DISCLOSURES
Honorarium – Research / Advisor, Expert Services and Conferences in Nuclear Cardiology
BMS, CVT, Astellas, Lantheus, PGx, IAEA
Royalties – Publications in Nuclear Cardiology Springer-Verlag-Nuclear Cardiology and Correlative Imaging: a teaching file, NY, 2004 Lippincott Williams & Wilkins, - Nuclear Medicine teaching File, 2009
João V. Vitola, MD, PhD
Cardiologist and Nuclear Medicine Physician
Quanta Diagnostico Nuclear
Curitiba - Brazil
New Developments / Technologies / Protocols in NC
• New Gamma Cameras: CZT technology
• New Perfusion Tracer for PET - BMS747158
To be discussed
Eliminates scintillation and photomultiplier tubes
• higher spatial resolution
• higher energy resolution
• smaller size
Provides:
• improved image contrast
• improved multi-isotope imaging
• faster scanning / lower dose scans
• more flexibility in scanner design
Cadmium Zinc Telluride (CZT) - Direct Conversion Technology whose time has come
NaI(Tl) Crystal
Limitation of Conventional SPECT
Only a small
portion of the NaI
Crystal is used to
view heart
Discovery NM 530c System Design Simultaneous Cardiac acquisition by all stationary detectors
Discovery NM 530c System Design
32 x 32 x 5 mm
Indirect vs. direct conversion
X-ray or g-ray
Q.E. 20%-80%
electronics
e e e
e e
e e e
e e e
e e e
e
Photosensor (PMT):
2000 photo-electrons
Noise (APD/PD)
Gain variation
Light transport
Light generation
Direct Indirect
Scintillator (e.g. NaI:Tl):
9000 photons @ 140 keV
X-ray or g-ray
electronics
e
h h
h
h h
e e e e
- cathode
+ anode
Noise
Charge generation
Charge transport
Assuming no other sources of noise,
Poisson statistics dictates energy resolution:
g energy light photo-electrons
g energy charge carriers
Direct Conversion (CZT):
30,000 photons @ 140 keV
CdZnTe Semiconductor
Energy Resolution
Energy resolution depends on
- Light output of scintillator
- Linearity & uniformity of scintillator
- Uniformity of light collection
- Quantum efficiency of PMT
- Electronic noise
Energy resolution can be improved by
- Better scintillator
- Better photosensor
- …
scintillator
lightguide
PMT
Energy Resolution for CZT is determined by:
- crystal quality
- incomplete charge collection
Energy resolution can be improved by:
- using perfect crystals
- measuring and correction defects
- compensating for incomplete charge collection:
- using signal shape
- using dual-sided readout:
CZT
Anger 9.5% 99mTc:
140 keV
123I:
159 keV
50 100 150 keV 200
point sources in air
Alcyone 6.0%
Anger 9.5% 99mTc:
140 keV
123I:
159 keV
50 100 150 keV 200
point sources in air
Alcyone 6.0%Alcyone 6.0%
Spatial Resolution
Resolution for PMT based system is determined by:
- Thickness of crystal (light spreading)
- Size of PMT
- Light output of scintillator
- Optimization of light spread function
- Position estimation algorithm
Spatial resolution can be improved by
- Segmenting scintillator
- Smaller (or multi-anode) photomultipliers
scintillator
lightguide
PMT
Resolution for CZT based system is determined by:
- anode pitch
- charge spreading
Spatial resolution can be improved (somewhat) by:
- using a smaller pitch
- using proportional readout
- more electronic channels
Not to scale
CZT
Discovery NM 530c System Design
Multiple-Pinhole Collimator Design
Front Back
Thick Pb septa
prevents crosstalk
between detectors
Tungsten 5mm pinhole inserts
provide high energy collimation
(I-123) and limits Pb x-rays (Tl-201)
Discovery NM vs. Ventri
Energy
Resolution
FWHM/Peak
Central
(mm)
Resolution
Tangential
(mm)
Radial
(mm)
Point
Kcts/min
Sensitivity
Phantom
Kcts/min
DNM
530c 5.7% 4.8 3.35 5.25 688 573
Ventri 9.4% 10.9 7.5 10.9 99.2 150
Ratio 1.65 2.27 2.24 2.08 6.94 3.82
19 pinholes
Normal Example
S-SPECT Discovery NM 530c
12 min stress/ 14 min rest 2 min stress/ 4 min rest
DNM 530c: Clinical Implications
• Fast 2-5 min acquisitions
– Increase patient throughput
– Increase protocol flexibility
– Increase patient comfort and convenience
– Decrease patient radiopharmaceutical dose
– Decrease patient motion
• Simultaneous dual isotope imaging (= 10 X sensitivity)
• Potential to improve CFR calculations
• Significantly improve I-123 (MIBG, BMIPP, rotenone ) imaging
• Improve bad beat rejection and diastolic function measurement (due to list mode acquisition)
Multicenter Comparison between DNM530c & Standard Dual Detector Cameras: Objectives
(n=161)
• To determine diagnostic agreement between the new Discovery NM 530c (DNM530c) and standard dual detector cameras (S-SPECT) in patients with known or suspected CAD.
• The secondary goals included the strength of agreement on a per-vessel analysis, the image quality, and the correlation of automated rest and stress left ventricular ejection fractions (LVEF).
Patient Example: Normal (male 5’6” 176 lbs)
S-SPECT Discovery NM 530c
12 min stress/ 14 min rest 2 min stress/ 4 min rest
Patient Example: Reversible LAD and RCA defects (male 5’5” 189 lbs)
S-SPECT Discovery NM 530c
12 min stress/ 14 min rest 2 min stress/ 4 min rest
Abnormal Example
S-SPECT Discovery NM 530c
12 min stress/ 14 min rest 2 min stress/ 4 min rest
Patient Example: Breast vs. Diaphragmatic Attenuation (female 5’3” 206 lbs)
S-SPECT Discovery NM 530c
12 min stress/ 14 min rest 2 min stress/ 4 min rest
Patient Example: Fixed defects
S-SPECT Discovery NM 530c
12 min stress/ 14 min rest 2 min stress/ 4 min rest
Image Quality
Rest
S-SPECT
(n=330)
Rest
DNM530c
(n=330)
Stress
S-SPECT
(n=330)
Stress
DNM530c
(n=330)
Excellent 232 (70.3%) 275 (83.3%) 224 (67.9%) 282 (85.5%)
Adequate 94 (28.5%) 47 (14.2%) 105 (31.8%) 41 (12.4%)
Suboptimal 4 (1.2%) 8 (2.4%) 1 (0.3%) 7 (2.1%)
Esteves et al. J Nucl Cardiol 2009, 16:927-24.
Conclusions about CZT
• A novel solid-state-detector dedicated cardiac camera (DNM530c) has been developed by GE Healthcare and tested in a multicenter study.
• DNM530c provides rest/stress Tc-99m tetrofosmin myocardial perfusion images comparable to S-SPECT at significantly shorter acquisition times.
Future Direction for Cardiac PET Ideal PET MPI Imaging Agent
• High cardiac uptake with minimal redistribution
• Near linear myocardial uptake vs. flow up to 5 mL/min/g or more (high first pass extraction fraction)
• High target to non-target ratio (vs. lung, liver, bowel)
• Usable for both exercise and pharmacologic stress
• Usable for quantitation of absolute myocardial flow
• Available as unit dose (18F-labeled compound)
Adapted from: Glover, D and Gropler, R., J. Nucl. Card 14:6 p765-8 Ver. 18Aug 09
Mitochondrial Complex 1 (MC-1) Inhibitor
2-tert-Butyl-4-chloro-5-[4-(2- (18F)fluoro-ethoxymethyl)-benzyloxy]-2H-pyridazin-3-one
N
N
O
C l
O
O 1 8
F
Ver. 18Aug 09
Yu, et al., J Nucl Cardiol. 2007;14(6):789-98
New PET perfusion tracer labeled with F-18 Chemical Structure of BMS747158
* Indicates p<0.05
BMS747158 (n=4)
201Tl (n=3)
99mTc-sestamibi (n=3)
* *
0
1
2
3
0 1 2 3 4 5 Coronary perfusion flow (ml/min/g)
Up
take
Yu, et al., J Nucl Cardiol. 2007;14(6):789-98
First Pass Uptake in Isolated Rabbit Hearts
Pre-Clinical Cardiac PET Imaging with BMS747158
Normal Rat
Yu, M et al. J Nucl Cardiol 2007, 14(6):789-98
Coronary
ligation in Rat
Normal primate
Ver. 18Aug 09
Study 101: Safety, dosimetry, and biodistribution. Single injection at rest. (n=13 healthy subjects)
Phase 1 Studies of BMS747158
Maddahi J, et al. JNM 2008 (abstract )
Ver. 18Aug 09
Study 102: Safety, dosimetry, and biodistribution.
Separate day injection at rest and stress (12
subjects)
• Independent Data Monitoring Committee and a renowned
electrophysiologist reviewed the entire safety data-set
• None of the AEs were considered serious or related to study drug
• No clinically significant changes in
Physical and neurological exams (incl. EEG)
Vital signs
Clinical labs (incl. Cardiac enzymes)
no safety concerns and no warnings in ECG data
Individual subjects had non-consistent single time-point
QT/QTc prolongation
BMS747158 Phase 1 Safety
Ver. 18Aug 09
Maddahi J, et al. JNM 2008 (abstract )
21 min. 202 min. 165 min. 35 min.
21 min. 202 min. 165 min. 35 min.
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• Highest dose organ: – Stress (pharmacologic and exercise): heart – Rest: kidneys
• Dosimetry is within the clinically acceptable range
• No adverse events related to the tracer were noted
• Stress imaging is feasible with both treadmill exercise and pharmacologic vasodilation
• Myocardium is clearly visualized for several hours after rest and stress injection with good myocardial to background ratio
• Five minute gated acquisition - starting 2 minutes after injection - yields high quality images
Summary and Conclusions Phase 1 BMS747158
Maddahi J, et al. JNM 2009
BMS747158 Phase 2 Clinical Studies
BMS747158-201 (first in patient)
– Cohort 1: develop a one-day rest/stress imaging protocol; safety
• Patients with reversible defects on SPECT
– Cohort 2: assess diagnostic efficacy compared to SPECT in detecting CAD; safety
• Patients classified as low, intermediate or high pre-test likelihood (ACC/AHA Guidelines for exercise testing)
Ver. 18Aug 09
Study 201 - Patient 006-003
31
J. Maddahi, U
CLA
BM
S747158
SA
BM
S747158
HLA
BM
S747158
VLA
Rest
Rest
Rest
Rest
Stress
Stress
Stress
Stress
Ver.18Aug 09
Phase III
• Ongoing
• Compare MIBI SPECT vs 18 F – BMS PET
• USA, Finland and Brazil