WIR SCHAFFEN WISSEN – HEUTE FÜR MORGEN

Nicholas P. van der Meulen:: Radionuclide Development :: Paul Scherrer Institut

SAMIRA Workshop (Medical Radioisotopes in the Future: European Perspective)

7 February 2019

Horizon scanning – overview of emerging technologies

Perspective Of Radioactivity: It Can Harm…

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…But It Can Heal!

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Kratochwil et al. 2015 Eur J Nucl Med Mol Imaging 42:997

12/1368Ga-PSMA-11

PET/CT Scan, MIP

68Ga-PSMA-11

PET/CT Scan, MIP

02/14177Lu-PSMA-617

SPECT

05/14177Lu-PSMA-617

SPECT

07/1468Ga-PSMA-11

PET/CT Scan, MIP

Visualization of the Distribution -

“During Therapy”Imaging «Before» Imaging «After»

PSMA: Prostate-Specific Membrane Antigen

Radionuclide Therapy on the rise…due to improvements in targeting agents

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Theragnostics: Image & Treat

Diagnosis

SPECT/PET Imaging

Visualization of Cancer Cells

Radionuclide Therapy

Killing of Cancer Cells

Therapy

“Matched Pairs” of Radionuclides for Theragnostics

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α-Therapy β--Therapy PET (β+) SPECT (γ)Auger-e- Therapy

225Ac-PSMA-617: α-Radionuclide Therapy

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12/2014

PSA = 2,923 ng/mL

7/2015

PSA = 0.26 ng/mL

9/2015

PSA < 0.1 ng/mL

Kratochwil et al. 2016 J Nucl Med 57:1941.

Imaging «Before» Imaging «After» Imaging «After»

Black Box:

“Therapy”

Black Box:

“Therapy”

EANM Marie Curie Award winner: 2017

Potential Concern about Actinium-225

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Kruijff et al. 2015 Pharmaceuticals 8:321-336.

Recoiling daughter radionuclide detaching from a targeting

agent as a consequence of alpha decay:

Released daughter nuclides are radioactive!

They accumulate in healthy tissue (bones and kidneys)

Side Effects!!

Issues To Take Into Consideration For New Nuclides

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Half-life of radionuclide (hours…to days);

Decay properties of radionuclide (β+ for diagnosis, β- or α for therapy);

Target material to be used and cross section measurements;

Distribution coefficient determination (literature or experiments)

- Determines chemical separation method (where is speed crucial?);

Radiolabelling determines chemical purity.

Importance Of Logistics - Example : 149Tb

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110

MBq

120

MBq

130

MBq

140

MBq

150

MBq

160

MBq

170

MBq

180

MBq

190

MBq

200

MBq

Routes of Radionuclide Development

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Targetry Irradiation Facility Chemical Separation

Before introduction to GMP…

or preclinical radiolabelling

Introduction of New Radionuclide Cycle

Translation to GMP module

Chemical Separation and ProcessingTarget Preparation Target Irradiation

Dossier and registration

of radiopharmaceutical (GMP)

Try to shorten time to clinical application

Time taken from radionuclide development to clinical application: ~15 years!

Importance Of Product Purity For Preclinical Or GMP

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Biomolecule

Chemical synthesis: metal-free working environment

Preparation of stock solution: in metal free environment (no metal spatula)

Radionuclide

Radionuclidic purity: >99.9%

Chemical purity: no metal ions (i.e. absence of Fe, Co, Cu, Zn, Gd, Pb etc.)

The macrocyclic Chelator is NOT selective for

the Radiometal of interest, but will coordinate

other (cold) metal ions.

Means Of Producing Radionuclides

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• Cyclotrons

• Research Reactors

• Electron Linear Accelerators (Linac)

• Isotope Separation Online (ISOL)

Cyclotrons

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• Proton, Deuteron or Alpha Beam (first built in 1934, biggest in ‘46)

• Tried and tested

• Commercially available, various beam energies

• Medical cyclotrons: predominantly PET nuclides (diagnostic)

Proposed radionuclides:

43/44Sc, 61/64/67Cu, 68Ga…

99mTc, 135La, 155Tb, 45Ti, 55Co…

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• Neutron Beam

• Various neutron flux

• Targetry requires quartz ampoules.

• Many reactors are aging…

Nuclear reaction: (n,γ) or (n,p)

Proposed radionuclides:

47Sc, 177Lu, 161Tb…

Nuclear Research Reactors

Reference machines: ILL & BR2

Soon: Pallas…

161Tb: An Auger/β--Emitter For Therapy

160Gd(n,γ)161Gd → 161Tb

161Tb therapy with low-energy β-particles

Neutron Irradiation of Target Material

Chemical Separation and Processing

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EANM Marie Curie Award winner: 2018

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Isotope Separation Online (ISOL) Facilities

Nuclear reaction: (p,spallation)

• Requires mass separation

• First performed in early 50’s!

• Facilities in their infancy (medical)

• Challenging chemical separations

Proposed radionuclides:

47Sc, 149/152/155Tb…

Reference machine: ISOLDE/MEDICIS (CERN)

Soon: MYRRHA, INFN (Legnaro)

An Example Of Isotope Separation Online (ISOL)

181Ta(p,10p + 23 n)149Tb

Translation to GMP module Chemical Separation and Processing

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ISOL As Part Of Nuclear Medicine…at CERN

Offline separation

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Electron Linear Accelerator (eLinac)

Nuclear reaction: (γ,n)

• Electron Beam (first built in 1928)

• Converter target… creates Bremstrahlung

• Cooling of system requires development.

• Targetry requires development.

• Requires processing of large targets.

• Commercial systems are available.

Proposed radionuclides:

47Sc, 67Cu, 225Ac…

Reference machine: Argonne National Laboratory

• Exciting times…Radionuclide therapy on the increase, new targeting agents requiring

new radionuclides.

• Proofs-of-principle on the increase, but facilities required to handle clinical studies.

• Bottleneck getting new radionuclides into GMP laboratories (dossier preparation and

licence from authorities).

• Cost of clinical trials restrictive, big pharma and patenting required to make it viable.

Conclusions/Outlook

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Thank You For Your Attention!