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

PET-Scanner

+

- Auger-e-

SPECTCamera

The Nuclear Medicine Alphabet

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

Efficient parallel operation

152Tb

149Tb

155TbHRS setup

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

Theranostic of Invasive Aspergillosisand Echinococcus Multilocularis

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.

Indirect production of 203Pb, 205Bi

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 ?

18F

E+ = 0.25 MeV

71As

E+ = 0.35 MeV

Excellent resolution with Derenzo phantom

Köster et al. 2014, Nucl Med Biol, submitted.