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IS528-ADD1Novel 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 1 Paul Scherrer Institut, Villigen – Universität Bern – ETH Zürich, Switzerland2 CHU – INSERM – Université Grenoble, France3 ARRONAX – INSERM – CRCNA – Subatech Nantes, France4 Risø National Laboratory, Roskilde, Denmark5 Institut Laue Langevin, Grenoble, France6 Universitätsklinik Tübingen, Germany7Institut de Recherche en Cancérologie de Montpellier, France
Objectives
PeptideAbs
Vitamins Chelator
M☢
Receptor
Radiometals for diagnostic imaging and therapy
Photon or positron emitters 99mTc, 68Ga, … for imaging
Particle emitters 90Y, 177Lu, … for radionuclide therapy
applicable only with high specific activity and chemical purity
Spallation of tantalum targets followed by resonant laser ionization of Dy precursor and mass separation
149,152,155Tb with some oxide sidebands
Production of n.c.a. [149/152/155Tb]-TerbiumISOLDE CERN and PSI
Paul Scherrer Institute
Separation by means of cation exchange chromatography
Tumor Tageting Agent for Tb-CoordinationChemical Structure with 3 Functionalities
folic acidalbumin binder
Tb-DOTA
Tb-folate
stable coordination of Tb-isotopes high affinity to the folate receptor prolonged blood circulation time
Chracteristics:
Terbium: the Swiss Army knife of Nuclear Medicine
Müller et al. 2012, J Nucl Med 53:1951.
149Tb-therapy 152Tb-PET
155Tb-SPECT161Tb-therapy& SPECT
Terbium-149: alpha-EmitterFolate Receptor Targeted -Radionuclide Therapy
Müller et al. 2013, Pharmaceuticals, submitted
Group A: controlGroup B: 149Tb-folate 2.2 MBqGroup C: 149Tb-folate 3.0 MBq
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
Müller et al. 2013, Nucl Med Biol, in press: doi:10.1016/j.nucmedbio.2013.11.002
Peptides monoclonal antibody folate MD DOTATATE chCE7 chCE7 cm09 cm09
140Nd/140Pr: an in vivo PET generator
Köster et al. 2014, Nucl Med Biol, submitted.
140Prβ+ 2.4
3.4 m
140Ce
140Ndε
3.37 d
Understanding the Auger release from chelators
140Nd
140Pr
140Ce
3.37 d
3.39 min
stable
QEC = 437
BR+ = 51%NdPrCe
Understanding the Auger release from chelators
140Nd
140Pr
140Ce
3.37 d
3.39 min
stable
QEC = 437
BR+ = 51%NdPr
Pr
?
Understanding the Auger release from chelators
140Nd
140Pr
140Ce
3.37 d
3.39 min
stable
QEC = 437
BR+ = 51%
134Ce
134La
134Ba
3.37 d
6.45 min
stable
QEC = 386
BR+ = 63.6%
44Sc
44Ca
2.44 d
stable
E4 271
BR+ = 94.3%
44mSc
3.97 h
1157
212Pb-Trastuzumab (0.37MBq)212Pb-Trastuzumab (0.74MBq)212Pb-Trastuzumab (1.48MBq) HE
R2
212212Pb-TrastuzumabPb-Trastuzumab
Time post-graft (days)
Sur
viva
l (%
)Survival with anti-HER2 Survival with anti-HER2 212212Pb-mABSPb-mABS
Boudousq et al., 2013; PLoS ONE 8(7):e69613.
Auger release of 212Bi ?
45.1% conversion electrons Auger cascades partial delabeling?
212Pb
10.6 h
212Bi
212Po
208Pb(Stable
)208Tl
0.3 s
60.5 min
3.05min
169Er (beta-) vs. 165Er (Auger) radiobiology
165Er3+
1.
2.
4.
5. 6.
7.
p+
Er
165Tm3+
165TmTmEr
165Er3+
SCX
165Tm-DOTA
165Er3+
3.
169Er
Beam request
Shifts
A) 149Tb-cm09 dose escalation study 8
B) 149Tb-PRRT pilot study 3
C) 152Tb/155Tb companion diagnostics incl.
D) 140Nd/134Ce chelator optimization 6140Nd/134Ce immuno-PET 6
E) exploratory experiments (Pb, Bi,…) 3
F) mass separation of 169Er/168Er 6 (offline)
Total 26 + 6
Available -10
New request 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.
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
Müller et al. 2012, J Nucl Med 53:1951.
Arsenic: another theranostic multiplet
77As:reactor-produced - emitter for therapy
74As:long-lived + emitter for longitudinal PET studies
72As:generator-produced + emitter for PET
71As:low-energy + emitter for
high-resolution PET ?