radioisotopes in diagnostics and therapy

Summary of Session 2:

Radioisotopes in Diagnostics and Therapy

Ulli Köster, Jean-François Chatal29 February 2012

M. de Jong, O. Ratib, D. Thers, S. Ziegler

Don’t forget the fuel!

Radioisotopes: the “fuel” for nuclear medicine

1. What is the optimum fuel for an application ?

2. Are we using today the optimum fuel ?

3. Is there sufficient supply of fuel at reasonable cost?

4. How reliable is the fuel supply ?

The quest for the optimum isotope

N

Z

Over 3000 radioisotopes known:

• half-life• decay properties• chemical properties

PET isotopesRadio-nuclide

Half-life (h)

Branchingratio + (%)

E mean (MeV)

Range (mm)

F-18 1.83 96.7 0.25 0.7C-11 0.34 99.8 0.39 1.3N-13 0.17 99.8 0.49 1.8O-15 0.03 99.9 0.74 3.2

Ga-68 1.13 89.1 0.83 3.8

Rb-82 0.02 95.4 3.38 20Sc-44 3.97 94.3 0.63 2.5

PET isotopesRadio-nuclide

Half-life (h)

Branchingratio + (%)

E mean (MeV)

Range (mm)

F-18 1.83 96.7 0.25 0.7C-11 0.34 99.8 0.39 1.3N-13 0.17 99.8 0.49 1.8O-15 0.03 99.9 0.74 3.2

Ga-68 1.13 89.1 0.83 3.8

Rb-82 0.02 95.4 3.38 20Sc-44 3.97 94.3 0.63 2.5

Diagnostic Accuracy: PET vs SPECT

Bateman et al, J Nucl Cardiol 2006Bateman et al, J Nucl Cardiol 2006

81

6676

86100

91

0

20

40

60

80

100

Sensitivity Specificity Accuracy

SPECTPET

** ** **p<0.001p<0.001

%%

#64: D. Le Guludec

PET isotopesRadio-nuclide

Half-life (h)

Branchingratio + (%)

E mean (MeV)

Range (mm)

F-18 1.83 96.7 0.25 0.7C-11 0.34 99.8 0.39 1.3N-13 0.17 99.8 0.49 1.8O-15 0.03 99.9 0.74 3.2

Ga-68 1.13 89.1 0.83 3.8

Rb-82 0.02 95.4 3.38 20Sc-44 3.97 94.3 0.63 2.5

Mother isotope:

271 d25 d60 y

Transport of shortTransport of short--lived radioisotopeslived radioisotopes

Small cyclotrons

#340: D. Lewis

Longer-lived PET isotopesRadio-nuclide

Half-life (h)

Branchingratio + (%)

E mean (MeV)

Range (mm)

Sc-44 3.97 94.3 0.63 2.5Cu-64 12.7 17.6 0.28 0.8Y-86 14.7 31.9 0.66 2.6Zr-89 78.4 22.7 0.40 1.4I-124 100.2 22.8 0.82 3.8Tb-152 17.5 17 1.08 5

Nanoparticle PET-CT Imaging of Macrophages in Inflammatory Atherosclerosis

Nahrendorf M et al, Circulation 2008, 117(3) 379-387

64Cu-TNP

#64: D. Le Guludec

Longer-lived PET isotopesRadio-nuclide

Half-life (h)

Branchingratio + (%)

Branchingratio (%)

h10(mSv/h/GBq)

Sc-44 3.97 94.3 101 0.324Cu-64 12.7 17.6 0.5 0.03Y-86 14.7 31.9 320 0.515Zr-89 78.4 22.7 100 0.182I-124 100.2 22.8 99 0.17Tb-152 17.5 17 142

Longer-lived PET isotopesRadio-nuclide

Half-life (h)

Branchingratio + (%)

Branchingratio (%)

h10(mSv/h/GBq)

Sc-44 3.97 94.3 101 0.324Cu-64 12.7 17.6 0.5 0.03Y-86 14.7 31.9 320 0.515Zr-89 78.4 22.7 100 0.182

I-124 100.2 22.8 99 0.17Tb-152 17.5 17 142

44Sc production: #275 F. Haddad, #268 M. Bunka, #276 E. Garrido

Scandium-44: image reconstructionF-18 AC Sc-44 NAC

Sc-44 AC/BG-SUB 0.9 Sc-44 AC/BG-SUB 1.3

Sc-44 NAC Sc-44 BG-SUB

T

air

W

Sc-44 AC/BG-SUB 0.5 Sc-44 AC/BG-SUB 1.7

#339: M. Miederer

3-photon-cameras

#168: D. Thers

20 10 0x106

x [m

m]

0 0.2 0.4 0.6-0.2-0.4-0.6 30

0.4

0.2

0

-0.2

-0.4

-0.6

0.6

z [mm]

#82: C. Lang

Applications:34mCl

44Sc52mMn

86Y94(m)Tc

124I152Tb

SPECT isotopesRadio-nuclide

Half-life (h) Eγγγγ(keV)

Branching ratio γγγγ (%)

Decay type

Ga-67 78 93 42 ECKr-81m 0.004 190 64 ITTc-99m 6 141 89 IT

In-111 67 171245

9094 EC

I-123 13 159 83 EC

Xe-133 126 81 38 β-

Tl-201 73 69-82 59 EC

Lu-177 161 113208

6.210.4 ββββ -Additional SPECT tracers needed for preclinical studies

and for tracing specific elements (e.g. 155Tb, 195mPt).

Imaging Studies Using PET and SPECTKB Tumor-Bearing Nude Mice

152Tb-folate: 9 MBqScan Start: 24 h p.i.

Scan Time: 4 h

155Tb-folate: 4 MBqScan Start: 24 h p.i.

Scan Time: 1 h

161Tb-folate: 30 MBqScan Start: 24 h p.i.Scan Time: 20 min

PET SPECT SPECT

#177: C. Müller

Immunology approach

Roelf Valkema, EANM-2008.

Target(antigen)

Antibody

Targeted radionuclide therapy

Roelf Valkema, EANM-2008.

ImmunologyStructural biology

Coordination chemistry

Nuclear physics and

radiochemistry

Target

ReceptorRadionuclide

LinkerPeptide, antibody,

etc.

M. Zalutsky

M. Zalutsky

Potential therapy isotopes ?

“In-cell heavy ion accelerator”:2 fission products per decay 2 x 100 MeV deposited over 25 µµµµm LET 4000 keV/µµµµm on average

38 keV average beta energyplus 1.6/decay conv. elect. 28-53 keVplus many Auger electrons <7 keV

33/decay Auger electronsM.T. Azure et al., AAPM Symp. 8 (1992) 336.J.D. Willins, G. Sgouros, JNM 36 (1995) 315.

production: #207 M.M. Günther, #319 U. Köster

Some interesting isotopes just cannot be produced well.

M. Zalutsky

M. Zalutsky

More on alpha therapy:#301 F. Davodeau#294 I. Kelson

Targeted Alpha Radionuclide TherapyKB Tumor-Bearing Mice Treated with 149Tb-Folate

A: control B: treated

32 d < 56 d

control 149Tb-folate

XX

- therapyα

#177: C. Müller

Folic acid

Targeted Beta Radionuclide TherapyKB Tumor-Bearing Mice Treated with 161Tb-Folate

C: control D: treated

28 d < ? d

- therapy

control 161Tb-folate

X X XX

β

#177: C. Müller

Radionuclides for RIT and PRRTRadio-nuclide

Half-life

E mean (keV)

E (B.R.)(keV)

Range

Y-90 64 h 934 - 12 mmI-131 8 days 182 364 (82%) 3 mmLu-177 7 days 134 208 (10%)

113 (6%)2 mm

Tb-161 7 days 154 5, 17, 40 e-

75 (10%) 2 mm1-30 m

Tb-149 4.1 h 3967 165,.. 25 mGe-71 11 days 8 e- - 1.7 mEr-165 10.3 h 5.3 e- - 0.6 m

localized

cross-fire

Modern, better targeted bioconjugates require shorter-range radiation need for adequate (R&D) radioisotope supply.

Estab-lished

isotopes

Emerging isotopes

R&D isotopes:supply-limited!

LET of Auger electrons

A.I. Kassis, Rad. Prot. Dosimetry 143 (2011) 241.

Micro-Injections of 71Ge

Injected volume is 0.05 to 0.3 pL

#338: M. Jensen

Nucleus and cytoplasm

Injected volume monitored by Quantum Dots (red)

#338: M. Jensen

Radioisotopes: the “fuel” for nuclear medicine

1. What is the optimum fuel for an application ?

2. Are we using today the optimum fuel ?

3. Is there sufficient supply of fuel at reasonable cost?

4. How reliable is the fuel supply ?

The traditional supply chain of 99Mo/99mTc

L'OCDE s'inquiète des risques de pénurie d'isotopes médicaux

53% demand 23% demand

20% demand

Back to the roots ?Original discovery of Tc in cyclotron-irradiated Mo !

C. Perrier, E. Segrè, J. Chem. Phys. 5 (1937) 712.

Sourcing of enriched 98MoNon-fission production of 99Mo needs often

large quantities of enriched Mo (1 kg 98Mo vs. 4 g 235U).

boiling point: UF6 56 °°°°C MoF6 34 °°°°C

Cost of enriched 98Mo or 100Mo: few hundred USD per gram for large quantities (kg).

Joint production of 98Mo and 100Mo more cost-effective.

Other suppliers?

Natanz, Iran

The producing reactor gets only 0.26 EUR per 99mTc patient dose, similar to the price of a single cheap pill.

Evolution of 82Sr demand in the USA

(source : Department of Energy, USA)

82Rb is used for PET in cardiology 82Sr/82Rb generator

Le Guludec (Paris) - PET-CT in cardio-vascular diseases

#275: F. Haddad

Facilities producing Sr-82 in the world

•LANL, USA –100 MeV, 200µA

•BNL, USA –200 MeV, 100µA

•INR, Russia –160 MeV, 120µA

•iThemba, South Africa –66 MeV, 250µA

•TRIUMF, Canada –110 MeV, 70 µA

BLIP

5 accelerators – 2 generator manufacturers – 1 generatorMar - Jul 2011: outage of 2 accelerators > 82Sr shortageJul ‘11-Feb ‘12: generator recalled

#275: F. Haddad

Problem: Concentration on few players

New players

#275: F. Haddad

Upcoming: 70 MeV cyclotron in LegnaroTwo new 82Sr/82Rb generators (Draximage, Quanticardi)

R&D isotopes

149Tb-therapy 152Tb-PET

155Tb-SPECT161Tb-therapy

& SPECT

#177: C. Müller

#146: T. Stora

#146: T. Stora

#220: D. Pauwels

Also possible at:TRIUMF, PSI, ISIS, SNS, LANL, J-PARC, ESS, EURISOL,…

Irradiation

Cooling

Dissolution

Filtering

Iodine removal

Acidifying

99Mo separation

99Mo purification

QC, calibration, distribution

Intermediate (ILW) and low level liquid waste (LLW)

Off-gas treatmentXenon decay

Ventilation

Precipitate(U, TU, RE, EA, Te, Zr, Nb, etc.)

High level solid waste

Extraction of fission-moly

133Xe

131I

Supply issues ?

1. 131I is coproduced with 99Mo by 235U fissionabout 1000 kCi 131I producible per yearcorresponding to about 5 million doses (100 mCi)exceeds demand by far[additional dedicated production via 130Te(n, 131I]

Fission waste recycling with the Purex process

Supply issues ?

1. 131I is coproduced with 99Mo by 235U fissionabout 1000 kCi 131I producible per yearcorresponding to about 5 million doses (100 mCi)exceeds demand by far[additional dedicated production via 130Te(n, 131I]

2. 90Y is obtained from 90Sr/90Y generatorsEDF reactors produce 1.4 tons of 90Sr per yearcorresponding to 200 MCi 90Sr from these 10 GCi of 90Y can be eluted per year, enough to supply one 90Y dose (100 mCi) per year for every human!

1990 1995 2000 2005 20100

10

20

30

40

50

90Y 177Lu

Pub MedTherapeutic Studies

Year

177Lu low energy beta-emitter for therapy

moderate β--energy- low side effects

- safe handling imageable γ-rays

- dosimetry- therapy control

Lu 177

6.647dββββ -

160.1 dββββ -

Hf 17718.60

#270: K. Zhernosekov

The rising star for therapy

Lu 1762.59

3 + 2070

Lu 17597.41

8

Yb 17612.7

3

Lu 177

6.647dββββ -

Yb 1771.9 hβ

160.1 dββββ -

Yb 1754.2 dβ

Yb 17431.8

68

Hf 17718.60

Hf 1765.206 specific activity 20 – 30 Ci/mg

(vs. theoretical 110 Ci/mg)

only 25 % of hot 177Lu atoms 75% of cold 175/176Lu atoms

176Lu(n,γ)177Lu

“Carrier-added” c.a. 177Lu

long-lived radioactive impurities:∼0.01 % of 177mLu

waste management; environment exposure

#270: K. Zhernosekov

Lu 1762.59

3 + 2070

Lu 17597.41

8

Yb 17612.7

3

Lu 177

6.647dββββ -

Yb 1771.9 hβ

160.1 dββββ -

Yb 1754.2 dβ

Yb 17431.8

68

Hf 17718.60

Hf 1765.206

176Yb(n,γ)177Yb 177Lu

“No -carrier-added” n.c.a. 177Lu

highest specific activity > 100 Ci/mg(vs. theoretical 110 Ci/mg)

and highest radionuclide purity

Yb-target must be quantitatively removed by chemical separtion

#270: K. Zhernosekov

0 2 4 6 8 10 12 140

25

50

75

100

0

25

50

75

100Sth = 110 Ci/mg

S1/2 = 92 Ci/mg

S1/2 = 16 Ci/mgSp

ecifi

c A

ctiv

ity [C

i/mg]

Days

Shelf-life/ c.a. vs n.c.a. 177Lu

#270: K. Zhernosekov

Physical quantity describing the activity per mass

(GBq/mg, Ci/mg),

basically the ratio of radioactive atoms to all atoms

(including stable ones).

Specific activity

Carrier added vs. non-carrier added

ca

nca

Saturation of selective receptors per cell

SPECT/CT day 1 p.t. Lu-octreotate

NCA 177Lu-octreotate, 2 µg Conv. 177Lu-octreotate, 11 µgadrenalsadrenals

tumourtumour

M. de Jong

Tumour uptake, based on SPECT quantification

Clearance rate was similar: 67 10 vs. 72 12 hNCA 177Lu-octreotate: ~2x higher tumour uptake 70 vs. 35 Gy tumour dose

M. de Jong

Pumping: power 120 – 130W, = 510nm, f = 10kHz, = 20ns.

Output of the system: 3 g/ yearFinal isotope content:

• Yb – 168 – 20.21% (only 0.14 % in natural Yb)

• Yb – 170 – 2.36%• Yb – 171 – 18.38% • Yb – 172 – 15.45%• Yb – 173 – 12.1%• Yb – 175 – 22.38%• Yb – 176 – 9.12%

Channel Wavelength, nm Dye Power, W Spectr.band,MHz

Pulse width, ns

1 555 R110 5 500 152 581 R6G 5 500 153 582 R6G 20 3104 20

Parameters of 3Parameters of 3-- Channel Dye Channel Dye -- Laser SystemLaser System for AVLIS of Ytterbiumfor AVLIS of Ytterbium

#157: S. Akulinichev

The history of lutetium separation1878 Separation of Yb in Genevaby Jean-Charles Galissard de Marignac

1907 Separation of Lu from YbGeorges UrbainCarl Auer von WelsbachCharles James

1995- Large-scale separation of Lu for production of LSO crystalsby Mark Andreaco (CTI) and George Schweitzer (Univ. Tennessee)

2007 Rapid large-scale separation of n.c.a. 177Lu from irradiated Ybby ITG Garching

OutlookThe ideal agent for cancer therapy would consist of heavy elements capable of emitting radiations of molecular dimensions, which could be administered to the organism and selectively fixed in the protoplasm of cells one seeks to destroy. While this is perhaps not impossible to achieve, the attempts so far have been unsuccessful.

C. Regaud, A. Lacassagne, Radiophysiologie et Radiotherapie 1 (1927) 95.Translation : A.I. Kassis, Int. J. Radiat. Biol. 80 (2004) 789.

Today we are closer than ever to reach this goal !