Adriano DuattiDepartment of Chemical and Pharmaceutical Sciences
University of Ferrara
Via L. Borsari, 46, 44121 Ferrara, [email protected]
Summary
Approved tracers for myocardial
perfusion imaging (MPI) with
radioisotopes
New tracers for MPI: PET and SPECT
New technologies
The Ideal Perfusion
Imaging Agent
High cardiac uptake to non-target ratio with minimal
redistribution
Better image quality and disease detection
Near linear myocardial uptake versus flow: up to 5
mL/min/g (high first-pass extraction)
Allow quantification of absolute myocardial flow
Effective with both exercise and pharmacologic stress
Appropriate safety profile
Available as unit dose (18F-labeled compound)
Glover, D. K., et al., Journey to find the ideal PET flow tracer for clinical use: Are we
there yet?, Journal of Nuclear Cardiology, 14 (2007) 765−767.
WHAT WE HAVE FOR MYOCARDIAL PERFUSION
IMAGING (MPI)
99mTc-Tetrofosmin 99mTc-Sestamibi
FDA Approved Cardiac PET Agents
Tracer Half-lifeβ+ Range in
Tissues (mm)Mechanism
82Rb 78 s 2.6Na/K-ATPase(perfusion)
13NH3 10 min 0.7Diffusion/metabolictrapping (perfusion)
18F-FDG 110 min 0.2Glucose
transport/hexokinase(viability)
Rischpler, C., et al., Advances in PET myocardial perfusion imaging: F-18 labeled
tracers, Annals of Nuclear Medicine 26 (2012) 1−6.
Rb-82
[13N]Ammonia
• T1/2 < 10 min
• Cyclotron produced
• Metabolic trapping (glutamine synthase)
• Non-linear relationship between uptake and flow.
• Heterogenous uptake (inferior in the lateral left ventricular wall)
• Not well-suited for peak stress gated imaging
[13N]Ammonia
Novel Potential Cardiac PET Agents
Tracer Half-life Mechanism
18F-
Flurpiridaz110 min Binding to mitochondrial complex I
18F-FBnTP 110 minPassive diffusion and trapping by the negative potential across the inner
mitochondrial membrane
Bengel, F. M., et al., Cardiac Positron Emission Tomography, Journal of the
American College of Cardiology 54 (2009) 1−15.
+
Kim, D-Y., et al., Radiolabeled Phosphonium Salts as Mitochondrial Voltage Sensors for Positron
Emission Tomography Myocardial Imaging Agents. Nucl. Med. Mol Imaging, 50 (2016) 185–195.
Berman, D. S., et al., Phase II safety and clinical comparison with single-photon emission computed
to- mography myocardial perfusion imaging for detection of coronary artery disease: flurpiridaz F-18
positron emission tomography. J Am Coll Cardiol, 61 (2013) 469–477
Yu, M., et al., The Next Generation of Cardiac Positron Emission Tomography Imaging Agents: Discovery of Flurpiridaz F-18 for Detection of Coronary Disease, Seminars in Nuclear Medicine 41 (2011) 305−313.
Mitochondrial Complex I
Yu, M., et al., The Next Generation of Cardiac Positron Emission Tomography Imaging Agents: Discovery
of Flurpiridaz F-18 for Detection of Coronary Disease, Seminars in Nuclear Medicine 41 (2011) 305−313.
Sogbein, O. O., et al., New SPECT and PET Radiopharmaceuticals for Imaging
Cardiovascular Disease, Biomed Research International 2014 (2014) 1−25.
10 min 30 min 50 min 120 min 150 min 210 min 270 min
18F-BMS-747158-02 (18F-Flurpiridaz)
Maddahi, J., Properties of an ideal PET perfusion tracer: New PET tracer cases and
data, Journal of Nuclear Cardiology, 19 (2012) S30−S37.
Bengel, F. M., et al., Cardiac positron emission tomography, Journal of the American
College of Cardiology, 54 (2009) 1−15.
Berman, D. S., et al., Phase II Safety and Clinical Comparison With Single-Photon Emission
Computed Tomography Myocardial Perfusion Imaging for Detection of Coronary Artery Disease ,
Journal of the American College of Cardiology 61 (2013) 469−477.
F-18-Flurpiridaz vs Tc-99m-MIBI
Lantheus' flurpiridaz F-18 PET agent for myocardial perfusion
imaging yielded 67% sensitivity and 73.8% specificity in
evaluating patients with coronary artery disease, compared
with 54.9% sensitivity and 85.4% specificity for SPECT.
Flurpiridaz F 18 PET imaging has greater sensitivity than
SPECT imaging, but lower specificity.
Under a U.S. Food and Drug Administration (FDA)-approved
special protocol assessment, Lantheus will soon start the
second of two phase III trials for the agent, the company said.
American College of Cardiology’s annual scientific session in 2016
Latest Results with 18
F-Flurpiridaz
Liu, S., et al., Evaluation of 18F-labeled BODIPY dye as potential PET agents for myocardial
perfusion imaging, Nuclear Medicine and Biology 41 (2014) 120−126.
Bartholoma, M. D., et al., 18F-labeled rhodamines as potential myocardial perfusion agents: comparison of
pharmacokinetic properties of several rhodamines, Nuclear Medicine and Biology 42 (2015) 796−803.
18F-FDG
(Glucose metabolism)
18F-FTHA, 11C-Palmitate, 11C-Acetate
(Fatty and tricarboxylic acid metabolism)
123I-MIBG, 11C-HED
(Norepinephrine transporter)
Synapse
Others Cardiac PET Agents
TracerHalf-life
(min)Mechanism
15OH2 2 Free diffusion
11C-Acetate 20 Oxidative metabolism
11C-Palmitate 20 Fatty acid metabolism
18F-FTHA 110 Fatty acid metabolism
11C-Hydroxyephedrine 20Catecholamine analog showing uptake and
reuptake by NET
11C-Epinephrine 20 Physiologic neurotransmitter
18F-FDOPA 110 Precursor of physiologic neurotransmitter
11C-CGP1277 20 β Adrenergic receptor density
11C-GB67 20 α1 Adrenergic receptor density
11C-MQNB 20 Muscarinic receptor density
Bengel, F. M., et al., Cardiac Positron Emission Tomography, Journal of the
American College of Cardiology 54 (2009) 1−15.
[11C]-m-HED
[123I]-MIBG
[18F]-FDOPA
Norepinephrine
Henneman, M. M., et al., Cardiac Neuronal Imaging: Application in the Evaluation of Cardiac Disease, Journal of Nuclear Cardiology, 15 (2008) 442–455.
(Idiopathic dilated cardiomyopathy)
[18F]Galacto-RGDTargeting ανβ3 integrins
Alanine-aspartate-glycine-arginine-lysine-Galactose-F-18
Haubner, R., et al., Noninvasive visualization of the activated 𝛼v𝛽3 integrin in cancer patients
by positron emission tomography and [18 F]Galacto-RGD, PLoS Medicine, 2 (2005) e70
Bengel, F. M., et al. Image-guided therapies for myocardial repair: concepts and practical
implementation, European Heart Journal – Cardiovascular Imaging 14 (2013) 741–751.
18F-Galacto-RGD
18NH3
Fused
LCA OcclusionControl
Clinical Myocardial Perfusion PET: Evidence and Potential Role
Imaging
Technique
High temporal resolution, dynamic imaging, absolute blood flow quantification,
spatial resolution superior to SPECT, attenuation correction, increased
specificity.
Radiotracers Extraction fraction superior to commercial SPECT tracers, shorter imaging
protocols and lower radiation exposure, but complicated use of exercise stress
(vasodilator stress preferred).
Diagnostic accuracy High sensitivity and specificity for detection of coronary artery stenosis.
Comparison to SPECT suggests superiority, but recent prospective head-to-head
comparison is not available.
Randomized trial Not available
Suggestions for clinical use
Second-line test after equivocal SPECT or other equivocal perfusion studies.
First-line test in groups where SPECT is frequently equivocal (obese patients).
First-line test in situations where quantification and reproducibility are important
(suspected balanced ischemia, longitudinal follow up studies).
Potential use Perhaps used as first-line test when diagnostic superiority to SPECT is confirmed
in head to-head or randomized trials and if cost-effectiveness is proven.
Bengel, F. M., et al., Cardiac Positron Emission Tomography, Journal of the
American College of Cardiology 54 (2009) 1−15.
Will (PET) Nuclear Cardiology Become
First Line or Is it Always Condemned to
Stay at the Second Line?
Dilsizian, V., Highlights from the Updated Joint ASNC/SNMMI PET Myocardial Perfusion and
Metabolism Clinical Imaging Guidelines, Journal of Nuclear Medicine, 57 (2016) 1327−1328
Bossone, E., et al. Takotsubo cardiomyopathy: an integrated multi-imaging approach,
European Heart Journal – Cardiovascular Imaging, 15 (2014) 366–377.
THE BEAUTY AND DAMNATION OF
MOLECULAR IMAGING IN NUCLEAR CARDIOLOGY
SPECT TECHNOLOGICAL ADVANCEMENTS
Spatial Response Comparison
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Solid State
Camera
Scintillation
Camera
Direct digital positioning provides for excellent intrinsic spatial resolution
and enhanced im
age contrast.
Courtesy Richard Conwell, DigiradCorp.
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•25.5•0.5 •4.5 •8.5 •12.5 •16.5 •20.5 •24.5•0 •0.2 •0.4 •0.6 •0.8 •1Relative ResponseX mm Y mm Solid StateCamera Scintillation Camera Direct digital positioning provides for excellent intrinsic spatial resolutionand enhanced image contrast.Courtesy Richard Conwell, DigiradCorp.
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•25.5•0.5 •4.5 •8.5 •12.5 •16.5 •20.5 •24.5•0 •0.2 •0.4 •0.6 •0.8 •1Relative ResponseX mm Y mm Solid StateCamera Scintillation Camera Direct digital positioning provides for excellent intrinsic spatial resolutionand enhanced image contrast.Courtesy Richard Conwell, DigiradCorp.CsI/Si Detector Module
Si Photodiode
CsI(TI) Scintillation Crystal
Circuit BoardReadout Electronics
CsI/Si Detector ModuleSi Photodiode CsI(TI) Scintillation CrystalCircuit Board Readout Electronics
Solid-state detectors
GE Discovery NM 530c D-SPECT
New Ultrafast SPECT Cardiac Tomographs
Multipinhole technology.
High intrinsic spatial resolution of solid state detectors.
Wide beam reconstruction methods:
o Resolution recovery
o Iterative reconstruction
o Noise reduction
o Higher sensitivity
o Higher image quality
SPECT with High Resolution
and High Speed
CZT-SPECT
Conventional CZT
CZT-SPECT
Conventional CZT
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Multiple focused pin-hole collimators
CZT (Stress, 2 min; Rest, 4 min)
NaI (Stress, 11.5 min; Rest, 14 min)
Acquisition time ranges 1 sec to 0.5 min for brain imaging
G-SPECT: Ultrafast, high-performance clinical SPECT
First-pass extraction > 90%
Washout half-time ≈ 5 minutes
Uptake mechanism: passive diffusion
Linear dependence of uptake on blood flow
Sogbein, O. O., et al., New SPECT and PET Radiopharmaceuticals for Imaging
Cardiovascular Disease, Biomed Research International 2014 (2014) 1−25.
‘Tc-99m teboroxime has been almost ignored as a
perfusion agent because its fast kinetics requires a
very rapid acquisition (below 5 min) to be performed
2–9 min after injection. Considering the high first-pass
extraction of Tc-99m teboroxime, we need to rethink
about the use of Tc- 99m teboroxime as a perfusion
agent for the CZT gamma camera’
Quoted from: Lee, W. W., Recent Advances in Nuclear
Cardiology, Nucl Med Mol Imaging, 50 (2016) 196–206
99mTcN-DBODC
Sogbein, O. O., et al., New SPECT and PET Radiopharmaceuticals for Imaging
Cardiovascular Disease, Biomed Research International 2014 (2014) 1−25.
99mTcN-MPO
99mTc-TMEOP
Sogbein, O. O., et al., New SPECT and PET Radiopharmaceuticals for Imaging
Cardiovascular Disease, Biomed Research International 2014 (2014) 1−25.
99mTcN-DTCL2
5 min 30 60 240
Cyclosporin A
60 min
Conclusions The ‘Beauty and Damnation’ of molecular imaging is that we are
using sophisticated molecular tools for exploring biological
processes, but unfortunately we don’t have yet a complete and
exhaustive picture of the underlying cellular biology.
However, for this very same reason there’s plenty of
opportunities for both SPECT and PET to keep a relevant
position in myocardial imaging.
Beside new promising tracers, there are still numerous tracers
left behind in a box because of their low commercial interest,
but that could be potentially beneficial for patients.
It is the responsibility of the nuclear physician to make the right
choice for the patient that sometime is not available on the
market, but can be easily set up in the radiopharmacy.
THANK YOU