Imaging of zinc metabolism using hyperpolarized …Project hypothesis –Image zinc with HP MRI...
Transcript of Imaging of zinc metabolism using hyperpolarized …Project hypothesis –Image zinc with HP MRI...
3/17/2019
Imaging of zinc metabolism using hyperpolarized 13C Magnetic Resonance Imaging
Robert Flavell, MD, PhD
Assistant Professor
Department of Radiology and Biomedical Imaging
Section of Nuclear Medicine
Hyperpolarized imaging of zinc metabolism2
Zinc – a disease biomarker
▪ Zinc is an essential mineral with high concentration in tissues
including pancreas and prostate
▪ Alterations in zinc homeostasis are implicated in disease states
including prostate cancer, diabetes, and neurodegenerative
disease
Hyperpolarized imaging of zinc metabolism3
Molecular imaging of zinc – prior work
J. Am. Chem. Soc. 2008, 130, 15788– 15789.
Cancer Research 2010, 70, 6119–6127.
Proc. Natl. Acad. Sci., 2016, 5464-5471
Fluorescense
MRI
Hyperpolarized imaging of zinc metabolism4
Hyperpolarized 13C MRI
Clinical MR
Scanner
Inject i.v. –
Fast 13C
MRI
Volume MRI in
10’s of seconds1
PyrLac
Pyr
Lac
D
Nelson, Kurhanewicz, Vigneron et al. Science Translational Medicine, 2013
Hyperpolarized imaging of zinc metabolism5
Project hypothesis – Image zinc with HP MRI
▪ Administer hyperpolarized probe with 13C
nucleus which is sensitive to the presence or
absence of zinc
Sinan Wang
Prior work – multi-metal HP sensor
Mishra et al. Anal Chem 2016
Hyperpolarized imaging of zinc metabolism6
Cysteine and iminodiacetic acid Hyperpolarized 13C zinc probes
Hyperpolarized imaging of zinc metabolism7
Cysteine – A zinc biosensor
Spectrum for 50 mM Cysteine with
various Zn2+ concentration
0 eq Zn2+0.25 eq Zn2+0.5 eq Zn2+1 eq Zn2+5 eq Zn2+
Hyperpolarized imaging of zinc metabolism8
IDA – also a zinc biosensor
Spectrum for 50 mM IDA with
various Zn2+ concentration
0 eq Zn2+
0.25 eq Zn2+
0.5 eq Zn2+
Zn2+ unbound peak
Hyperpolarized imaging of zinc metabolism9
Hyperpolarization parametersCysteine
T1 = 36.0 ± 1.8 s (n = 3)
% pol = 12.8 – 14.0
Cysteine + 1 eq Zn
T1 = 17.5 s
IDA
T1 = 39.3 ± 1.0 s (n = 3)
% pol = 5.8 – 7.5%
IDA + 1 eq Zn
T1 = 16.6 s
Hyperpolarized imaging of zinc metabolism10
Hyperpolarized 13C zinc phantom experiments - cysteine
Δppm in thermo Δppm in HP
0 eq Zn 9.9 10.1 0.25 eq Zn 12.0 12.1 0.5 eq Zn 13.1 13.1 1.0 eq Zn 14.5 14.2
Hyperpolarized imaging of zinc metabolism11
Biological phantom experiments - cysteine
serum
Serum + Zn2+
Rat prostate
Rat prostate + DPA
Δ ppm Zn2+ conc by HP Zn2+ conc by kit
Rat serum 10.0 0.1 mM 0.1 mM Rat serum + Zn2+ 11.7 2.1 mM 2.0 mM Rat prostate + DPA 10.1 0.2 mM 0.1 mM Rat prostate 11.5 1.9 mM 1.8 mM
Hyperpolarized imaging of zinc metabolism12
Conclusions and future directions
▪ Cysteine and IDA are hyperpolarized 13C biosensors for zinc
▪ Hyperpolarized compounds can accurately quantify zinc
concentrations in solution and in biological extracts
▪ Potential applications in imaging of prostate cancer, diabetes,
and neurodegenerative disease
Hyperpolarized imaging of zinc metabolism13
Acknowledgements
Flavell lab
Sinan Wang
Dave Korenchan
Celine Taglang
Kristina Liu
Andrew Hong
Collaborators
David M. Wilson
John Kurhanewicz
Dan Vigneron
Henry VanBrocklin
Joseph Blecha
Michael Evans
Jane Wang
Mark Van Criekinge
Renuka Sriram
Robert Bok
Funding:
Society of Abdominal Radiology Howard S. Stern Research
Award
Prostate cancer foundation young investigator award
NIH R21 CA0121429
DoD physician research training grant
American Cancer Society Individual Research Award
Startup funds from UCSF Department of Radiology
Thank you for your attention!