2013 - phd presentations ciclo xxvi radioisotopes production via ... · radioisotopes production...

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

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LAboratory of RAdioisotopes for MEDicine

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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)


• 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


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)


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


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


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)


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


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


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


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


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


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


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


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)


http://www.nndc.bnl.gov/

http://www.nndc.bnl.gov/exfor/exfor00.htm

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


• 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


https://www-nds.iaea.org/radionuclides/emerging.html



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


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

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Grazie !

Thank you !!

Merci beaucoup !!!

MARRY

XMAS


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)

http://dx.doi.org/10.1155/2013/972381

http://dx.doi.org/10.1155/2013/379283


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 !


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!!


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 ( )


2013 - phd presentations ciclo xxvi radioisotopes production via ... · radioisotopes production...

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