Radioisotopes production via accelerator
for nuclear medicine applications
Gaia Pupillo
Tutor: Prof. Mauro Gambaccini
University and INFN of Ferrara (Italy)
2013 - PhD Presentations
Ciclo XXVI
OUTLINES
Feasibility study of 99Mo - 99mTc production based on
• 100Mo(p,x) reaction:
o Estimation of 99Mo and 99mTc Yield, RNP(t), IP(t)
o Examination of possible 99gTc / 99mTc ratio R impact on
radiopharmaceuticals RCP and stability
o Development of a β-spectrometer for 99gTc activity measurements
• 96Zr(α,n) reaction:
o Cross section measurement @ ARRONAX
67Cu production via 68Zn(p,x) reaction:
o Cross section measurement @ ARRONAX
Pupillo, PhD Presentation, Ferrara, 13th December 2013
AP
OT
EM
A
LAboratory of RAdioisotopes for MEDicine
LA
RA
ME
D
LARAMED LAboratory of RAdionuclides for MEDicine
Applied physics facility @ LNL: radioisotopes production based on the
coming SPES cyclotron (99Mo, 99mTc, 52Fe, 64Cu, 67Cu, 82Sr, 68Ge ...)
Selective Production of Exotic Species
Cyclotron features:
• Dual beam operation:
EXIT 1, H- : IMAX=200 µA, E = 40 MeV
Nuclear physics research on RIBs
• Max current at the exit port: ITOT = 500 µA
EXIT 2, H- : IMAX=300 µA, E = 35 - 70 MeV
Applied physics: LARAMED (APOTEMA)
Pupillo, PhD Presentation, Ferrara, 13th December 2013
• 99mTc: most important radionuclide in nuclear medicine ( > 30 millions SPECT
diagnostic procedures worldwide*)
• 99mTc: available via the 99Mo/99mTc generator system:
* NEA and OECD, (2010) IAEA-TECDOC-1601; ** NNDC, http://www.nndc.bnl.gov/exfor/exfor.htm.
99mTc: τ1/2 = 6.0067 h
99Mo: τ1/2 = 65.976 h
99gTc: τ1/2 = 2.111·105 y γ
• 99Mo: produced in nuclear reactors by HEU- 235U fission (weapon-grade)
• « 99mTc crisis » : in 2009/2010 unscheduled shutdowns of reactors caused a
worldwide 99Mo shortening
New ideas for 99Mo and 99mTc production*: ACCELERATOR-BASED
routes: 100Mo(p,x)99Mo,99mTc and 96Zr(α,n)99Mo
Tc-99m radiation:
E(γ) = 140.511 keV
I(γ) = 89% **
APOTEMA - INFN 2012-2014
Accelerator-driven Production Of TEchnetium/Molybdenum for medical Applications
Pupillo, PhD Presentation, Ferrara, 13th December 2013
100Mo(p,x)xxTc
• Feasibility study of 99Mo - 99mTc production with coming SPES cyclotron via
the 100Mo(p,x) reaction:
o Estimation of 99Mo and 99mTc Yield, RNP(t), IP(t)
APOTEMA
100Mo(p,2n)99mTc 100Mo(p,pn)99Mo
Article ID 972381
(2013)
Pupillo, PhD Presentation, Ferrara, 13th December 2013
APOTEMA
99mTc activity similar to that of standard 99Mo/99mTc generator systems
Best irradiation conditions: energy window EP = 15-20 MeV, tIRR = 1-3 h
ISSUE: co-production of Tc-isotopes (no chemical separation): 99gTc !
99mTc REGIONAL demand fulfilled !
Estimated 99Mo Specific Activity [MBq/g]
too low in comparison with commercial 99Mo/99mTc generator systems
DIRECT 99mTc PRODUCTION !
o
Pupillo, PhD Presentation, Ferrara, 13th December 2013
o Examination of possible impact of different 99gTc / 99mTc ratio R in
radiopharmaceuticals RCP and stability
APOTEMA
Elutions of commercial 99Mo/99mTc generators with different 99gTc/99mTc ratio R:
Quality Controls (QC) tests* on elutions: yield, pH, Al content, RNP, RadioChemical Purity (RCP)
Article ID 379283
(2013)
* All tests indicated by European and Italian Pharmacopoeia have been performed
Pupillo, PhD Presentation, Ferrara, 13th December 2013
APOTEMA
• All elutions (99gTc / 99mTc ratio R = 2.5 - 11.8, i.e. tELU=24-72 h) fulfilled all QC tests !
• RCP of pharmaceutical kits (Table) tested at tELU and at tEX (end of stability period)
RCP NOT affected up to R = 11.8
both at tELU and at tEX !
Stability guarantee up to R = 11.8
Imaging tests with YAP-(S)-PET
scanner* and NEMA phantom
confirmed NO variations in
images up to R = 15.2
* A. Del Guerra et al., IEEE Transactions on Nuclear Science, 53 (2006)
Pupillo, PhD Presentation, Ferrara, 13th December 2013
o Development of a β-spectrometer* for 99gTc activity measurements
APOTEMA
* L. Fornasini, Bachelor's thesis in Physics at UNIFE (2013) AA 2011-2012
• Characterization of each PMT by using a LED source:
QPMT = PMT exit charge [C]
e = -1.602·10-19 C Npe = Number of PhotoElectrons A = Constant related to PMT gain
k = Constant = 0.7 – 0.8 N = Number of dinodes
V = PMT Voltage [V]
PMT
PMT
c
c
cADC
c
Coinci- dence
Sum- mation
TRIGGER
cADC
Ampli ADC
PC
Spectrum Analyzer c
β
Scheme of the β-spectrometer
y = a + b·x
Scheme of the experimental set-up
Hamamatsu R329-02
Pupillo, PhD Presentation, Ferrara, 13th December 2013
APOTEMA
Transit Time Spread
TTS < 1ns = (19.3 ±0.3) ch
Gain alignment
TTS measurement
Dark current measurement
β-spectrometer assembly !
PMT1
y = a + b·x
Pupillo, PhD Presentation, Ferrara, 13th December 2013
APOTEMA
* F.Haddad et al., Eur J Nucl Med Mol Imaging (2008) NNDC, http://www.nndc.bnl.gov
Collaboration between INFN and GIP ARRONAX* in the framework of LARAMED
α Beam Accelerated
Particles Energy
Range [MeV] Intensity
[µA]
Protons H- 30-70 < 350 (x2)
Deuterons D- 15-35 50
α-particles He++ 70 < 35
96Zr(α,n)99Mo Accelerator for Research in Radiochemistry
and Oncology at Nantes Atlantic
99Mo production via the 96Zr(α,n) nuclear reaction
Pupillo, PhD Presentation, Ferrara, 13th December 2013
Stacked foil targets with highly pure foils: natZr (target),natTi (monitor)
and natAl (catcher-energy degrader)
γ-spectrometry analysis
Monitor reaction* natTi(α,x)51Cr
natTi(α,x)51Cr*
APOTEMA
* International Atomic Energy Agency (IAEA) http://www-nds.iaea.org/medical/monitor_reactions.html
Aluminium Titanium Zirconium
Irr. Date natZr No. E(α)
[MeV] Irr. Time
[s] <I>
[nA]
03/05/2013 2 67.4 17100 184.3
10/05/2013 3 67.2 19500 118.6
27/05/2013 3 67.4 12540 190.3
05/06/2013 4 67.2 15900 140.9
Stacked-foil
Target holder
96Zr(α,n)99Mo cross section: measurement details
Pupillo, PhD Presentation, Ferrara, 13th December 2013
Perfect agreement
of results !
100% enriched 96Zr
(2.8% of natZr) *
96Zr(α,n)99Mo cross section: results
Overall uncertainty (<13%) as square root of individual squares: Ref.xs (8-12%),
detector eff. (5%), stat. err. (2-6%), target thickness (1%), decay data err. (<1%)
51Cr recoil not negligible: ActTOT = ActTi + ActZr σ(ActTOT) = σ(ActTi) + σ(ActZr)
APOTEMA
Code** used for spline
curve, considered the unc.
related to each value:
ρ depends on the xs, k=0.01
and P = -3 (cubic functions)
** Code developed by F Haddad ,S David and
E Garrido at ARRONAX (2009)
Energy unc. calculated
from an estimated unc.
of 300 keV on the
incident alpha-beam
* D.P. Chowdhury et al., Nucl Instrum Meth B, 103 (1995) 261-266
Pupillo, PhD Presentation, Ferrara, 13th December 2013
APOTEMA
96Zr(α,n)99Mo cross section: yield
Estimations of 99Mo yield vs beam-energy and vs target thickness (96Zr)
Estimations of 99Mo and 99mTc yield vs beam-energy and vs target thickness (100Mo)
considering previous 100Mo(p,x)99Mo,99mTc xs measurements
On the hypothesis of 3 cm diameter beam and single-use targets, the activity costs
have been estimated (based on the price of highly enriched materials)
96Zr(α,n)99Mo 100Mo(p,x)99Mo 100Mo(p,x)99mTc
44000 225 14
Pupillo, PhD Presentation, Ferrara, 13th December 2013
Collaboration between INFN and GIP ARRONAX* in the framework of LARAMED
67Cu production:
the 68Zn(p,2p) reaction
68Zn(p,2p)67Cu
• 67Cu promising nuclide in RAdioImmunoTherapy (RAIT)
• The limiting factor of 67Cu widespread use in RAIT trials is its AVAILABILITY
• Preclinical tests with 67Cu-labelled antibodies show HIGH tumor uptake* (better than 131I-labelled compounds)
* I Novak-Hofer and PA Schubiger,
Eur J Nucl Med (2002) 29:821-830
67Cu is one of the selected
nuclide for future
production at LARAMED
and at ARRONAX
Pupillo, PhD Presentation, Ferrara, 13th December 2013
Energy
[keV]
Cu-67
Int. [%]
Ga-67
Int. [%]
184.6 48.7 3 21.41 1
209.0 0.115 5 2.46 1
300.2 0.797 11 16.64 12
393.5 0.220 8 4.56 24
NNDC, http://www.nndc.bnl.gov ; * EXFOR database,http://www.nndc.bnl.gov/exfor/exfor00.htm
68Zn(p,2p)67Cu
Cross section measurement: 67Ga co-production
In irradiations 67Ga is co-produced in target (and also 66Ga)
67Ga has the same γ-lines of 67Cu and similar half-life
A chemical process is mandatory in order separate Cu/Ga atoms and calculate
nuclide activities at EOB
61Cu and 66Ga: tracer nuclides used to know chemical separation efficiency and yield
(66Ga co-produced in 68Zn, 61Cu produced in natCu foil)
67Cu (t1/2 = 61.83 h) 67Ga (t1/2 = 78.24 h)
Pupillo, PhD Presentation, Ferrara, 13th December 2013
9 irradiations performed on stacked targets with different conditions:
EP = 42 – 70.5 MeV , I = 100 – 200 nA , tIRR = 1 – 1.5 hours
Monitor reaction* used: E<50,natNi(p,x)57Ni ; E>50,27Al(p,x)22Na,24Na
Chemical process applied in order to separate Cu/Ga;
61Cu and 66Ga as tracer nuclide for chemical yields and efficiency
calculation
* International Atomic Energy Agency (IAEA) http://www-nds.iaea.org/medical/monitor_reactions.html
68Zn(p,2p)67Cu
Cross section measurement details*
Target foil pictures: 68Zn electrodeposited on Ag (L)
Target with monitor foil (R) Stacked foil target structrure
* Collaboration with Thomas Sounalet
(PhD student at ARRONAX) Dissolution
of 68Zn
Cu/Ga
Separation
Pupillo, PhD Presentation, Ferrara, 13th December 2013
• E < 50 MeV : discrepancy in comparison
with the recommended one (20-30%) .
Agreement with Bonardi (2005) and Stoll
et al. (2002)
There is PERFECT repeatibility within
different irradiation results!
• E > 50 MeV : good agreement with
IAEA recommended* cross section !
68Zn(p,2p)67Cu
Cross section results 100% enriched 68Zn
(98.78% of zinc powder)
IAEA, https://www-nds.iaea.org/radionuclides/emerging.html
Pupillo, PhD Presentation, Ferrara, 13th December 2013
68Zn(p,2p)67Cu
Cross section measurement: yield
Estimations of 67Cu yield vs beam-energy and vs target thickness (68Zn) have been
done, considering our measurement of the 68Zn(p,2p)67Cu reaction, as well as the
IAEA recommended and Tendl-2012 theoretical cross sections
Pupillo, PhD Presentation, Ferrara, 13th December 2013
Act. Cost [k€/(MBq/μAh] This work IAEA Tendl-2012
68Zn(p,2p)67Cu [MeV] 2.21 [70 – 25] 2.07 [70 – 18] 1.29 [70 – 14]
70Zn(p,x)67Cu - 24.39 8.87
natZn(p,x)67Cu - 0.04 0.02
Co-production of
Cu-isotopes !
(64Cu, 61Cu)
CONCLUSIONS
Feasibility study of 99Mo,99mTc production via 100Mo(p,x) and 96Zr(α,n) reactions:
• From yield estimations, direct 99mTc production is the best solution
(co-production of Tc-nuclides issue!)
• RCP and stability of 99mTc-labeled radiophamaceuticals are NOT affected
by 99gTc presence up to R = 11.8
• β-spectrometer underdeveloped for 99gTc activity measurements
• 96Zr(α,n) reaction provides highly pure 99Mo but a target recovery
process is mandatory (activity costs reduction)
68Zn(p,x)67Cu cross section measurement:
• Good agreement with IAEA recommended cross section
• The 68Zn(p,x)67Cu reaction is the best to produce 67Cu
AP
OT
EM
A
LA
RA
ME
D
Pupillo, PhD Presentation, Ferrara, 13th December 2013
Pupillo, PhD Presentation, Ferrara, 13th December 2013
PhD activities
Periods @ ARRONAX
• 3 months in 2012 (01/06-31/08): FINANZIAMENTO 5x1000 UNIFE
• 1 month in 2012 (15-29/11 and 3-16/12)
• 4 months in 2013 (08/04-08/08): ERASMUS PLACEMENT
Pubblications
• G Pupillo et al., Experimental Cross Section Evaluation For Innovative 99Mo Production via
the (α,n) Reaction on 96Zr Target, Journal of Radioanalytical and Nuclear Chemistry,
Proceedings of ARCEBS-14 Conference, Next to be reviewed
• J Esposito et al., Evaluation of 99Mo and 99𝑚Tc Productions Based on a High-Performance
Cyclotron, Hindawi Publishing Corporation, Science and Technology of Nuclear
Installations (2013) Article ID 972381 - http://dx.doi.org/10.1155/2013/972381
• L Uccelli et al., Influence of the Generator in-Growth Time on the Final Radiochemical
Purity and Stability of 99mTc Radiopharmaceuticals, Hindawi Publishing Corporation,
Science and Technology of Nuclear Installations (2013) Article ID ID 379283
http://dx.doi.org/10.1155/2013/379283
• P Cardarelli et al., Energy distribution measurement of narrow-band ultrashort x-ray
beams via K-edge filters subtraction, Journal of Applied Physics
• Proceedings SIF 2011 (Pupillo et al., pg.21; Pupillo et al., pg.37)
• Proceedings SIF 2013 (Pupillo et al., pg.248; Mucollari et al., pag.214)
Pupillo, PhD Presentation, Ferrara, 13th December 2013
PhD activities
Schools, Congresses, Workshops - IV Scuola Nazionale INFN: «Rivelatori ed Elettronica per Fisica delle Alte Energie,
Astrofisica, Applicazioni Spaziali e Fisica Medica» LNL 11-14/04/2011
- SIF 2011: «Il generatore 44Ti\44Sc per la medicina nucleare: studio della sezione d’urto
45Sc(p,2n)44Ti»; «Metodi di correzione della radiazione diffusa nell’imaging SPECT su
piccoli animali con Iodio-123», L’Aquila 26-30/09/2011
- International Conference on Clinical PET and Molecular Nuclear Medicine (IPET
2011), Vienna 8-11/11/2011
- IAEA Workshop on Monte Carlo Radiation Transport and Associated Data Needs
for Medical Applications, Trieste 17-28/10/2011
- SIF 2013: «Evaluation of the proton induced reaction 68Zn(p,2p)67Cu», Trieste 23-27/09
- AIFM 2013 (poster): «Comparison of innovative 99Mo production routes aimed at the
realization of 99Mo/99mTc generators», Torino 16-19/11/2013
- ARCEBS-14 (oral presentation): «Experimental Cross Section Evaluation For
Innovative 99Mo Production via the (α,n) Reaction on 96Zr Target», Kolkata, 12-19/01/2014
Activities @ UNIFE
• Esercitazioni e attività di tutorato (50 ore). Fisica 1, LT in Chimica - Natoli (2012)
• Progetto Lauree Scientifiche (2011-2012), Porte Aperte (2011-2012), UniJunior
con Prof. Gambaccini (January 2013) • Commissione Problemi dell'Universo (2011-2012)
• FIRST certificate (January 2012)
APPENDIX - the 68Zn(p,2n)67Ga cross section
68Zn(p,2n)67Ga
68Zn(p,2n)67Ga
The recommended cross section
seems to be OVERestimated for
E > 35 MeV!
New fitting function!!
Good agreement !!
In particular with the values of
Szelecsenyi ( ), 2005
Hermanne ( ), 1991
Mcgee ( ), 1970
The results of Stoll ( ),
2002 seem to OVERestimate
the cross section !
Pupillo, PhD Presentation, Ferrara, 13th December 2013
68Zn(p,2n)66Ga
APPENDIX: the 68Zn(p,2n)66Ga cross section
Good agreement !!
ALSO with Stoll ( ) , 2002 NOT ONLY with Szelecsenyi ( ) , 2005 !!
Future fitting function!!
Pupillo, PhD Presentation, Ferrara, 13th December 2013
APPENDIX - The monitor reaction 27Al(p,x)24Na
Taking as REFERENCE nuclide:
24Na UNDERestimation of the 68Zn(p,2p)67Cu reaction !!
22Na GOOD estimation of the
cross section !
The choice of the MONITOR
reaction is really IMPORTANT !!
27Al(p,x)24Na
27Al(p,x)24Na
Considering the 27Al(p,x)22Na as
MONITOR reaction,
it was evaluated the 27Al(p,x)24Na cross section ( )
Pupillo, PhD Presentation, Ferrara, 13th December 2013