Radiopharmaceuticals

S Richard UnderwoodProfessor of Cardiac Imaging

Royal Brompton Hospital &

Imperial College London, UK

Radiopharmaceuticals in Nuclear Cardiology

Single photon emitters99mTc erythrocytes, albumin ventriculography

pyrophosphates acute infarction

annexin-V apoptosis

microspheres, MIBI, tetrofosmin perfusion201Tl ionic perfusion195mAu ionic angiocardiography111In platelets thrombus

white cells infection

anti-myosin antibody acute infarction, transplant rejection

67Ga citrate inflammation81Kr gos or solution pulmonary ventilation, right

ventriculography131I meta-iodo-benzylguanidine sympathetic innervation

Positron emitters11C microspheres perfusion

pyruvate, lactate, lactate, acetate, ß-methyl fatty acids, palmitate

metabolism

13N ammonia perfusion

glutamate metabolism15O water perfusion18F 2-fluoro-deoxyglucose metabolism

Myocardial perfusion tracers

Thallium MIBI Tetrofosmin

New tricks?

Thallium-201 MIBI & tetrofosmin

Radionuclide properties

Thallium-201

Cyclotron produced

79keV X-ray emission

Half life 72 hours

Technetium-99m

Generator produced

140keV γ emission

Half life 6 hours

99mTc perfusion tracers

MIBI tetrofosmin furifosmin

NOETteboroxime

+ + +

Uptake Mechanisms

Thallium– Part passive into negative intracellular potential

– Part active via Na+/K+ ATPase dependent pump

– Free exchange with extracellular thallium

MIBI– Passive into negative intracellular potential

– Fixed in mitochondria

Tetrofosmin– Passive into negative intracellular potential

– Fixed in cytosol

Implications of non-linear uptake

1 Intercept above zero– Overestimation of reduced perfusion

– Reduced defect contrast

– Overestimation of viability

2 Reduced slope– Reduced extraction and low counts

– Reduced defect contrast

3 Early plateau– Underestimation of hyperperfusion

– Reduced defect contrast

Properties of tracers

Thallium MIBI Tetrofosmin

Extraction (max) 0.80 0.39 0.30

Extraction (5 min) 0.60 0.41 0.30

Cell injury reduces uptake

++++ ++++ ++++

Redistribution yes minimal ?

Measure of hyperaemia +++ ++ ++

After Leppo JA

Tracer uptake versus stenosis

Glover DK . . . Beller GA. Circulation 1997; 96: 2332-816 dogs with ex vivo imaging, adenosine stress

thallium tetrofosmin

severestenosis

mildstenosis

0.63 0.70

0.860.70

Dilsizian V. JACC Img 2009; 2: 1209-12Mekkaoui C, et al. JACC Img 2009; 2: 1198-208

Glover DK, et al. Circulation 1997; 96: 2332-8

Myocardial perfusion and tracer uptake

Technetium MPS

adenosine technetium

LVEF 69%

• 86 yr female

• Chest pain on ward before rectal prolapse surgery

• T wave changes, troponin 0.3

1. Normal

2. Probably normal

3. Indeterminate

4. Probably abnormal

5. Abnormal

The study is?

Thallium-201 MPS

LVEF 76%

• Repeat MPS the next day

• Identical adenosine stress

• Thallium-201

1. Normal

2. Probably normal

3. Indeterminate

4. Probably abnormal

5. Abnormal

The study is?

Technetium

LVEF 69%LVEF 76%

Thallium

The effects of resolution

Defectlarger

Defectsmaller

Decreasing resolution

Decreasingcontrast

The effects of resolution

Imaging protocols

Thallium Stress – redistributionStress – redistribution – reinjectionStress – reinjectionStress – reinjection – 24 hour imagingRestRest – redistribution

Technetium Two dayOne day, stress – restOne day, rest – stress

Dual isotope Rest thallium – stress technetiumOthers

Adjuncts NitrateFatty meal

Thallium protocol

Stress

Tl 80MBq

Redistribution image

Tl 40MBq

Reinjection image

5 min 4 hr 5 hr

Stress image

Thallium protocol

Stress

Tl 80MBq

Stress image

Tl 40MBq

Reinjection image

5 min 1 hr

One day technetium protocols

Stress

Tc 250MBq

Stress image

Tc 750MBq

Rest image

1 hr 5 hr4 hr

Tc 250MBq

Stress image

Tc 750MBq

Rest image

1 hr 5 hrStress

Stress-rest

Rest-stress

History

• 49 year old man, hypertension and hyperlipidaemia

• single episode of epigastric discomfort and abdominal bloating, no ECG or troponin changes

• no exertional symptoms

• Upper GI endoscopy normal

MPS

Adenosine + 75W stress

Thallium-201 80 + 40MBq

1. Is not possible with thallium-201

2. Is only possible at 6 frames/s

3. Is only possible if <60kg

4. Is usually possible

5. Is always possible

ECG-gated SPECT?

ECG gated thallium

LVEF 70%

Reduced thickening infero-laterally

Coronary angiogram

LAD

LCx/OM1

RCA

Lung uptake of tracer

• Lung : heart > 0.5

• Marker of raised pulmonary capillary pressure

• In IHD, marker of adverse outcome

• Seen with both thallium & technetium

• May clear by 1 hour when using technetium

Transient ischaemic dilatation

• Stress : rest cavity volume > 1.2

• Confirm appearance from raw data

• Caution if severe ischaemia

• Marker of adverse outcome

• Indicates:

– Stress cavity dilation (stunning)

– Subendocardial ischaemiastress rest

Quality score

0%

20%

40%

60%

80%

100%

Thallium MIBI Tetrofosmin

Good

Average

Poor

Inadequate

Tl < MIBI = Tf, P < 0.001

Mean 2.13 2.28 2.33

ROBUST study. EJNM 2002; 29: 1608-16

Attenuation artefact

None

Mild

Moderate

Severe

Female, P = 10-9

0%

20%

40%

60%

80%

100%

Male, P = ns

ROBUST study. EJNM 2002; 29: 1608-16

Summed uptake score

0

20

40

60

Stress Rest

Thallium

MIBI

Tetrofosmin

P = 0.05 P = ns

ROBUST study. EJNM 2002; 29: 1608-16

Recommended usual activities

Thallium Minimum (MBq) Maximum (MBq)

USA 74 111

Europe 74 111

UK - 80

Technetium two day

USA 1110 1110

Europe 600 900

UK - 800

Technetium one day

USA 296 + 888 444+ 1332

Europe 400 + 1200 500 + 1500

UK - 400 + 1200

ARSAC notes for guidanceEJNM 2005; 32: 855-97

JNC 2006; 13: e97-120

Adverse effects of radiation

0.056 per Sv total risk0.04 fatal cancer

0.008 non-fatal cancer

0.008 inherited defect in off-spring

Thus for 10mSv:total risk is 0.00056 = 1 in 1800

Effective dose equivalents

Examination Dose (mSv) Years background

CNS death in 24 hours 87,000GI death in 7 days 8,700Bone marrow death, lethal 1 month? 4,500Transient WBC suppression/RT dose 870Effects in animal foetus 87

Annual limit (workers) 50 25

Gallium-87 6-18 9CT coronary angiogram 15 7.5Thallium-201 MPS 14 7Invasive coronary angiogram 10 5Technetium-99m MPS 8 4CT chest 8 4Barium enema/Abdominal CT 6 3EBCT for coronary calcification 1 0.5Chest XR 0.05 9 days

Annual limit (public) 5 2.5

Natural background 2 1

Tetrofosmin

MBq mCi mSv Risk 1 in

500 13.5 4 0.0002 5000

1000 27.0 8 0.0004 2500

1500 40.5 12 0.0007 1429

2000 54.1 16 0.0009 1111

2500 67.6 20 0.0011 909

3000 81.1 24 0.0013 769

Dual isotope: 3.5mCi Tl + 30mCi tetrofosmin = 1 in 556 risk

2009 Dose List price Volume price

Thallium 80 MBq £47 £35

MIBI 1600 MBq £78 £56

Tetrofosmin 1600 MBq £80 £62

Factors favouring technetium

• Stress and imaging at a distance

• Patient mix

– Obese

– Female

– Acute chest pain service

• Superior image quality

• Lower radiation burden

Factors favouring thallium

• 25 years experience

• superior perfusion tracer

• low extra-cardiac activity

• cost

Royal Brompton practice

• All three tracers

• Simultaneous thallium and technetium in parallel sessions on two cameras

• Technetium for obese and impaired LV function

• Thallium for evening and weekend sessions

• Stress – reinjection for gated thallium

• One-day stress-rest for technetium