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