CYCLOTRON-BASEDPRODUCTION OF THE

THERANOSTIC RADIONUCLIDES67Cu AND 47Sc

Gaia Pupillo, L. Mou, P. Martini, M. Pasquali,

J. Esposito, A. Duatti, C. Rossi Alvarez, H. Skliarova,

S. Cisternino, A. Boschi, L. Canton, A. Fontana,

T. Sounalet, F. Haddad

gaia.pupillo@lnl.infn.it

Istituto Nazionale di Fisica Nucleare, Laboratori Nazionali di Legnaro (INFN-LNL)

OUTLOOK

THE LARAMED PROJECT @ INFN-LNL

Results of the project COMECOpper MEasurement

Preliminary results of the project PASTAProduction with Accelerator of Sc-47 for Theranostic Applications

Cu-67 Sc-47

Legnaro is close to Venice, Padova and Ferrara

INFN Laboratoriesand sections

New

THE I.N.F.N. NATIONAL LABORATORIES IN LEGNARO (PADOVA)

Map of INFN-LNL Laboratories

SPES/LARAMEDINFRASTRUCTURE

CYCLOTRON 35-70 MeVControl room

Bunker layout (-1 level)

Laboratory layout (+2 level)

The New 70 MeV Proton Cyclotron

Main Cyclotron Parameters

Accelerator type Cyclotron AVF with 4 sectors, ResistiveMagnet

Particle Protons (H- accelerated)

Energy range 35-70 MeV

Max CurrentIntensity

700 µA (variable within the range 1µA-700µA)

Extraction Dual stripping extraction

Max MagneticField

1.6 T (Bo = 1 T)

RF System nr. 2 delta cavities; harmonic mode=4; f RF

=56 MHz; 70 kV peak voltage; 50 kW RF power (2 RF amplifiers)

Ion Source Multi-cusp volume H-

source; Iext =8mA; Vext=40 kV; axial injection

Dimensions Φ=4.5 m, h=2 m, W=190 tons

Radioactive ion beam facility

Accelerator based neutron source

THE SPES PROJECT @ INFN-LNLSELECTIVE PRODUCTION OF EXOTIC SPECIES

a

d

b

gRadionuclides for health and

research

LARAMED

Cyclotron & Infrastructure

ISOLPHARM

SPES projectRi-acceleration of

neutron-rich nuclei produced by fission of

UCx targets

ISOL facility

LARAMED is composed by:

A production facility (RIFAC)operated by INFN and a private partner• Production of 82Sr/82Rb and 68Ge/68Ga

A research laboratory (RILAB)jointly owned by INFN and CNRTarget preparation, target processing, radiochemistry, spectrometry, QC labs for:

• Nuclear cross section measurements• Low-activity-production• High power target development

Bunker layout (-1 level)

SPES projectRi-acceleration

LARAMED project

RiFACRiLAB

Final Layout RiLAB bunkers(L3b+L3c)

THE LARAMED PROJECT @ INFN-LNLLABORATORY OF RADIONUCLIDES FOR MEDICINE g

2018

2019

THE LARAMED PROJECT @ INFN-LNLLABORATORY OF RADIONUCLIDES FOR MEDICINE g

Level +2

Final Layout LARAMED laboratories LARAMED laboratories (floor +2):

✓ Layout and installation of the compound

(including plant design)

✓ Hot-cell (70 mm frontal Pb thickness)

✓ Two γ-spectrometers bought

• Transport of irradiated target (from both bunkers)

• Completion of compound (2018)

• Completion of laboratories (2020)

Futu

re G

MP

-are

a

THE LARAMED (NET)WORK g

INFN LNL

S.C. Don Calabria Hospital

(VR) University of Ferrara

(FE)

St. Orsola

Hospital (BO)

CNR

(MI)

ARRONAX (Nantes, France)

INFN PD

INFN PV

INFN already funded/running projects Project name

Accelerator-Tc-99m alternative (direct) production route through hospital cyclotrons

APOTEMA (2012-2014)TECHNOSP (2015-2017)

“Coordinated Research Project ' (CRP) on“Alternative, non HEU-based, Tc-99m /Mo99 supply”

IAEA CRP (2011-2015)

Alternative Cu-64/Cu-67 production for theranosticapplication

COME (2016)

Alternative Sc-47 production for theranostic application PASTA (2017-2018)

CRP on “Radiopharmaceuticals Labelled with New Emerging Radionuclides” Cu-67, Re-186, Sc-47”

IAEA CRP (2016-2019)

High Power Target concepts R&D (64/67Cu)TERABIO comp. project(2016-2019)

High intensity vibrational powder plating E_PLATE (2018-2019)

Multimodal pET/mRi Imaging with Cyclotron-produced Mn-52/51 and stable paramagnetic Mn iSotopes

METRICS (2018-2020)

THERANOSTIC RADIONUCLIDES

Therapeutic RadiopharmaceuticalsLabelled with New Emerging

Radionuclides (67Cu, 47Sc, 186Re)

2° Research Coordination Meeting (RCM) INFN-LNL, 5 – 9 March 2018

Coordinated Research Project (CRP) by the International AtomicEnergy Agency IAEA (2016-2019)

Theranostics utilize a combination of therapeutic emissions such as alpha, beta, or Auger (‘thera’-) and diagnostic emissions

such as gamma or positrons (-‘nostic’). The key advantages of theranostics include the personalization of therapybased on uptake of the lower-dose diagnostic. This includes the optimization of dose based on personal dosimetry, and more

importantly the selection of patients who have a high chance of responding to therapy.

* H Herzog et al., Journalof Nuclear Medicine, Vol 34, No.2 (1993)

THE COME PROJECT - COpper MEasurement

• 67Cu promising radionuclide in theranostic and radioimmuno therapy→Selection of patient prior therapy (diagnostic before therapy with the same radiopharmaceutical)

• 67Cu’s limiting factor: low availability (produced only at NIDC-OAK RIDGE*)

Injection of 100 mCi 64CuCl2

AfterBefore

* NIDC- OAK RIDGE, https://www.isotopes.gov/catalog/product.php?element=Copper&type=rad&rad_product_index=15

67Cu Production

𝑆𝐴𝐶𝑢−67(𝑡) =𝐴𝑐𝑡𝐶𝑢−67(𝑡)

𝑀

Specific Activity (SA)

→ Efficient chemistry

Radio Nuclidic Purity (RNP)

𝑅𝑁𝑃𝐶𝑢−67(𝑡) =𝐴𝑐𝑡𝐶𝑢−67(𝑡)

σ𝐴𝑐𝑡𝐶𝑢−𝑥𝑥(𝑡)

→ Optimization of irradiation parameters

Isotopic Purity (IP) 𝐼𝑃𝐶𝑢−67(𝑡) =

𝑁𝐶𝑢−67(𝑡)

σ𝑁𝐶𝑢−𝑥𝑥(𝑡)

→ Use of reliabletheoretical codes

• 67Cu production relies on the 68Zn(p,2p)67Cu reaction

• During the irradiation of 68Zn targets there is a large

co-production of 64Cu (isotopic impurity)

Alternative 67Cu Production

?

Alternative 67Cu Production: The 70Zn(p,x)67Cu reaction

Collaboration with experts in nuclear models! Luciano Canton (INFN-PD) Andrea Fontana (INFN-PV)

Collaboration with ARRONAX facility to measure the nuclear

cross section atEp > 35 MeV

IRRADIATION RUNS @ ARRONAX FACILITY

IBA Cyclone 70

Beam Energy [MeV] Intensity [µA]

Proton 30-70 < 350 (x2)

Deuteron 15-35 50

Alpha 68 < 35

Irradiationrun

EP

(MeV)Time irr. (s)

Meancurrent (nA)

1 70.3 5390 98.8

2 56.0 5396 100.4

3 61.0 4895 110.5

4 68.0 5406 100.7

5 48.0 7270 102.5

6 56.0 5400 100.4

STACKED-FOILS TARGET STRUCTURE

* Target foil laminated at INFN-LNL by M. Loriggiola

Degrader (Aluminium)

Target (enriched 70Zn)

Monitor & Catcher (natAl)

Stacked-foils target structure with monitor foils

Source of Cu-61 (63Cu)

Recoil Recoil

CO-PRODUCTION OF 67Ga

Energy [keV]

Cu-67Intensity

Ga-67Intensity

91.266 5 7.0 1 3.11 4

93.311 5 16.1 2 38.81 3

184.577 10 48.7 3 21.41 1

208.951 10 0.115 5 2.46 1

300.219 10 0.797 11 16.64 12

393.529 10 0.220 8 4.56 24

494.166 15 0.0684 14

703.106 15 0.0105 9

794.381 15 0.0540 18

887.688 15 0.148 3

Co-production of 67Ga during 70Zn irradiation:

• 67Cu and 67Ga both decay to 67Zn → same γ rays• 67Cu and 67Ga have similar half-lives

67Cu (t½ 61.83 h)67Ga (t½ 78.24 h)

A chemical separation

Cu/Ga is mandatory !!

Tracer: Cu-61 and Ga-66

RADIOCHEMICAL SEPARATION Cu/Ga

1° step 2° step 3° step

Petra Martini, PhDMicòl Pasquali, PhD

(INFN-LNL)

petra.martini@lnl.infn.itmicol.pasquali@lnl.infn.it

Calculation of the Activity @ The End Of IstantaneousBombardment (EOIB)

Corrections to the Activity @ EOIB

1.Recoil effect

2.Chemical Yield(tracer radionuclides: Cu-61, Ga-66, Zn-69)

3.Branching Ratio (BR) Method

4.Weight factor(aliquot of 5 ml

from 20 ml solution)

Recoil24Na ≈ 16-21%

Recoil67Cu, 64Cu 66Ga,67Ga

≈ 1-2%

MIX solution

𝐴𝑐𝑡𝑡𝑟𝑎𝑐𝑒𝑟𝐵 ∶ 𝐴𝑐𝑡𝑥𝑥

𝐵 = 𝐴𝑐𝑡𝑡𝑟𝑎𝑐𝑒𝑟𝐴 ∶ 𝐴𝑐𝑡𝑥𝑥

𝐴

xCu, xGa, xZn solutions

Energy [keV] Cu-67 (%) Ga-67 (%)

184.577 10 48.7 3 21.41 1

300.219 10 0.797 11 16.64 12

Stacked-foils target structure with monitor foils

Recoil Recoil

CROSS SECTION CALCULATION

𝜎 𝐸 = 𝜎′ 𝐸𝐴𝑐𝑡𝐸𝑂𝐼𝐵 𝐴 𝜌′ 𝑃′ 𝑥′𝜆′

𝐴𝑐𝑡′𝐸𝑂𝐼𝐵 𝐴′𝜌 𝑃 𝑥 𝜆

𝜎′ 𝐸 = Reference cross sectionA = Mass number of the foilρ = Density of the foilP = Purity of the foilx = Thickness of the foil

Degrader (Aluminium)

Target (enriched 70Zn)

Monitor & Catcher (natAl)

Stacked-foils target structure with monitor foils

Source of Cu-61 (63Cu)

Monitor cross section recommended by International Atomic Energy Agency (IAEA)

More important contribution to systematic error (≈7-8%)

RESUME OF THE COME PROJECT

• No. 6 irradiation runs done at Arronax facility

• No.7 cross section values obtained for the nuclear reactions

70Zn(p,x)67Cu, 64Cu, 67Ga, 66Ga

• Radiochemical process for the cross section measurement

developed and applied to the irradiated target (collaboration with

University of Ferrara & Sant’Orsola Hospital in Bologna)

• Collaboration with experts in nuclear reactions modelling

PASTA Project (2017-2018)Production with Accelerator of Sc-47 for Theranostic Applications

• 47Sc is a promising radionuclide in Radioimmunotherapy(RIT), its half-life is suitable to follow the slow biodistribution of monoclonal antibodies (mAbs)

• 47Sc current production methods through neutroninduced nuclear reactions at reactor sites: 47TiO2(n,p)47Sc or 46Ca(n,γ)47Ca → 47Sc

Aim of the PASTA project: 47Sc cyclotron-production studies

❖ Evaluation of the proton-induced nuclear reactions on 48Ti , 49Ti , 50Ti and natV targets

❖ Optimization of the production parameters to minimize the co-production of contaminants:

44mSc (58.61 h, β+); 44Sc (3.97 h, β+); 46Sc (83.79 d, β- )

❖ Enriched metallic Ti target preparation (HiViPP technique; E_Plate project by H. Skliarova)

❖ Development of a separation procedure

Realization of Enriched Titanium Metal Targets: E_PLATE Project (Grant Giovani CSN5 2018-2019)

High intensity vibrational powder plating – HiViPP :This deposition technique exploits the phenomenon of vibrational motion of metallic particles in a static electric field [1].

Experimental set up

1 – backing (upper electrode, anode)2 – backing (lower electrode, cathode)3 – quartz or glass cylinder4 – pressing plate5 – spring6 – insulator holder

[1] An application of a new type deposition method to nuclear target preparation, Isao Sugai

natTi metal on Al foil(25 µm thick) for the

PASTA project

Advantages:• Two targets are deposited simultaneously• High Efficiency: 95-98%! • High uniformity• Small amount of starting material (≈50 mg)

Target deposition homogeneity and surface mass density measured with

RBS technique @ INFN-LNL

hanna.skliarova@lnl.infn.it

IRRADIATION RUNS @ ARRONAX FACILITY

Run # Date Reaction Target foils # Proton Energy (MeV) Duration (minutes) Current (nA)1 11/04/2017 natV(p,x)47Sc 3 70.3 90 ≈ 1002 27/06/2017 natV(p,x)47Sc 3 54.0 90 ≈ 1003 04/07/2017 natV(p,x)47Sc 3 61.0 90 ≈ 100

4 10/10/201748Ti(p,x)47ScnatV(p,x)47Sc

3* → 2

334.0 90 ≈ 120

5 22/11/201748Ti(p,x)47ScnatV(p,x)47Sc

4

140.0 50 ≈ 130

6 17/04/201848Ti(p,x)47ScnatV(p,x)47Sc

3

134.0 90 ≈ 100

Data analysis is in progress .. we show some preliminary results

Total # foils: natV = 14 ; 48Ti = 10 → 9

STACKED-FOILS STRUCTURE OF THE IV IRRADIATION RUN @ ARRONAXEnriched 48Ti Metal Targets on Al Support

Proton beam

liliana.mou@lnl.infn.it

Sc-47 , Sc-46 , Sc-44 , Sc-44m , Sc-43 , Sc-48 V-48 , K-43 , Cr-48 , Cr-49 , Cr-51

SOME DETAILS ON DATA ANALYSIS (PASTA)

• ALL the produced radionuclides are considered

• ALL the γ-lines are considered→ check for discrepancies..

• ALL the samples are acquired with HPGe detectors up to 5 days after irradiation and also once more than 30 daysafter EOB (in order to measure the long-lived Sc-46 contaminant radionuclide)

• The measured activity (corrected for the measuring time, Real time) for one γ-line of one radionuclide of all the spectra of the same target are analysed with a FIT in order to:

• Control that we do not have an interference (proper decay constant)

• Calculate the Activity @ EOB → Correction for irradiation time → Activity @ EOIB

→ Cross section calculation (by using the reference nuclear reaction by IAEA)!

• THE ENTIRE ANALYSIS IS DONE IN BLIND BY Gaia PUPILLO AND Liliana MOU

Sc-47V-12 foil159 keV

Thank you for your attention!

You are always welcome in Legnaro..

RESUME OF THE PASTA PROJECT

• No. 6 irradiation runs done at Arronax facility

• Data analysis in progress for the nuclear reactions:

natV(p,x)47Sc, 46Sc, 48Sc, 44Sc, 44mSc, 48V, 48Cr, 49Cr, 51Cr

48Ti(p,x)47Sc, 46Sc, ..

• Radiochemical process for the separation Sc/Ti under development

Collaboration with experts in nuclear reactions modelling Interdisciplinary work!

Nuclear physics , Modelling & ExperimentsTargetry , Material science , Engineering

Radiochemistry, RadiopharmacyBiology, Dosimetry, Imaging

Nuclear Medicine …

.. you can also visit Venezia, Padova and Ferrara!