
+
Na+
-O
O
N
O
O
O
N
S
O
O
S
O-
O
O
N
O
NHS
M.W. 115
O
Na+
O-
O
S
O-
O
Pam78
M.W. 1388
O
S
O
ONa+
N
N+
O
Na+
O-
O
O
S
O
N+
OH
S
S
O
O
Na+
-O
O
O
IRDye78
M.W. 1180
O
S
O-
O
Na+
†
Zaheer et al., Nature Biotech. 2001; 19: 1148-1154
High-Resolution Imaging of the Living Animal
6 Hours Post-Injection of Pam78
Na
Mx
1 mm
1 mm
APF
TP
1 cm
Ma
CCJ
P
1 mm
1 cm
CV
H
SP
Raman spectroscopy shows two kinds of
micro-calcifications
Calcium oxalate-primarily benign arising from
ductal secretions
Hyroxyapatite -primarily malignant necrotic
mineralized cells
Published in: Kumar R. Bhushan; Preeti Misra; Fangbing Liu; Sanjeev Mathur; Robert E. Lenkinski; John V. Frangioni; J. Am. Chem. Soc. 2008, 130,
17648-17649.
DOI: 10.1021/ja807099s
Copyright © 2008 American Chemical Society
Published in: Kumar R. Bhushan; Preeti Misra; Fangbing Liu; Sanjeev Mathur; Robert E. Lenkinski; John V. Frangioni; J. Am. Chem. Soc. 2008, 130,
17648-17649.
DOI: 10.1021/ja807099s
Copyright © 2008 American Chemical Society
\
In vitro specificity of Pam-Tc/Re-800 6 (mixture) for crystals of HA and other calcium salts. (A) Optical and SPECT images are shown. (B)
Quantification (mean ± SD) of crystals from (A) using a gamma counter. All measurements (3 independent experiments) were from identically
sized and shaped regions of a 96-well plate.
Published in: Kumar R. Bhushan; Preeti Misra; Fangbing Liu; Sanjeev Mathur; Robert E. Lenkinski; John V. Frangioni; J. Am. Chem. Soc. 2008, 130,
17648-17649.
DOI: 10.1021/ja807099s
Copyright © 2008 American Chemical Society
In vivo imaging of rat breast cancer microcalcification. (A) Intraoperative NIR-fluorescence imaging and (B) SPECT/CT imaging. Arrows
mark location of breast cancer microcalcification. (C) Blood clearance and (D) biodistribution of Pam-Tc-800 6a compared to 99mTc MDP.
Figure data are representative of 3 independent experiments.
Published in: Kumar R. Bhushan; Preeti Misra; Fangbing Liu; Sanjeev Mathur; Robert E. Lenkinski; John V. Frangioni; J. Am. Chem. Soc. 2008, 130,
17648-17649.
DOI: 10.1021/ja807099s
Copyright © 2008 American Chemical Society
Micro-injection Model
Figure 2. In vivo MRI study: HA crystals were implanted subcutaneously at right ;lank of a mouse. CT scan (right) was performed to locate implanted HA crystals (arrow). UTE MR imaging was performed before (top left) and after injection of Gd-­‐DOTA-­‐Ser-­‐PAM and after 6h clearance (bottom left). Conclusions
We have developed a gadolinium-based, MR-compatible
contrast agent specific for hydroxyapatite, the calcium salt
most commonly associated with malignant calcification.
We employed a ultra-short echo time (UTE) pulse
sequence, and characterized the sensitivity,specificity of
and relaxivity of this agent in vitro and in vivo.
We have demonstrated contrast-enhanced detection of
hydroxyapatite by UTE MRI in a syngeneic rat model of
breast cancer microcalcification.
Schematic of some key steps involved in a molecular imaging study.
Michelle L. James, and Sanjiv S. Gambhir Physiol Rev
2012;92:897-965
©2012 by American Physiological Society