1. No category

IS528-ADD1
Novel diagnostic and therapeutic radionuclides
for the development of innovative radiopharmaceuticals
Katharina Domnanich1, Catherine Ghezzi2, Ferid Haddad3, Mikael Jensen4,
Christian Kesenheimer6, Ulli Köster5, Cristina Müller1, Bernd Pichler6,
Jean-Pierre Pouget7, Anna-Maria Rolle6, Roger Schibli1, Gregory Severin4,
Andreas Türler1, Stefan Wiehr6, Nick van der Meulen1
Local contact: Karl Johnston
Paul Scherrer Institut, Villigen – Universität Bern – ETH Zürich, Switzerland
2 CHU – INSERM – Université Grenoble, France
3 ARRONAX – INSERM – CRCNA – Subatech Nantes, France
4 Risø National Laboratory, Roskilde, Denmark
5 Institut Laue Langevin, Grenoble, France
6 Universitätsklinik Tübingen, Germany
7Institut de Recherche en Cancérologie de Montpellier, France
1
Objectives
Radiometals
for diagnostic imaging and therapy
M☢
Chelator
Peptide
Abs
Vitamins
Receptor
Photon or positron emitters 99mTc, 68Ga, … for imaging
Particle emitters 90Y, 177Lu, … for radionuclide therapy
applicable only
with high specific activity and chemical purity
The Nuclear Medicine Alphabet
SPECT
Camera
PET-Scanner
+

-

Auger-e-
Production of n.c.a. [149/152/155Tb]-Terbium
ISOLDE CERN and PSI
Paul Scherrer Institute
Separation by means of cation
exchange chromatography
Spallation of tantalum targets followed by
resonant laser ionization of Dy precursor and
mass separation
 149,152,155Tb with some oxide sidebands
Tumor Tageting Agent for Tb-Coordination
Chemical Structure with 3 Functionalities
albumin binder
folic acid
Tb-folate
Chracteristics:
stable coordination of Tb-isotopes
high affinity to the folate receptor
prolonged blood circulation time
Tb-DOTA
Terbium: the Swiss Army knife of Nuclear Medicine
149Tb-therapy
152Tb-PET
161Tb-therapy
155Tb-SPECT
& SPECT
Müller et al. 2012, J Nucl Med 53:1951.
Terbium-149: alpha-Emitter
Folate Receptor Targeted -Radionuclide Therapy
Group A: control
Group B: 149Tb-folate 2.2 MBq
Group C: 149Tb-folate 3.0 MBq
Müller et al. 2013, Pharmaceuticals, submitted
155Tb:
low-dose SPECT prior to therapy
Müller et al. 2013, Nucl Med Biol, in press: doi:10.1016/j.nucmedbio.2013.11.002
in vivo validation with peptides, mAbs and vitamins
Peptides
MD
DOTATATE
monoclonal antibody
chCE7
chCE7
folate
cm09
Müller et al. 2013, Nucl Med Biol, in press: doi:10.1016/j.nucmedbio.2013.11.002
cm09
Efficient parallel operation
152Tb
149Tb
155Tb
HRS setup
140Nd/140Pr:
an in vivo PET generator
140Nd
ε
3.37 d
140Pr
β+ 2.4
3.4 m
140Ce
Köster et al. 2014, Nucl Med Biol, submitted.
Understanding the Auger release from chelators
3.37 d
140Nd
QEC = 437
3.39 min
140Pr
Nd
Pr
Ce
BR+ = 51%
stable
140Ce
Understanding the Auger release from chelators
3.37 d
140Nd
QEC = 437
3.39 min
140Pr
Pr
?
Nd
BR+ = 51%
stable
140Ce
Pr
Understanding the Auger release from chelators
3.37 d
140Nd
QEC = 437
3.39 min
140Pr
3.37 d
134Ce
stable
QEC = 386
6.45 min
134La
44mSc
140Ce
BR+ = 63.6%
stable
2.44 d
E4 271 3.97 h
44Sc
BR+ = 51%
134Ba
BR+ = 94.3%
1157
stable
44Ca
Theranostic of Invasive Aspergillosis
and Echinococcus Multilocularis
Survival with anti-HER2 212Pb-mABS
212Pb-Trastuzumab
212Pb-Trastuzumab
(0.37MBq)
212Pb-Trastuzumab (0.74MBq)
212Pb-Trastuzumab
HER
2
(1.48MBq)
100
Survival (%)
80
60
40
Boudousq et al., 2013; PLoS ONE 8(7):e69613.
20
0
0
20
40
60
80
100
Time post-graft (days)
120
140
Auger release of 212Bi ? 0.3 s
60.5 min
10.6 h
212Pb


212Bi


36%
208Tl
212Po
208Pb
(Stable)
3.05min
45.1% conversion electrons
 Auger cascades
 partial delabeling?
169Er
(beta-) vs. 165Er (Auger) radiobiology
169Er
2.
Er
1.
p+
3.
4.
Tm 3+
165
165Er3+
TmEr
165 Tm
5.
165Er3+
6.
7.
165Er3+
SCX
165
Tm-DOTA
Beam request
A)
B)
C)
D)
149Tb-cm09
dose escalation study
149Tb-PRRT pilot study
152Tb/155Tb companion diagnostics
140Nd/134Ce chelator optimization
140Nd/134Ce immuno-PET
E) exploratory experiments (Pb, Bi,…)
F) mass separation of 169Er/168Er
Total
Available
New request
Shifts
8
3
incl.
6
6
3
6 (offline)
26 + 6
-10
16 + 6 (offline)
Off-line separation of 169Er
•
•
•
•
Therapy study with 6 mice, 70 MBq 169Er-DOTATOC per mouse
factor 2 for decay losses and labeling yield
850 MBq needed (1E15 atoms collected)
LA[169Er]=5 MBq  up to 500 MBq can be handled in “class C” bat. 170
 collect and ship two separate samples of 425 MBq each
 ship as UN2910 (“excepted package”)
• implantation current 1 nA of 169Er for 24 h (3 shifts per sample)
• total current 1 A Er (168Er + 169Er) [cf. 7Be collections]
• ionization potential 6.11 eV > 0.5% thermal ionization efficiency
• RILIS efficiency >5%? (to be tested!)
• ship 20 GBq from ILL (2% of A2 limit > “type A” transport)
• Note: 169Er is a low-energy beta emitter, with very low emission of  rays:
0.16% 8 keV, 0.01% 110 keV
 very low dose rate: <1 Gy/h at 1 m from unshielded 1 GBq sample.
Indirect production of 203Pb, 205Bi
Imaging Studies Using PET and SPECT
KB Tumor-Bearing Nude Mice
PET
152Tb-folate:
9 MBq
Scan Start: 24 h p.i.
Scan Time: 4 h
SPECT
155Tb-folate:
SPECT
4 MBq
Scan Start: 24 h p.i.
Scan Time: 1 h
161Tb-folate:
30 MBq
Scan Start: 24 h p.i.
Scan Time: 20 min
Müller et al. 2012, J Nucl Med 53:1951.
Arsenic: another theranostic multiplet
71As:
low-energy + emitter for
high-resolution PET ?
74As:
long-lived + emitter for
longitudinal PET studies
72As:
generator-produced
+ emitter for PET
77As:
reactor-produced emitter for therapy
Excellent resolution with Derenzo phantom
18F
71As
E+ = 0.25 MeV
E+ = 0.35 MeV
Köster et al. 2014, Nucl Med Biol, submitted.