incaps (iaea nuclear cardiology protocol...

INCAPS (IAEA Nuclear CArdiology Protocol Survey)

1. In this survey please include all SPECT Myocardial

Perfusion Imaging studies completed during the

specified week (Monday-Sunday), whether the study

was begun during the specified week or previously.

2. Only include studies in which patients were imaged at

your facility, excluding studies read at your facility but

performed elsewhere.


1. In this survey please include all SPECT Myocardial

Perfusion Imaging studies completed during the

specified week (Monday-Sunday), whether the study

was begun during the specified week or previously.

2. Only include studies in which patients were imaged at

your facility, excluding studies read at your facility but

performed elsewhere.

3. Only fill in fields colored green in boxed areas. Lighter

green denotes choose from drop-down menu. Darker

green denotes type-in.

4. Please report data for 1 week period; if less than 25

studies are performed during that week then please

report data for the subsequent week as well.


Study

Number Age Sex Weight Technology 1 Technology 2

Example 1 57 M 68 kg

Example 2 82 F 59 kg Transmission source AC

Example 3 65 F 78 kg GE Alcyone technology Prone Imaging

Example 4 64 M 77 kg

CT AC (MDCT –

Multislice CT) Philips Astonish


First Injection

Date 1 Activity 1 Units 1 Radiopharmaceutical 1 R/S 1

3-Sep-2012 9.9 mCi Tc-99m sestamibi (Cardiolite®) Rest

4-Sep-2012 3.1 mCi Tl-201 Rest

4-Sep-2012 31.1 mCi Tc-99m tetrofosmin (Myoview®) Stress

5-Sep-2012 10.1 mCi Tc-99m sestamibi (Cardiolite®) Stress


Second Injection

Date 2 Activity 2 Units 2 Radiopharmaceutical 2 R/S 2

3-Sep-2012 35.4 mCi Tc-99m sestamibi (Cardiolite®) Stress

4-Sep-2012 28.7 mCi Tc-99m tetrofosmin (Myoview®) Stress

5-Sep-2012 30.5 mCi Tc-99m tetrofosmin (Myoview®) Rest

None

72/M, resting angina, exertional dyspnea, 3-vessel disease on CTCA

40-50%

Rest Low dose DB 3 mo later

LVEF=52%

EDV=111ml

ESV=54ml

LVEF=70%

EDV=93ml

ESV=28ml

LVEF=56%

EDV=103ml

ESV=45ml

Pre-PTCA Post-PTCA

CNUHH, the most beautiful hospital in KOREA

Henry Bom

Department of Nuclear Medicine,

Chonnam National University Hwasun Hospital, Hwasun, Korea

New Experimental Radiotracers

for Myocardial Perfusion

Tc-99m sestamibi

Tc-99m tetrofosmin

Tl-201

Rb-82

Mitochondrium

Uptake of Flow Tracers

Na-K ATPase

Na K

O-15 H2O

free

diffusion

N-13 NH3

carrier

Glutamine

Glutamine synthetase

diffusion

What we need?

SPECT ([99mTc]MIBI) PET ([13N]NH3)

What we need?

• Better image

• Quantitation

• Easy to use

18F perfusion agents

[18F]BMS-747158, Flurpiridaz

Pyridaben

Circulation. 2009, 119: 2333-2342.

Contrast ratios for [13N]NH3

(dashed lines) and

[18F]BMS (solid lines)

measured over 40 minutes.

[18F]BMS-747158, Flurpiridaz

2-Tert-butyl-5-[2-(2-[18F]fluroethoxy)ethoxy]benzyloxy]-4-chloro-2H-pyridazin-3-one

Mitochondrial complex I (MC-I) inhibitor

Bioorganic & Medicinal Chemistry. 2010, 18: 1312–1320


[18

F] FP2OP

Pyridaben

Flurpiridaz

[18

F] FP2OP

Cardiac PET images of a healthy Chinese mini-swine with 85 MBq

[18F]FP2OP in 5% ethanol solution. The images were collected at 5, 15, 30,

60 min after injection, respectively.

18F or 11C18F or 11C

Voltage Sensor : Measurement of

Mitochondrial Membrane Potential

• Rhodamine 123

• Phosphonium salts

P+ 3H


Voltage Sensors

http://en.wikipedia.org/wiki/File:Rhodamine_skeleton.svg

http://en.wikipedia.org/wiki/File:Rhodamine_123.svg

Non-radiolabeled rhodamines are known to accumulate in the

mitochondria in proportion to mitochondrial membrane potential and

are substrates for Pgp, a protein-implicated in multidrug resistance.

Nuclear Medicine and Biology. 2010, 37: 365–370


2-[18

F] fluoroethylrhodamine B

http://en.wikipedia.org/wiki/File:Rhodamine_B.svg

2-[18

F] fluoroethylrhodamine B

MicroPET images of a rat injected with 2-

[18F]fluoroethylrhodamine B.

Time activity curve of a rat myocardium and liver

after injection with 2-[18F]fluoroethylrhodamine B.

18F or 11C18F or 11C

(4-carboxybutyl)

Triphenylphosphonium

Methyltriphenylphosphonium

Tetraphenylphosphonium

Triphenyl

(2pyridylmethyl)phosphonium

tetrabutylphosphonium

P+ COOH P+

P+N

P+ CH3

P+P+ 3H


Phosphonium salts

JJ Min, et al. J Nucl Med. 2004, 45:636–643

P+ 3H

Tetraphenylphosphonium (TPP)

10%

ID/g

0%

2 min 0.5 hr 1 hr 2 hr 4hr

2 min 0.5 hr 1 hr 2 hr 4 hr

Molecular Imaging Program at Stanford (MIPS)

P+ 18F

Cheng Z, et al. J Label Compd Radiopharm. 2005, 48: 131–137


[18F] TPP

Igal Madar, et al. Eur J Nucl Med Mol Imaging. 2007, 34:2057-2065

Igal Madar et al. J Nucl Med. 2006, 47:1359-1366

[18F] fluorobenzyltriphenylphosphonium


[18F] FBnTP

HOX

OH TsOX

OTs TsOX

18Fn n n

+P

R

R

R

P+

R

R

R

X18F

TsOX

18Fn n

[18F]FPTP : X=C, n=1, R=H. Kim et al. J Nucl Med. 2012, 53: 1779-1785

[18F]FHTP : X=C, n=2, R=H. Kim et al. Bioconjugate Chem. 2012, 23(3): 431-437

[18F]FETP : X=O, n=1, R=H. Kim et al. Bioorg. Med. Chem. Lett. 2012, 22: 319–322

[18F]FETMP : X=O, n=1, R=OMe. Kim et al. Nucl Med Biol. 2012, 39: 1093-1098

18F P+ R

Chonnam Style

P+

MicroPET study – [18

F] FPTP

0

2.5

SUV

H

L

H

L

H

L

H

L

1 min 10 min

30 min 60 min

P+18F

[18F]-(fluoropentyl )triphenylphosphonium

J Nucl Med. 2012, 53: 1779-1785

(min)

Ac

tivit

y (

co

un

ts /

pix

el

/ s

ec

)


F] FPTP

Co

ntr

as

t ra

tio

Time (min)


F] FPTP

a

Normal

MI model

MicroPET study in Rats – [18

F] FPTP

y = 0.78 x – 3.39

r 2 = 0.92

TT

C (

%)

Polar map (%)


F] FPTP

2.5

0

S

U

V

[18F]FPTP [13N]NH3

[18

F] FPTP vs. [13

N]NH3

[18F]FPTP TTC

staining 1.0 3.5

[18

F] FPTP vs. [13N]NH3

[13N]NH3

0.6 1.0

Human PET study [18

F] FPTP

[18

F] FHTP

30 min 60 min

0

4

SUV

H

L

H

L

P+

18F

[18F]-labeled (6-fluorohexyl)triphenylphosphonium

[18

F] FETP

0

3.0

SUV

30 min 60 min

H H

L L

P+O

18F

[18F]-labeled (2-(2-fluoroethoxy)ethyl)triphenylphosphonium

[18

F] FETMP

30 min 60 min

H H

L L

P+O

18F

OMe

MeO

OMe

[18F]-labeled (2-(2-fluoroethoxy)ethyl)

tris(4-methoxyphenyl)phosphonium

0

3.0

SUV

SUV

H

L

H

L

H

L

H

L

H

L

H

L

H

L

H

L

MicroPET study

30 min

60 min

[18F]FPTP [18F]FHTP [18F]FETP [18F]FETMP

Take Home Message

• Developed 18F-labeled myocardial perfusion agents target

mitochondria either blocking complex I or being trapped by

electrical charge difference.

Acknowledgments

Laboratory of In Vivo

Molecular Imaging (LOVMI)

Jung-Joon Min, MD, PhD

JiHwa Chong, PhD

Seung-Hwan Park, PhD

Sheng-Nan Jiang, MD

Hyeon-Sik Kim, MS

Vu H. Nguyen, MS

Yoon-Soon Moon, BS

Hyun Hong, BS

Deok-Mi Kim, BS

Dinh V. H. Van

Dongguk University

Laboratory of Instrumental analysis

Kook-Hyun Yu, PhD

Youn-Do Choi, MS

Nuclear Medicine

Hee-Seung Bom, MD, PhD

Ho-Chun Song, MD, PhD

Byeong-Il Lee, PhD

Byung-Hyun Byun, MD

Sun-Pyo Hong, MD

Hwa-Youn Jang, BS

Sang-Min Shin, BS

Stanford University School of Medicine

(Molecular Imaging Program at Stanford)

Sanjiv S. Gambhir, MD, PhD

Zhen Cheng, PhD

Korea Atomic Energy Research Institute

Radiation Biotechnology Research Division

Seung-Dae Yang, PhD

Sang-Wook Kim, PhD

Jeong-Hoon Park, PhD

Hee-Jung Kim, MS

Korea Institute of Radiological and

Medical Sciences (KIRAMS)

Department of Nuclear Medicine

Kyo-Chul Lee, PhD

Sang-Keun Woo, PhD

Chonnam Nat’l University Medical School

Seoul

Chonnam

Bio-Medical Cluster

62Cu-PTSM

N

N

S

N

N

S

H3C

H

62Cu

NH

CH3

N

H

CH3

[62Cu]pyruvaldehyde bis(N4-methylthiosemicarbazone)

• lipophilic, neutral

• FDA approval (Dec 21, 1995)

• Phase I, II, III

J Nucl Med. 1988, 29: 1549-1557

J Nucl Med. 1996, 37: 1294-1300

J Nucl Cardiol. 2001, 8: 67-74.

62Cu-PTSM

68Ga labeling candidates

Lipophilic, cationic complexes



68Ga labeling candidates

Ammonium salt chemical skeleton

Mol Imaging Biol. 2011, 13:128-139

11C-ammonia

11C-ammonia

sestamibi tetrofosmin

99mTc-lipophilic cation

Bioconjugate Chem. 2010, 21: 928–939.

Lipophilic cations

N

N

O

B

O

CH3

O

Cl

O H H

O

99mTc

N

N

NO

N

teboroxime

99mTc-lipophilic, neutral

NOET

Bis[N-ethoxy,N-ethyl(dithiocarbamato)]nitrido Tc (V)

99mTc-calcium channel?

Tc-99m sestamibi

Tc-99m tetrofosmin

Tl-201

Rb-82

Mitochondrium

Uptake of Flow Tracers

Na-K ATPase

Na K

O-15 H2O

free

diffusion

N-13 NH3

carrier

Glutamine


diffusion

Mitochondrium

Q. Entry for all F-18 perfusion agents?

diffusion

carrier

Glutamine


diffusion

1 2

3 4

Mitochondrium

SUMMARY

diffusion

carrier

Glutamine


diffusion

Tc-99m MIBI, TF

F-18 flupiridaz and others

Ga-68 agents

Tl-201, Rb-82

Tc-99m NOET

O-15 water

Cu-62 PTSM

Tc-99m teboroxime

N-13 ammonia

C-11 ammonia

UNESCO Triple Crown in Nature & Science

Biosphere Reserve (2002)

World Natural Heritage (2007)

Global Geopark Networks (2010)

New 7 Wonders of Nature (2011)

JEJU island, no VISA entry

ISRS, May 2013

CJK, Nov 2013

AOFNMB, Oct 2015

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