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

For Gd(H2O)93+, tauM= 1.24 ns

GdDTPA2- ταυM = 303 ns GdDOTA- tauM = 244 ns

MRI contrast agents rely upon rapid exchange of Gd3+-bound water with bulk water

0

10

20

30

40

50

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ity, m

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τR = 0.3 ns

τR = 30 ns

τR = 3 ns

The optimal inner-sphere water lifetime is ~20-30 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.

Michelle L. James, and Sanjiv S. Gambhir Physiol Rev 2012;92:897-965

©2012 by American Physiological Society

http://www.utsouthwestern.edu/research/ core-facilities/sair/index.html

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

Robert E. Lenkinski , John V. Frangioni, and Elena Vinogradov

Departments of Radiology and Medicine Beth Israel Deaconess Medical Center

Harvard Medical School

Contrast Agent Development for the Visualization of Micro-

calcifications

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Synthesis of a Near-Infrared Fluorescent Bisphosphonate

† Zaheer et al., Nature Biotech. 2001; 19: 1148-1154

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High-Resolution Imaging of the Living Animal 6 Hours Post-Injection of Pam78

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

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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).  

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.

Conclusions

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