DISCLOSURESDISCLOSURESHonorarium Honorarium –– Research / Advisor, Expert Services and Conferences in NuclearResearch / Advisor, Expert Services and Conferences in Nuclear CardiologyCardiology

BMS, CVT, Astellas, Lantheus, PGx, IAEABMS, CVT, Astellas, Lantheus, PGx, IAEARoyalties Royalties –– Publications in Nuclear CardiologyPublications in Nuclear CardiologySpringerSpringer--VerlagVerlag--Nuclear Cardiology and Correlative Imaging: a teaching file,Nuclear Cardiology and Correlative Imaging: a teaching file, NY, 2004NY, 2004Lippincott Williams & Wilkins, Lippincott Williams & Wilkins, -- Nuclear Medicine teaching FileNuclear Medicine teaching File, 2009, 2009

João V. Vitola, MD, PhDJoão V. Vitola, MD, PhD

Cardiologist and Nuclear Medicine Physician Cardiologist and Nuclear Medicine Physician Quanta Diagnostico NuclearQuanta Diagnostico Nuclear

Curitiba Curitiba -- BrazilBrazil

New Developments / Technologies / Protocols in NC

•• New Gamma Cameras: New Gamma Cameras: CZT technologyCZT technology•• New Hybrid systems: New Hybrid systems: SPECT/CT andSPECT/CT and PET/CT 64 slicesPET/CT 64 slices•• New Perfusion Tracer for PET New Perfusion Tracer for PET -- BMS747158BMS747158•• New pharmacologic stressors New pharmacologic stressors –– the 2 min stress test: the 2 min stress test:

–– RegadenosonRegadenoson –– (FDA approved, n=784, USA, Brazil and (FDA approved, n=784, USA, Brazil and Argentina) Argentina) -- bolus IV 400ugbolus IV 400ug

–– BMS068645 BMS068645 -- ApadenosonApadenoson -- (PGx Health (PGx Health -- Phase III, n = Phase III, n = 753 , USA and Brazil) bolus IV 100 or 150 ug753 , USA and Brazil) bolus IV 100 or 150 ug

To be discussed

CZT TechnologyCZT TechnologyErnest V. Garcia, PhD*Ernest V. Garcia, PhD*

Emory University School of MedicineEmory University School of Medicine

Hi Joao,Please give my Cuban colleagues my best wishes for 2010!Ernie

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) Cadmium Zinc Telluride (CZT) -- Direct ConversionDirect ConversionTechnology whose time has comeTechnology whose time has come

D e t ec t o

r 1 Detector 2

NaI(Tl) Crystal

Limitation of Conventional SPECTLimitation of Conventional SPECT

Only a smallportion of the NaI Crystal is used toview heart

Discovery NM 530c System DesignDiscovery NM 530c System DesignSimultaneous Cardiac acquisition by all stationary detectors

Discovery NM 530c System DesignDiscovery NM 530c System Design

2 . 4 6 m m 32 x 32 x 5 mm

Indirect vs. direct conversionIndirect vs. direct conversionX-ray or γ-ray

Q.E. 20%-80%

electronics

ee e

e e

ee eee e ee ee

Photosensor (PMT):2000 photo-electrons

Noise (APD/PD)

Gain variation

Light transport

Light generation

DirectIndirect

Scintillator (e.g. NaI:Tl):9000 photons @ 140 keV

X-ray or γ-ray

electronics

ehh

h

hh

eeee

- cathode

+ anode

Noise

Charge generation

Charge transport

Assuming no other sources of noise,Poisson statistics dictates energy resolution:

γ energy � light � photo-electronsγ energy � light � photo-electrons

γ energy � charge carriersγ energy � charge carriers

Direct Conversion (CZT):30,000 photons @ 140 keVCdZnTe Semiconductor

Energy ResolutionEnergy Resolution

Energy resolution depends on- Light output of scintillator- Linearity & uniformity of scintillator- Uniformity of light collection- Quantum efficiency of PMT- Electronic noiseEnergy resolution can be improved by- Better scintillator- Better photosensor- …

scintillator

lightguide

PMT

Energy Resolution for CZT is determined by:- crystal quality- incomplete charge collectionEnergy 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 airAlcyone 6.0%

Anger 9.5% 99mTc: 140 keV

123I: 159 keV

50 100 150 keV 200

point sources in airAlcyone 6.0%Alcyone 6.0%

Spatial ResolutionSpatial 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 spreadingSpatial resolution can be improved (somewhat) by:- using a smaller pitch- using proportional readout- more electronic channels

Not to scale

CZT

Discovery NM 530c System DesignDiscovery NM 530c System DesignMultiple-Pinhole Collimator Design

Front BackThick Pb septaprevents crosstalkbetween detectors

Tungsten 5mm pinhole insertsprovide high energy collimation(I-123) and limits Pb x-rays (Tl-201)

Discovery NM vs. VentriDiscovery NM vs. VentriEnergyEnergyResolutionResolutionFWHM/PeakFWHM/Peak

CentralCentral(mm)(mm)

ResolutionResolutionTangentialTangential

(mm)(mm)RadialRadial(mm)(mm)

PointPointKcts/minKcts/min

SensitivitySensitivityPhantomPhantomKcts/minKcts/min

DNMDNM530c530c

5.7%5.7% 4.84.8 3.353.35 5.255.25 688688 573573

VentriVentri 9.4%9.4% 10.910.9 7.57.5 10.910.9 99.299.2 150150

RatioRatio 1.651.65 2.272.27 2.242.24 2.082.08 6.946.94 3.823.82

19 pinholes

Normal ExampleNormal Example

S-SPECT Discovery NM 530c12 min stress/ 14 min rest 2 min stress/ 4 min rest

DNM 530c: Clinical ImplicationsDNM 530c: Clinical Implications•• Fast 2Fast 2--5 min acquisitions5 min acquisitions

–– Increase patient throughputIncrease patient throughput–– Increase protocol flexibilityIncrease protocol flexibility–– Increase patient comfort and convenienceIncrease patient comfort and convenience–– Decrease patient radiopharmaceutical doseDecrease patient radiopharmaceutical dose–– Decrease patient motionDecrease patient motion

•• Simultaneous dual isotope imaging Simultaneous dual isotope imaging (= 10 X sensitivity)(= 10 X sensitivity)•• Potential to improve CFR calculationsPotential to improve CFR calculations•• Significantly improve ISignificantly improve I--123 (MIBG, BMIPP, rotenone ) 123 (MIBG, BMIPP, rotenone )

imagingimaging•• Improve bad beat rejection and diastolic function Improve bad beat rejection and diastolic function

measurement (due to list mode acquisition)measurement (due to list mode acquisition)

Multicenter Comparison between DNM530c & Multicenter Comparison between DNM530c & Standard Dual Detector Cameras: Standard Dual Detector Cameras: Objectives Objectives

(n=161)(n=161)

•• To determine diagnostic agreement between To determine diagnostic agreement between the new Discovery NM 530c (DNM530c) and the new Discovery NM 530c (DNM530c) and standard dual detector cameras (Sstandard dual detector cameras (S--SPECT) in SPECT) in patients with known or suspected CAD. patients with known or suspected CAD. •• The secondary goals included The secondary goals included the strength of the strength of

agreement on a peragreement on a per--vessel analysis, vessel analysis, the the image quality, and the correlation of image quality, and the correlation of automated rest and stress left ventricular automated rest and stress left ventricular ejection fractions (LVEF).ejection fractions (LVEF).

Patient Example: Normal Patient Example: Normal (male 5(male 5’’66”” 176 lbs)176 lbs)

S-SPECT Discovery NM 530c12 min stress/ 14 min rest 2 min stress/ 4 min rest

Patient Example: Reversible LAD and RCA defects Patient Example: Reversible LAD and RCA defects (male (male 55’’55”” 189 lbs)189 lbs)

S-SPECT Discovery NM 530c12 min stress/ 14 min rest 2 min stress/ 4 min rest

Abnormal ExampleAbnormal Example

S-SPECT Discovery NM 530c12 min stress/ 14 min rest 2 min stress/ 4 min rest

Patient Example: Breast vs. Diaphragmatic Attenuation Patient Example: Breast vs. Diaphragmatic Attenuation (female 5(female 5’’33”” 206 lbs)206 lbs)

S-SPECT Discovery NM 530c12 min stress/ 14 min rest 2 min stress/ 4 min rest

Patient Example: Fixed defectsPatient Example: Fixed defects

S-SPECT Discovery NM 530c12 min stress/ 14 min rest 2 min stress/ 4 min rest

Image QualityImage Quality

Rest Rest SS--SPECTSPECT(n=330)(n=330)

RestRestDNM530cDNM530c(n=330)(n=330)

StressStressSS--SPECTSPECT(n=330)(n=330)

StressStressDNM530cDNM530c(n=330)(n=330)

ExcellentExcellent 232 (70.3%)232 (70.3%) 275 275 (83.3%)(83.3%) 224 (67.9%)224 (67.9%) 282 282 (85.5%)(85.5%)

AdequateAdequate 94 (28.5%)94 (28.5%) 47 (14.2%)47 (14.2%) 105 (31.8%)105 (31.8%) 41 (12.4%)41 (12.4%)

SuboptimalSuboptimal 4 (1.2%)4 (1.2%) 8 (2.4%)8 (2.4%) 1 (0.3%)1 (0.3%) 7 (2.1%)7 (2.1%)

Esteves et al. J Nucl Cardiol 2009, 16:927-24.

Conclusions about CZTConclusions about CZT•• A A novel solidnovel solid--statestate--detector dedicated detector dedicated cardiac camera (DNM530c) has been cardiac camera (DNM530c) has been developed by GE Healthcare and tested in developed by GE Healthcare and tested in a multicenter study. a multicenter study. •• DNM530c provides rest/stress TcDNM530c provides rest/stress Tc--99m 99m tetrofosmin myocardial perfusion images tetrofosmin myocardial perfusion images comparable to Scomparable to S--SPECT at significantly SPECT at significantly shorter acquisition times.shorter acquisition times.

ATEN. CORRECTION CALCIUM SCORE

ANATOMY – 64 SLICES

PERFUSION (Absolute)VIABILITY

LV FUNCT (True Str)

Hybrid Technology PET/CT and SPECT/CT and

New Perfusion Agent for PET

Vitola JV, Cerci J, Delbeke D. PET/CT em Cardiologia, Ed. Revinter, Rio de Janeiro, 2010 (in Press)

CLINICAL CASES

Routine Attenuation Correction SPECT/CTPotential artifacts

Routine Attenuation Correction PET/CTPotential artifacts

55 yo, Family Hx, No Known CAD, Atypical Pain

AVAILABILITY OF PET TECHNOLOGY 2009AVAILABILITY OF PET TECHNOLOGY 2009MOST FOR ONCOLOGY USEMOST FOR ONCOLOGY USE

PH – 19

SIEMENS – 24

GE - 29

0

5

10

15

20

25

30

2007 2009

GEPHSI

Future Direction for Cardiac PETFuture Direction for Cardiac PETIdeal PET MPI Imaging AgentIdeal PET MPI Imaging Agent

•• High cardiac uptake with minimal redistributionHigh cardiac uptake with minimal redistribution•• Near Near linear myocardial uptake vs. flowlinear myocardial uptake vs. flow up to 5 up to 5 mL/min/g or more (high first pass extraction mL/min/g or more (high first pass extraction fraction)fraction)•• High target to nonHigh target to non--target ratio (vs. lung, liver, target ratio (vs. lung, liver, bowel)bowel)•• Usable for both Usable for both exerciseexercise and pharmacologic stressand pharmacologic stress•• Usable for quantitation of absolute myocardial Usable for quantitation of absolute myocardial flowflow•• Available as unit dose (Available as unit dose (1818FF--labeled compoundlabeled compound))

Adapted from: Glover, D and Gropler, R., J. Nucl. Card 14:6 p765-8Ver. 18Aug 09

Mitochondrial Complex 1 (MCMitochondrial Complex 1 (MC--1) Inhibitor1) Inhibitor

22--terttert--ButylButyl--44--chlorochloro--55--[4[4--(2(2-- ((18F)fluoro18F)fluoro--ethoxymethylethoxymethyl))--benzyloxy]benzyloxy]--2H2H--pyridazinpyridazin--33--oneone

N

N

O

C l

O

O18F

Ver. 18Aug 09Yu, et al., J Nucl Cardiol. 2007;14(6):789-98

New PET perfusion tracer labeled with FNew PET perfusion tracer labeled with F--1818Chemical Structure of BMS747158Chemical 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 5Coronary perfusion flow (ml/min/g)

Uptak

e

Yu, et al., J Nucl Cardiol. 2007;14(6):789-98

First Pass Uptake in Isolated Rabbit HeartsFirst Pass Uptake in Isolated Rabbit Hearts

PrePre--Clinical Cardiac PET Imaging with BMS747158Clinical 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:Study 101: Safety, dosimetry, and biodistribution. Single Safety, dosimetry, and biodistribution. Single injection at rest. (n=13 healthy subjects)injection at rest. (n=13 healthy subjects)

Phase 1 Studies of BMS747158Phase 1 Studies of BMS747158

Maddahi J, et al. JNM 2008 (abstract )Ver. 18Aug 09

Study 102Study 102:: Safety, dosimetry, and biodistribution. Safety, dosimetry, and biodistribution. Separate day injection at rest and stress (12 Separate day injection at rest and stress (12 subjects)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 signsClinical labs (incl. Cardiac enzymes)no safety concerns and no warnings in ECG dataIndividual subjects had non-consistent single time-point QT/QTc prolongation

BMS747158 Phase 1 SafetyBMS747158 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.

AdenosineExerciseBMS747158

Maddahi J, et al. JNM 2008; abstract

••Highest dose organ:Highest dose organ:–– Stress (pharmacologic and exercise): heart Stress (pharmacologic and exercise): heart –– Rest: kidneysRest: kidneys

••Dosimetry is within the clinically acceptable rangeDosimetry is within the clinically acceptable range••No adverse events related to the tracer were notedNo adverse events related to the tracer were noted•• Stress imaging is feasible with both treadmill exercise and Stress imaging is feasible with both treadmill exercise and pharmacologic vasodilationpharmacologic vasodilation

••Myocardium is clearly visualized for several hours after rest Myocardium is clearly visualized for several hours after rest and stress injection with good myocardial to background and stress injection with good myocardial to background ratioratio

•• Five minute gated acquisition Five minute gated acquisition -- starting 2 minutes after starting 2 minutes after injection injection -- yields high quality imagesyields high quality images

Summary and Conclusions Summary and Conclusions Phase 1 BMS747158Phase 1 BMS747158

Maddahi J, et al. JNM 2009

BMS747158 Phase 2 Clinical StudiesBMS747158 Phase 2 Clinical Studies

BMS747158BMS747158--201 201 (first in patient)(first in patient)–– Cohort 1:Cohort 1: develop a onedevelop a one--day rest/stressday rest/stress imaging protocol; imaging protocol; safetysafety•• Patients with reversible defects on SPECTPatients with reversible defects on SPECT

–– Cohort 2:Cohort 2: assess diagnostic efficacy compared to SPECT in detecting assess diagnostic efficacy compared to SPECT in detecting CAD; safetyCAD; safety•• Patients classified as low, intermediate or high prePatients classified as low, intermediate or high pre--test likelihood test likelihood

(ACC/AHA Guidelines for exercise testing)(ACC/AHA Guidelines for exercise testing)

Ver. 18Aug 09

Study 201 Study 201 -- Patient 006Patient 006--003003

39

J. Maddahi, UCLA

BMS7

4715

8SA

BMS7

4715

8HL

ABM

S747

158

VLA

Rest

Rest

Rest

Rest

Stress

Stress

Stress

Stress

Ver.18Aug 09

Phase IIIPhase III•• Ongoing discussion regarding protocolOngoing discussion regarding protocol•• Compare MIBI SPECT vs 18 F Compare MIBI SPECT vs 18 F –– BMS PETBMS PET•• Latin American PatientsLatin American Patients

–– first visit Brazil Feb / 2010first visit Brazil Feb / 2010–– Goal to start second semester 2010Goal to start second semester 2010

J Nucl Cardiol 2007; 14:645-58

Regadenoson (Lexiscan) FDA approved in April 2008

N = 784

New Pharmacologic Stressors: A2a

WHAT DO WE KNOW NOW ?WHAT DO WE KNOW NOW ?

REGADENOSON = ADENOSINEREGADENOSON = ADENOSINE

•• IDENTIFY INDIVIDUALS WITH ISCHEMIAIDENTIFY INDIVIDUALS WITH ISCHEMIA•• QUALITY OF IMAGESQUALITY OF IMAGES•• SOME POTENTIAL ADVANTAGES TO BE DISCUSSEDSOME POTENTIAL ADVANTAGES TO BE DISCUSSED

New PerspectivesNew Perspectives•• Bolus administrationBolus administration

RegadenosonRegadenoson--induced Blood Flowinduced Blood FlowTime to 2.4-fold above baseline: 33 secDuration at ≥2.5-fold above baseline: 2.3 min

0 2 4 6 8 10

APV

ratio

1.0

1.5

2.0

2.5

3.0

3.5

Time (min)

400 mcg regadenoson

Lieu HD, et al. J Nucl Cardiol. 2007;14(4):514-520.

Window for Tracer Uptake

How do Patients Feel Compared to Adenosine ?How do Patients Feel Compared to Adenosine ?

84% equal or better

New PerspectivesNew Perspectives•• Bolus administrationBolus administration•• Standard doseStandard dose

Standard dose 400 ug independent of body weightStandard dose 400 ug independent of body weight

RationalRational

Receptor binding = First pass phenomenonReceptor binding = First pass phenomenonInitial experience Initial experience -- works regardless of body weightworks regardless of body weight

further evaluation desirablefurther evaluation desirable

New PerspectivesNew Perspectives

•• Bolus administrationBolus administration•• Standard doseStandard dose•• Selectivity and low to moderate receptor Selectivity and low to moderate receptor binding affinitybinding affinity

Xu Circ 2000

SelectivitySelectivity

A1 A2BA3

Undesirable effects (eg, bronchospasm)

Undesirable effects (eg, AV block)

A2A

Increase coronary blood flow

SelectivitySelectivity

Gao Journal of Pharm Exp Ther 2001

SelectivitySelectivity

A1 A2BA3

Undesirable effects (eg, bronchospasm)

Undesirable effects (eg, AV block)

A2A

Increase coronary blood flow

SelectivitySelectivity

Perspective to apply in COPDPerspective to apply in COPD

•• Various types of COPD patients Various types of COPD patients •• Limited data Limited data –– still needs cautionstill needs caution•• Further studies, larger experience is Further studies, larger experience is

neededneeded•• What is the literature showing ?What is the literature showing ?

New PerspectivesNew Perspectives•• Bolus administrationBolus administration•• Standard doseStandard dose•• Selectivity and low to moderate receptor Selectivity and low to moderate receptor bindingbinding•• Special issuesSpecial issues

–– Potential to combine with exercisePotential to combine with exercise

Eixo Curto

Eixo Longo Vertical

Eixo Longo Horizontal

Cortes Tomográficos-Referência

Potential for “ on the fly ” protocol

• 30 secs from peak hyperemia•Pts on meds•Depressed chronotropic response•Effects of Max Hyperemia on MPI Sensitivity ?

Adenosine

Binodenoson

HO O

OH OH

NNH2

N

N

N

Selective ASelective A2A2A Adenosine Receptor AgonistsAdenosine Receptor Agonists

NHN

HO O

OH OH

NNH2

N

N

N

H3C O

OH OH

NNH2

N

N

NHN O

OH3C O

O

HO OH

H2N

N

NHO N

NN

N

O

HNCH3

Zablocki J et al. Nucleosides Nucleotides Nucleic Acids. 2001;20:343-360.Gao Z et al. J Pharmacol Exp Ther. 2001;298:209-218.

Regadenoson

Apadenoson

Adapted from Hendel RC et al. Abstract presented during the 2005 Annual Scientific Sessions of the American Heart Association. Dallas, Texas.

Fixed doses100 µg (< 100 kg) or 150 µg (> 100 kg)

Potential Apadenoson ProtocolPotential Apadenoson Protocol

Minutes0 1 2

Saline flush

Bolus apadenoson

Inject tracer

Phase III ApadenosonPhase III Apadenoson•• Goal of 753 patientsGoal of 753 patients•• Compare adenosine to apodenoson (1:2)Compare adenosine to apodenoson (1:2)•• 75 US and 20 Brazil centers75 US and 20 Brazil centers

–– Goal to start second semester 2010Goal to start second semester 2010

ConclusionsConclusions• Regadenoson is similar to adenosine to detect ischemia.

Apadenoson will be tested in Phase III.

• Regadenoson has the advantage of bolus administration andless side effects than adenosine. Apadenoson also bolus.

• Potential for utilization in COPD patients.

• Potential for combination with exercise – new protocols

• Regadenoson FDA approved in 2008.

• Will cost allow wide spread utilization ?

Selective ASelective A2A2A Adenosine Receptor AgonistsAdenosine Receptor Agonists