presentazione di powerpoint€¦ · others cardiac pet agents tracer half-life (min) mechanism 15oh...

Adriano DuattiDepartment of Chemical and Pharmaceutical Sciences

University of Ferrara

Via L. Borsari, 46, 44121 Ferrara, [email protected]

[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.

[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

tomography 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



[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.



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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Relative Response

X mm

Y mm

Solid State

Camera

Scintillation

Camera

Direct digital positioning provides for excellent intrinsic spatial resolution

and enhanced im

age contrast.

Courtesy Richard Conwell, DigiradCorp.

Spatial Response Comparison•0.5

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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.

Spatial Response Comparison•0.5

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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

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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

‘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



99mTcN-MPO

99mTc-TMEOP



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

presentazione di powerpoint€¦ · others cardiac pet agents tracer half-life (min) mechanism 15oh...

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