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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…
06.02.2019CRS Page 2
…But It Can Heal!
06.02.2019CRS Page 3
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
06.02.2019 Page 4
Theragnostics: Image & Treat
Diagnosis
SPECT/PET Imaging
Visualization of Cancer Cells
Radionuclide Therapy
Killing of Cancer Cells
Therapy
“Matched Pairs” of Radionuclides for Theragnostics
Page 5
α-Therapy β--Therapy PET (β+) SPECT (γ)Auger-e- Therapy
225Ac-PSMA-617: α-Radionuclide Therapy
06.02.2019CRS Page 6
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
06.02.2019 Page 7
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
Page 8
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
06.02.2019PSI, Seite 9
110
MBq
120
MBq
130
MBq
140
MBq
150
MBq
160
MBq
170
MBq
180
MBq
190
MBq
200
MBq
Routes of Radionuclide Development
06.02.2019CRS Page 10
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
06.02.2019CRS Page 12
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
06.02.2019CRS Page 13
• Cyclotrons
• Research Reactors
• Electron Linear Accelerators (Linac)
• Isotope Separation Online (ISOL)
Cyclotrons
06.02.2019CRS Page 14
• 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…
15
• 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
Page 16
EANM Marie Curie Award winner: 2018
17
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
19
ISOL As Part Of Nuclear Medicine…at CERN
Offline separation
20
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
Page 21
Page 22
Thank You For Your Attention!
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