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!