Adriano Duatti Department of Chemical and Pharmaceutical Sciences University of Ferrara Via L. Borsari, 46, Ferrara, Italy

Transcription

1 Adriano Duatti Department of Chemical and Pharmaceutical Sciences University of Ferrara Via L. Borsari, 46, Ferrara, Italy

2 Summary Approved tracers for myocardial perfusion imaging (MPI) with radioisotopes New tracers for MPI: PET and SPECT New technologies

3 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 ( 18 F-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)

4 WHAT WE HAVE FOR MYOCARDIAL PERFUSION IMAGING (MPI)

5 99m Tc-Tetrofosmin 99m Tc-Sestamibi

6 FDA Approved Cardiac PET Agents Tracer Half-life β + Range in Tissues (mm) Mechanism 82 Rb 78 s NH 3 10 min F-FDG 110 min 0.2 Na/K-ATPase (perfusion) Diffusion/metabolic trapping (perfusion) Glucose transport/hexokinase (viability)

7 Rischpler, C., et al., Advances in PET myocardial perfusion imaging: F-18 labeled tracers, Annals of Nuclear Medicine 26 (2012) 1 6.

8 Rb-82

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10 [ 13 N]Ammonia T 1/2 < 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

11 [ 13 N]Ammonia

12 Novel Potential Cardiac PET Agents Tracer Half-life Mechanism 18 F- Flurpiridaz 18 F-FBnTP 110 min 110 min Binding to mitochondrial complex I Passive 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.

13 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) 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)

14 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)

15 Mitochondrial Complex I

16 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)

17 Sogbein, O. O., et al., New SPECT and PET Radiopharmaceuticals for Imaging Cardiovascular Disease, Biomed Research International 2014 (2014) 1 25.

18 18 F-BMS ( 18 F-Flurpiridaz) 10 min 30 min 50 min 120 min 150 min 210 min 270 min Maddahi, J., Properties of an ideal PET perfusion tracer: New PET tracer cases and data, Journal of Nuclear Cardiology, 19 (2012) S30 S37.

19 Bengel, F. M., et al., Cardiac positron emission tomography, Journal of the American College of Cardiology, 54 (2009) 1 15.

20 F-18-Flurpiridaz vs Tc-99m-MIBI 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)

21 Latest Results with 18 F-Flurpiridaz 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

22 Liu, S., et al., Evaluation of 18 F-labeled BODIPY dye as potential PET agents for myocardial perfusion imaging, Nuclear Medicine and Biology 41 (2014) 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)

23 18 F-FTHA, 11 C-Palmitate, 11 C-Acetate (Fatty and tricarboxylic acid metabolism) Synapse 123 I-MIBG, 11 C-HED (Norepinephrine transporter) 18 F-FDG (Glucose metabolism)

24 Tracer Others Cardiac PET Agents Half-life (min) Mechanism 15 OH 2 2 Free diffusion 11 C-Acetate 20 Oxidative metabolism 11 C-Palmitate 20 Fatty acid metabolism 18 F-FTHA 110 Fatty acid metabolism 11 C-Hydroxyephedrine 20 Catecholamine analog showing uptake and reuptake by NET 11 C-Epinephrine 20 Physiologic neurotransmitter 18 F-FDOPA 110 Precursor of physiologic neurotransmitter 11 C-CGP β Adrenergic receptor density 11 C-GB67 20 α 1 Adrenergic receptor density 11 C-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.

25 [ 123 I]-MIBG [ 11 C]-m-HED [ 18 F]-FDOPA Norepinephrine

26 (Idiopathic dilated cardiomyopathy) Henneman, M. M., et al., Cardiac Neuronal Imaging: Application in the Evaluation of Cardiac Disease, Journal of Nuclear Cardiology, 15 (2008)

27 [ 18 F]Galacto-RGD Targeting α ν β 3 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

28 18 F-Galacto-RGD Fused 18 NH 3 Control LCA Occlusion Bengel, F. M., et al. Image-guided therapies for myocardial repair: concepts and practical implementation, European Heart Journal Cardiovascular Imaging 14 (2013)

29 Clinical Myocardial Perfusion PET: Evidence and Potential Role Imaging Technique Radiotracers Diagnostic accuracy Randomized trial Suggestions for clinical use Potential use High temporal resolution, dynamic imaging, absolute blood flow quantification, spatial resolution superior to SPECT, attenuation correction, increased specificity. Extraction fraction superior to commercial SPECT tracers, shorter imaging protocols and lower radiation exposure, but complicated use of exercise stress (vasodilator stress preferred). 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. Not available 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). 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.

30 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)

31 THE BEAUTY AND DAMNATION OF MOLECULAR IMAGING IN NUCLEAR CARDIOLOGY Bossone, E., et al. Takotsubo cardiomyopathy: an integrated multi-imaging approach, European Heart Journal Cardiovascular Imaging, 15 (2014)

32 SPECT TECHNOLOGICAL ADVANCEMENTS

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34 Circuit Board Readout Electronics Solid-state detectors CsI/Si Detector Module Si Photodiode CsI (TI) Scintillation Crystal Courtesy Richard Conwell, Digirad Corp. X mm CsI/Si Detector Module Y mm Direct digital positioning provides for excellent intrinsic spatial resolution and enhanced image contrast. Relative Response Spatial Response Comparison Courtesy Richard Conwell, Digirad Corp Scintillation Camera 1 Solid State Camera Spatial Response Comparison

35 New Ultrafast SPECT Cardiac Tomographs GE Discovery NM 530c D-SPECT

36 SPECT with High Resolution and High Speed 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

37 CZT-SPECT Conventional CZT

38 CZT-SPECT Conventional CZT

39 Courtesy, E. Garcia, Emory Univ t in I s in Courtesy, E. Garcia, Emory University Courtes t n Rest 14 min ndard 0c NaI Garcia, Emory University ss n Stress 11.5 min Courtesy, E. Garcia, Em y NM 530c Courtesy, E. Garcia, Emory University etectors Rest 4 min pinhole collimators Stress 2 min s e collimators c CZT Detectors cused pinhole co tectors pinhole collimat mators Multiple focused pin-hole collimators CZT (Stress, 2 min; Rest, 4 min) NaI (Stress, 11.5 min; Rest, 14 min) rs e collimators

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41 G-SPECT: Ultrafast, high-performance clinical SPECT Acquisition time ranges 1 sec to 0.5 min for brain imaging

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43 First-pass extraction > 90% Washout half-time 5 minutes Uptake mechanism: passive diffusion Linear dependence of uptake on blood flow

44 Sogbein, O. O., et al., New SPECT and PET Radiopharmaceuticals for Imaging Cardiovascular Disease, Biomed Research International 2014 (2014) 1 25.

45 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)

46 99m TcN-DBODC 99m TcN-MPO Sogbein, O. O., et al., New SPECT and PET Radiopharmaceuticals for Imaging Cardiovascular Disease, Biomed Research International 2014 (2014) 1 25.

47 99m Tc-TMEOP 99m TcN-DTCL2 Sogbein, O. O., et al., New SPECT and PET Radiopharmaceuticals for Imaging Cardiovascular Disease, Biomed Research International 2014 (2014) 1 25.

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49 5 min

50 60 min Cyclosporin A

51 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.

52 THANK YOU