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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: [email protected]
