radioisotopes in diagnostics and therapy
TRANSCRIPT
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 !