Non-energy Nuclear Applications: Nuclear Medicine

Dr. John F. ValliantAssociate Professor Chemistry and Medical

PhysicsScientific Director Centre for Probe

Development and Commercialization

WNU - July 2008

Keys to Good Healthcare

• Prevention• Early detection• Accurate assessment and staging• Effective therapies• Heath promotion and education

Anatomical Imaging

X-ray CT MRI

X-ray

Functional Imaging

• “Reveal structure through function”

• Image produced depends on biological distribution of compound in vivo

Jones and Thornback, Medical Applications of Coordination Chemistry, RSC Publishing: 2007, Cambridge, UK.

The Evolution of Imaging

Anatomy Biochemistry

Economic growth:

$14.2 billion industry by

2010

Improved health care

Expedite drug development

Outcomes

Molecular Imaging

• Involves an imaging modality (MRI, ultrasound, PET, etc.) and specially designed probes that bind to and reveal specific biological targets

• Enables scientists and clinicians to visualize specific biological processes non-invasively in vivo.

Nuclear Imaging

OHO

HO OH

OH

F

http://en.wikipedia.org/wiki/Image:PET-schema.png

What is needed?

RadiochemistryIsotope Production Biodistribution &PreclinicalImaging

Clinical trials

Compound Discovery

OH

FOH

OH

OOH

10-11 10-10 10-9 10-8 10-7 10-60.0

0.1

0.2

0.3

0.4

0.5

I li (M)

OD

450

nm

ScreeningBiology

Patient

Isotope Supply

“The major safety snafu behind the

isotope shortage”

“Canada’s nuclear fallout”

The Globe and Mail, December 6, 2007; The Ottawa Citizen, December 12, 2007; CMAJ, 2008,178, 536.

Medical Isotopes

• ~3000 nuclides are known, ~2700 are radioactive

• Majority are produced in a reactor or cyclotron

Gopal B. Saha, Physics and Radiobiology of Nuclear Medicine, Springer: 2001, New York.

http://www.sprawls.org/ppmi2/MATTER/4MATTER02.gif

http://www.meta-synthesis.com/webbook/33_segre/segre2.html

Locations of Canada’s Nuclear Reactors

National Research Universal (NRU) Reactor

McMaster Nuclear Reactor

• 5 MW • Full Containment Structure • In-core Irradiations• Neutron Beams• Neutron Activation

Analysis• Medical and Commercial

Isotopes• Neutron Radiography

Nuclear Reactor

http://mnr.mcmaster.ca/index.htm

Fission

• Products typically neutron rich and decay by β-emission

• Mixture of isotopes (including 99Mo)• No carrier added ∴ high specific activity

23592 U 1

0n+ 92 U236 13153 I

10239Y 3 1

0n+ +

Neutron Capture

• Target nucleus captures 1 thermal neutron and emits γ-rays to produce isotope of same element

• Not carrier free ∴ low specific activity

98Mo (n, γ) 99Mo

Nuclear Decay

99mTc Generator

99MoO42-

99mTcO4-

Why is 99mTc so important and how is it used?

99mTc

– Commercially available from a generator– 140 keV γ-ray– 6 hour half life– Low dose burden to the patient– Inexpensive

Radiopharmaceuticals

• To generate images, a small amount of a radiolabeled compound (about 1-10 ng) is administered to the patient prior to scanning

• The small amount used allows biochemical processes to be studied without perturbing the system (The Tracer Principle)

Scale

x 10-9 x 10-9

Medical Isotopes

Requirements:– Readily available– Suitable t1/2

– Emit radiation of usable energy

Imaging

• SPECT = single photon emission computed tomography

W. W. Moses, Proceedings of the SCFIF97 Conference on Scintillating and Fiber Detectors, A. D. Bross, R. C. Ruchti, and M. R. Wayne, Eds. Woodbury, NY: AIP Conference Proceedings 450, pp. 477-488, 1998.

Animal Imaging

Animal Imaging

Imaging Agents-Radiopharmaceuticals

Two main types:1. Nuclide-essential- Uses molecule with no specific biological

distribution plus nuclide- Biodistribution depends on the nature of the

complex

Cardiolite

NCTcC

CC

CC

N

N

NN

N

OMe

OMe

OMe

MeO

MeO

MeO+

99mTcO4-

Imaging Agents

2. Bifunctional- Conjugate molecule with biologically active

carrier plus radionuclide binding areas- Carrier interacts with receptor site and controls

biodistribution

D. M. Goldenberg, J Nucl Med 2002; 43:693–713

R

Targeting agent

Bone Imaging

• 99mTc-phosphate complexes• 99mTc-MDP (Osteolite)

– Exact nature of 99mTc complex unknown (polymer/oligomer)

PO

OH

OH

P

O

OH

OH

Bone Imaging

O. Buckley, et al, Nucl. Med. Commun. 2007, 28, 521.

Metastases from Lung Carcinoma

RadioGraphics 2003; 23:341–358

Cardiac Stress Test

http://www.nlm.nih.gov/medlineplus/ency/images/ency/fullsize/1097.jpg

Heart Imaging

• Myocardial perfusion imaging

Tc

CNR

CNRCNR CNR

CNR CNR

R = O

+

Tc

O

O

P

P

OEt

OEt

OEt

OEt

P

P

EtO

EtO

EtO

EtO

+

Myoview

Cardiolite

Heart Imaging

Gopal B. Saha, Physics and Radiobiology of Nuclear Medicine, Springer: 2001, New York.

Brain Imaging

• Complicated by Blood Brain Barrier (BBB)– Need to have neutral charge,

low MW, balance between lipophilicity and hydrophilicity

Cerebral Perfusion Agents

Tc

O

N N

N N

CH3 CH3

CH3

CH3

CH3

CH3

O O

H

Tc

O

N N

N N

CH3 CH3

CH3

CH3

CH3

CH3

O O

H

Tc

O

NN

NN

CH3CH3

CH3

CH3

CH3

CH3

OO

H

meso, syn-Ceretec d, l-Ceretec

SPECT Image of Brain

O. Kuniaki, et al, Am J Neuroradiol 1999, 20, 626–628.

Targeted Brain Imaging

• Can also use a bifunctional receptor specific imaging agent to cross BBB

Tc

NCH3

N

S

N

S

O

Cl

Tc-TRODAT

99mTc-TRODAT Brain Image

Wang J, Jiang Y-P, et al, Acta Neurol Scand. 2005, 112, 380–385

131I for Thyroid Tumor Imaging

D. A. Collins et al, Mayo Clin Proc. 2000;75:568-580

http://www.imaginis.com/nuclear-medicine/nuc_history.asp

OctreoScan

• Labeled with In-111, used to image neuroendocrine tumors (Covidien)

• Somatostatin analogue

Molecular Imaging and Contrast Agent Database (MICAD) [database online]. Bethesda (MD): National Library of Medicine (US), NCBI; 2004-2008. Available from: http://micad.nih.gov.

OctreoScan

http://www.dhmc.org/

MIBG

• Labeled with I-131, used to image neuroendocrine tumors

• Used to diagnose neuroblastoma in children

MIBG

http://www.ruh.nhs.uk/departments/medical_physics/nuclear_medicine/training/training_home_page.htm

Why does carrier free matter?

• Tumor cell have a finite number of binding sites on the surface of the cell for the imaging agent

• Less than 0.1% of the molecules contain a radioisotope

Cancer cell

Alternative Sources of Isotopes

Cyclotron• Ernest Lawrence;1929 (University of California)• Used to produce isotopes for positron emission

tomography

http://www2.slac.stanford.edu/VVC/accelerators/circular.html

Cyclotron vs. Reactor

Cyclotron Reactorcharged particles neutral particlesshort lived isotopes longer lived isotopesneutron deficient nuclei neutron rich nuclei

PET Imaging• PET = Positron Emission Tomography

S. M. Ametamey, M. Honer and P. A. Schubiger, Chem. Rev. 2008, 108(5), 1501.

http://en.wikipedia.org/wiki/Image:PET-schema.png

PET Isotopes

• F-18 (most common)– Low positron energy– 110 min half life

• C-11– 20 min half life– Good for compounds with short biological

half-lives or for repeated investigations

FDG

• Fluorodeoxyglucose• taken up by glucose-using cells eg.

brain, kidney, tumours• phosphorylated by hexokinase and

retained by tissues with high metabolic activity, ie, malignant tumours.

• also used to diagnose Alzheimer’s disease

Molecular Imaging and Contrast Agent Database (MICAD) [database online]. Bethesda (MD): National Library of Medicine (US), NCBI; 2004-2008. Available from: http://micad.nih.gov.

Following Glucose Transport and Metabolism

OH

OHOH

OH

OOH

OH

FOH

OH

OOH

18F-FDG

Normal glucosemetabolism

OH

FOH

OH

OOP

OO

O

Trapped(thus notmetabolized,and detected).

18F-FDG of the Brain

FDG

http://www.chm.bris.ac.uk/webprojects2002/wrigglesworth/brainimaging.htm

FDOPA

• 6-[18F]Fluoro-L-DOPA • used with PET to evaluate the

central Dopaminergic function in humans

• FDOPA PET reflects DOPA transport into the neurons, DOPA decarboxylation, and dopamine storage capacity

• Particularly useful in diagnosing and monitoring Parkinson’s disease

Molecular Imaging and Contrast Agent Database (MICAD) [database online]. Bethesda (MD): National Library of Medicine (US), NCBI; 2004-2008. Available from: http://micad.nih.gov.

FDOPA

J Neurol Neurosurg Psychiatry. 1997 June; 62(6): 622–625.

FLT

• 3'-deoxy-3‘-[18F]fluorothymidine • Analogue of thymidine which is

involved in DNA synthesis• FLT is phosphorylated during

DNA synthesis and trapped in the cell

• Used to detect and monitor cancer proliferation and metastases

Molecular Imaging and Contrast Agent Database (MICAD) [database online]. Bethesda (MD): National Library of Medicine (US), NCBI; 2004-2008. Available from: http://micad.nih.gov.

FLT

Saga T, et al. Evaluation of primary brain tumors with FLT-PET: usefulness and limitation.Clin Nucl Med 2006 ; 31(12):774-80.

Tumor hypoxia in lung cancer with 60Cu-ATSM - Responder

Dehdashti et al; Eur J Nucl Med Mol Imaging 30:844-50, 2003

Tumor hypoxia in lung cancer with 60Cu-ATSM - Nonresponder

Survival Curves

Dehdashti F et al; Int J. Radiation Oncology Biol. Phys. 55:1233-38, 2003

• Proton bombardment (25 MeV) of 124Xe• Decay from 123Xe to 123I• The target is washed with dilute NaOH, then

concentrated to give carrier-free product

SPECT Isotopes from a Cyclotron: 123I

J.E.H. Eersels, et al, J Label Compd Radiopharm 2005; 48: 241–257

How do you take a medical isotope and make it into a clinically useful compound?

Chemistry, Chemical Biology and Chemical Engineering

Manufacturing Agents for Clinical Use

• Must be completed quickly (less than one half-life) and in high yield (only one product can be formed)

• Done under sterile conditions• Radiation dose to operator

must be minimized

Instant Kits

• Instant kits provide cold, lyophilized product that can be mixed with the isotope on site immediately prior to delivery to the patient.

Instant Kit

99MoO42-

99mTcO4-

99mTcO4-

Tc

CNR

CNRCNR CNR

CNR CNR

+

Making FDG

• Half-life of 18F = 109.8 minutes

• Synthesis and purification: some yield loss occurs

Automated Synthesis Boxes

History of Nuclear Medicine1896 Henri Becquerel discovered mysterious "rays" from

uranium. 1897 Marie Curie named the mysterious rays "radioactivity.“1901 Henri Alexandre Danlos and Eugene Bloch placed radium

in contact with a tuberculous skin lesion. 1903 Alexander Graham Bell suggested placing sources

containing radium in or near tumors.1924 Georg de Hevesy, J.A. Christiansen and Sven

Lomholt performed the first radiotracer (lead-210 and bismuth-210) studies in animals.

1932 Ernest O. Lawrence and M. Stanley Livingston invented the cyclotron (Lawrence won the 1939 Nobel Prize)

http://interactive.snm.org/index.cfm?PageID=1107&RPID=924

History of Nuclear Medicine

1940 The Rockefeller Foundation funded the first cyclotron dedicated for biomedical radioisotope production at Washington University in St. Louis.

1950 Abbott Laboratories sold the first commercial radiopharmaceutical, iodine-131 human serum albumin (RISA).

1957 W.D. Tucker's group at the Brookhaven National Laboratory invented the iodine-132 and technetium-99m generator, making these short-lived radionuclides available at distant sites from the production of the parent radionuclides.

1970 W. Eckelman and P. Richards developed Tc-99m "instant kit" radiopharmaceuticals. The first one was Tc-99m-DTPA.

http://www.chm.bris.ac.uk/webprojects2002/wrigglesworth/history.htm

History of Nuclear Medicine1983 William Eckelman and Richard Reba carried

out the first successful SPECT imaging of a neuroreceptor in humans.

1983 Henry Wagner carried out the first successful PET imaging of a neuroreceptor using himself as the experimental subject

1998 FDG PET studies were used to assess the response of an initial dose of chemotherapy to predict the response to subsequent high-dose chemotherapy.

2001 16.9 million nuclear medicine procedures were performed in the United States.

http://www.chm.bris.ac.uk/webprojects2002/wrigglesworth/brainimaging.htm

The Future

Batch vs. Flow Chemistry

Microfluidics

• Microreactors– Enhanced reaction kinetics– Smaller quantities of reagents and solvents

S. M. Ametamey, M. Honer and P. A. Schubiger, Chem. Rev. 2008, 108(5), 1501.

Advion’s Nanotek can synthesize high purity PET compounds in a few minutes.

How can Microfluidics impact PET tracer research?

By reducing the linear dimension:– surface area decreases to the power two – volume to the power three.

Result: Increased surface to volume ratio compared to conventional lab glassware:Typical specific values (surface [m2]/volume [m3]) – microreactors range between 10 000 and 50 000 m-1

– conventional lab-scale vessels are about 1000 m-1

• The consequence of the increased surface to volume ratio is that diffusion-based phenomena such as mass and heat transfer are much higher in microreactors compared to conventional lab glassware.

Temperature Effects

• The high degree of temperature control prevents side-reactions occurring in microreactors.

• Thermal decomposition of the target product is reduced, resulting in overall increased product yield and purity

How do the next generation of agents and technologies get developed?

Industry – Academia Collaborations

• Much of the early work in the nuclear medicine and radiochemistry fields was done at academic and government labs

• Industry partners are needed to translate discoveries and commercialize intellectual property in order to make them available to physicians and patients

Translation into Humans

• Toxicology: the relationship between the dose and the affect on the human

• Pathology: the diagnosis and characterization of disease by examining tissues or cells• Experimental pathology attempts to determine the

consequence of intended or unintended pharmacological activity

Probe Development

• Most groups do not have the ability to get beyond the research phase

Chemistry Preclinicalassessment

Scale-upGMP

Regulatory affairs

Clinicaltrials

In vitroscreening New product

Research Development Commercialization

Figure 1

Chemistry Preclinicalassessment

Scale-upGMP

Regulatory affairs

Clinicaltrials

In vitroscreening New product

Research Development Commercialization

Figure 1

Centre for Probe Development and Commercialization(CPDC)

Vision• To create a world-class centre for the

development, validation, translation and commercialization of molecular imaging probes and associated technologies

• Bridge the gap between basic research and commercialization

• Areas of activity:– Probes for the four major modalities

(radioimaging, MRI, ultrasound, CT)– Imaging in drug development

Rationale for the CPDC• Take advantage of the rapid growth in the field of

molecular radioimaging– Increasing use clinically – Pharma. investing heavily in MI to accelerate DD

• Missed opportunity to leverage existing Canadian industries and academic IP– Canada is a world leader in isotope production – few

added value products– Substantial expertise in Canada in early probe

development – poor record of translation to the clinic and commercialization

Activities

1) Probe Development and Commercialization

2) Attracting Investment to Ontario and Company Creation

3) Supporting Clinical Trials Applications 4) Internal IP Generation

Centre’s Business Plan Goals

• To validate, translate and commercialize innovative imaging probes

• To increase the number of agents entering trials for clinical and drug development studies

• To attract investment in probe development to Ontario

• Creation of new companies• Sustainable after the initial five years of

operations

The Centre

CPDC

Private Sector Partners

Medical Isotopes New probes

CTAs

Commercialization

Core 1-Probe Dev. & Prod.Core 2-Validation, Reg. AffairsCore 3-Commercialization

Example of the Future

ZemivaI-123-BMIPP (Iodofiltic Acid I 123)

ZemivaI-123-BMIPP (Iodofiltic Acid I 123)

Improving detection of cardiac ischemia in the acute chest pain patient and beyond

Metabolism as a Source of Energy for ContractionMetabolism as a Source of Energy for Contraction

Metabolism

Contraction

Courtesy of Heinrich Taegtmeyer, MD, DPhil.

“Heart muscle is a metabolic omnivore with the capacity to oxidize fatty acids, carbohydrates and amino acids

either simultaneously or vicariously”

Why radiolabeled fatty acids for cardiac ischemia?Why radiolabeled fatty acids for cardiac ischemia?

Cardiac energy metabolic shifts occur as a normal response to diverse physiologic and dietary conditions and as a component of the pathophysiologic processes which accompany cardiac hypertrophy, heart failure, and myocardial ischemia.

Barger PM, Kelly DP. Trends Cardiovasc Med. 2000 Aug;10(6):238-45

Myocardial Adaptation to Reduced Oxygen DeliveryMyocardial Adaptation to Reduced Oxygen Delivery

↓Flow

↓Oxygen supply

Alteration in fatty acid(↓)and glucose(↑) metabolism

↓ Intracellular ATP

The patho-physiological rationale for FA imaging in ACSThe patho-physiological rationale for FA imaging in ACS

The hierarchy of cardiac fuel consumption forms the basis of fatty acid imaging of the myocardium in acute and chronic ischemic heart disease.

In the setting of ischemia or hypoxia, ß-oxidation is reduced, and glucose becomes the primary source of energy.

The switch to glucose metabolism therefore provides for more efficient energy production in an oxygen deprived state.

Zemiva (Iodofiltic acid I 123)aka: BMIPPZemiva (Iodofiltic acid I 123)aka: BMIPP

BMIPP is a branched-chain fatty acid that is transported via FATP/CD36 but does not readily

undergo β-oxidation

123I (CH2)12 CH CH2

CH3

COOH

15-(p-iodophenyl)-R,S-methyl pentadecanoic acid (BMIPP)

β-methyl groupinhibits β-oxidationMetabolically stable iodine

Zemiva Has Potential to Facilitate and Accelerate Detection of Cardiac IschemiaZemiva Has Potential to Facilitate and Accelerate Detection of Cardiac Ischemia

The heart is a pump that uses fat as its primary fuel. Fat processing requires adequate oxygen delivery (blood flow) to ensure healthy heart function

During ischemia (insufficient oxygen due to reduced blood flow) the heart switches from fatty acid to carbohydrate metabolism to survive.

Zemivadetectsischemia

Healthy Heart

Sufficientoxygen

Lack ofoxygen

Imaging cardiac metabolismImaging cardiac metabolism

Courtesy of Drs G Zervos & A Fischman, Massachusetts General Hospital.

Zemiva Phase 1: Images in Normal VolunteerZemiva Phase 1: Images in Normal Volunteer

The high uptake and long retention of BMIPP in the myocardium result in high-quality SPECT studies

BMIPP Phase 2: Ischemic myocardium is detected at rest with BMIPP after flow normalizes post stressBMIPP Phase 2: Ischemic myocardium is detected at rest with BMIPP after flow normalizes post stress

Thallium Blood Flow Stress Rest

BMIPP Rest

Ischemic areadetected after 20 minutes of

exercise

Fill-in 3 hours latershows viableheart muscle

Decreased fatty acid metabolism shows “ischemic memory”

>4 Hours 5 Hours Post-ExerciseTotal TimeBMIPP = 15-(p-iodophenyl)-R,S-methyl pentadecanoic acid. Source: Dilsizian V, et al. Circulation. 2005;112:2169-2174.

Ischemia Ruled OutDischarged

(= 40,000 missed heart attacks)

EquivocalAdmitted for observation

(= $6 billion in unnecessaryhospitalizations)

Definitive Heart Attack

Admitted forintervention/treatment

3.5M

1.5M 1.0M

Zemiva Opportunity: Timely and Accurate Chest Pain Evaluation in the Emergency Department Can Provide Significant Medical and Economic Benefits

Zemiva Opportunity: Timely and Accurate Chest Pain Evaluation in the Emergency Department Can Provide Significant Medical and Economic Benefits

Centers for Disease Control and PreventionNolan T, Espinosa J. 4th Annual Chest Pain Congress 2001Storrow AB, Gibler WB. Ann Emerg Med. May 2000 35:5

Initial testsMedical history/exam

ECGBlood tests

6 Million PatientsPresent with Chest Pain

6 Million PatientsPresent with Chest Pain

Zemiva Phase 2b Trial Case # 1:The Patient Who Was Sent HomeZemiva Phase 2b Trial Case # 1:The Patient Who Was Sent Home

45 year old man with chest pain

Normal ECG and negative troponin

Sent home with non-cardiac diagnosis

Zemiva images detected significant defect in LSC territory

Patient then contacted for immediate cardiac work-up, which demonstrated severe ACS

Patient stented

Zemiva Phase 2b Trial Example:The Elderly Woman Who Initially Tested NormalZemiva Phase 2b Trial Example:The Elderly Woman Who Initially Tested Normal

75 year old patient with ongoing chest painInitial ECG and troponin tests were normal

Zemiva™ images demonstrate significant defect in apex of heart9 hours later positive troponin confirmed Zemiva result

Catheterization confirmed coronary artery disease

Patient stented

Rapid diagnosis and reduced hospitalization risks important to elderly

inferior

apexbasal

anterior

septal

apex

basal

lateral

Summary and Conclusions

Conclusions

• Molecular imaging is changing health care (early detection, better treatment outcomes)

• Relies upon a steady supply of medical isotopes (cyclotron and reactor)

• The development of new molecular imaging probes will rely upon many sectors Multi-disciplinary

The Big Picture

Engineer

ChemistBiologist

Physician

Technologist

Regulatory Affairs

Commercial expert

Pharmacy

Roles For Engineers

• Design new reactors and cyclotrons• New isotope production and separation

techniques• New imaging devices• Waste handling and recovery• Automation/robotics

• An institute that is dedicated to work involving ionizing radiation (CFI 1999)

• Between Faculties: Science, Engineering, Health Sciences/Medicine• Houses the expertise to cover every area of nuclear sciences &

engineering:– Chemistry– Physics (medical and health)– Nuclear Engineering– Environmental sciences and biology– Health and safety

www.science.mcmaster.ca/mciars

Acknowledgements

• Dr. Laura Harrington• Mr. Chris Heysel• Kelvin Hammond, Advion• Dr. John Babich• Dr. Karen Gulenchyn• Dr. Troy Farncombe• The WNU-Summer Institute

Coordinating Team

Contact InformationThank You!

Contact Information:Dr. John Valliant

McMaster University1280 Main St. West

Nuclear Research Building, Room 104Hamilton, Ont. Canada L8S 4M1

P: 905-525-9140 ext. 22840Fax: 905 522-7776

Email: valliant@mcmaster.ca