64 cu radioisotope production capability at ANSTOs national medical cyclotron AUSTRALIAN NUCLEAR SCIENCE AND TECHNOLOGY ORGANISATION radiopharmaceutical research institute medical radioisotope development project r

- The larger cyclotron with proton beam energy not adjustable to lower than 13 MeV is difficult to be used for the 64Ni target based 64Cu production due to the need for a larger amount o

AUSTRALIAN NUCLEAR SCIENCE AND TECHNOLOGY

ORGANISATION

Radiopharmaceutical Research Institute Medical Radioisotope Development Project RRI-0168

64

Cu radioisotope production capability at

ANSTO’s National Medical Cyclotron

Le Van So

ANSTO, 01 January 2008

• β- energy, β max =0.578 MeV (39 %).Low tissue penetration is suitable for

treatment of small tumors

• Electron capture decay with its associated Auger emission can yield more

efficient cell killing

Diagnostic imaging advantages:

• β+ emission (17.4 % ) for PET imaging

Advantageous chelating chemistry useful for labelling biomolecules via strong

formation of stable coordinative complexes with bifunctional chelators 1-2 - acyclic polyaminocarboxylate (DTPA, EDTA), cyclic polyamines (Cyclam) and macrocyclic polyaminocarboxylates (TETA, DOTA, NOTA)

Bio-molecule labelling:

• The 64,67Cu-Chelator-antibody conjugates (MAb35-against carcinoembryonic antigen, SEN7 and SWA20-against lung cancer antigen, VG76e, B72.3

antibodies)

• The 64Cu labelled ligands targeting receptors (64Cu-DOTA-[Pro1,

Tyr4]-bombesin[1-14] for targeting GRP receptors , 64Cu-TETA-somatostatin analogs,

64

Cu-DOTA-Annexin V, ) are conjugates being widely investigated .

64Cu’s preferable properties involved in physiological pathways 1-4 make radioactive Copper complex molecules useful (in their own right) as targeting radiopharmaceuticals, PTSM for brain and myocardial imaging studies and PTSM & ATSM for tumour

treatment

Production capability

Two cyclotron based methods are used for 64Cu production

64Cu preparation based on the 64Ni target

- Very expensive enriched 64Ni target

- The larger cyclotron with proton beam energy not adjustable to lower than

13 MeV is difficult to be used for the 64Ni target based 64Cu production due

to the need for a larger amount of 64Ni target and a special target design

64Cu preparation based on the 68Zn target

• Advantage:

- This production route seems more economic in the target utilisation,

because both 67Ga and 64Cu can be produced from the same low cost target

• Disadvantages

- Radiochemical separation is more complex

- High potential of contamination from several impure radionuclides

- Low 64Cu yield

B Production procedures

I. 64Cu preparation based on the 64Ni target

1 Target & irradiation

The cross section of the 64Ni nuclide reach the maximum at the proton energy of 10.5 MeV (Fig 1) The empirical excitation was found as below (fitting calculation from the experimental data available from the NNDC’s library- EXFOR/CSISRS)

Y=2.1199+0.00208X+8.03383E-7X2+1.56738E-10X3+1.60368E-14X419X5+2.17695E-23X6+5.00974E-29X7+8.25815E-33X8+1.14924E-37X9

+8.65788E-So a proton energy higher than 10.5 MeV should be considered when choosing a cyclotron available for 64Cu production using 64Ni

Fig.1 Excitation function of 64Ni nuclide

The theoretical calculation results of the stopping power and the range of proton

particles in the Nickel target are shown in Figs.2&3 This is used for further calculation

of the proton range in the Ni target and assessment of 64Cu yield in the nuclear reaction

64

Ni(p,n)64Cu

There is low stopping power at the 10.5 MeV proton energy ( Fig 2) where the reaction cross section reaches the maximum ( Fig.1) The stopping power get the maximum at the proton energy of 0.12 MeV ( Fig.2) at which the reaction cross section drops and

become insignificant (Fig.1) All these data reveal the fact that the ions, but not

radioactive 64Cu nuclides, formed from proton stopping power along the proton pathway

is concentrated at near the back of Ni target where the proton energy reduce to 0.12 MeV ( at maximum stopping power , see Fig.2 ) which corresponds the 0.05 micrometer value of the target thickness from the back of the target (see Fig 3)

Fig.2 : Stopping power of proton in Ni target

Fig.3 shows the range of protons (d 90) in the Ni target which is perpendicular to the proton beam line ( see the description in Fig.4)

The real solid target arrangement of NMC tilted 60 compared to the beam line as shown in

Fig 4 Based on this arrangement and the range values (d 90) found in Fig.3 the real Ni target

thickness (d 6) for the NMC bombardment can be calculated

As an example, for the proton energy of 10.5 MeV at the maximum cross section mentioned above ( Fig.1), the range in the Ni target ( or target thickness ) for the perpendicular proton

beam is d 90 = 254 µm ( see Fig 3) and the relevant value of the 60 tilted Ni target

thickness was deduced as d 6 =26.6 µm

S T O P P IN G P O W E R IN N IC K E L T A R G E T

0 5

Fig.3 Range of protons in the Ni target perpendicular to the proton beam line (d 90)

(d90) RANGE OF HYDROGEN IONS IN NICKEL TARGET

Fig.4 Proton beam line and solid target position at NMC

The 10.5 MeV proton energy at the maximum cross section value and the relevant

target thickness d 6 = 26.6 µm (as mentioned above) are definitely not relevant to an

economic bombardment and the targetry of Ni-64 target, because the integral 64Cu yield

doesn’t reach the maximum

For an economic 64Cu production from an expensive 64Ni target, the optimisation

calculation of incident & outgoing proton energy, real target thickness and bombardment

time were performed based on the above obtained excitation and stopping power functions

The achieved results are shown in figs.5&6 and Table 1

Real thickness of

64

Ni target (d 6), µm

Specific yield

of 64Cu, (µCi /µA/µm)

Overall production yield, (µCi 64Cu/µA)

Table 1 The maximum 64Cu yields at optimised incident proton energies with variable

outgoing proton energies (the saturated yield for thick target was applied)

As shown in Fig.5 and Table 1, the 64Cu specific yield (µCi per µm target thickness) reaches the maximum at incident proton energy of 13,5 MeV, 13 MeV and 11 MeV for the outgoing proton energy of 0.0 MeV, 2.5 MeV and 9.2 MeV , respectively The outgoing proton energy is the residual proton energy after its passes through the target It should be minimised to reduced activation of target support ting material (NatAu, NatNi) The corresponding 64Cu yield values are 6.9, 7.3 and 10.6 (µCi 64Cu/µA/µm)

The proton energy of 11 MeV (incident) - 9.2 MeV (out) gives the highest specific yield value, however, the overall production yield was the lowest due to reduced target

thickness In this case, we waste the proton energy to get the highest specific yield but with the loss of overall production yield

In contrast, in the case of the proton range 13.5 MeV (incident) – 0.0 MeV (out), we increase the target weight to get the highest overall production yield but we have a loss

of specific yield

Based on the results listed in the table 1, the optimised proton energy was justified at the incident proton energy of 13 MeV with the 2.5 MeV outgoing proton This condition resulted in an optimised 64Ni target thickness of 36.20 µm (Fig.5, Table1)

These optimised conditions resulted in a profitable production of 64Cu with a good yield and less radionuclidic impurities (Fig.7) which is favourable in both views of radiation protection and product quality improvement ( Table 1)

The bombardment time should be around 10 hours Longer bombardment will increase the cyclotron running cost (Fig 6)

Fig 5: Reaction yield of 64Cu from the 64Ni target vs incident proton energy

Fig 6 : Reaction yield of 64Cu from the 64Ni target vs bombardment time

Target design

Based on the calculations performed above, the 64Ni target was designed and the results are shown below

 64Ni target thickness: 36.20 µm

 Target material weight: 289.68 mg 64Ni (98 % enrichment)

 The Nat Ni thickness: 10.0 µm

 The NatAu thickness: 30.0 µm

The Copper substrate thickness: 4.5 mm

Fig.7 The target assembly cross-section and the radionuclides induced by proton

Bombardment

Target preparation by electroplating

Fig.8 Electroplating 64Ni target nuclide on the gold + nickel coated target substrate

 64Ni target bombardment

Nuclear reaction: 64Ni (p,n) 64Cu

Proton beam 13 MeV and 100 microamperes for activation

Bombardment time: 10 hours

Cooling time: 23 hours

 Target dissolution & processing

Digestion solution: 40 ml 8M HCl at 50 oC temperature

Digestion process and apparatus

2 Finished product processing ( 64 Cu radiochemical separation from 64 Ni target)

Anion-exchange chromatographic separation of 64Cu from 64Ni target solution is performed as shown below

The 64Ni target solution, as mentioned above, was added with some drops of H2O2

(30%) , boiled for 5 minutes and cooled to room temperature before loading onto the anion exchange resin column The separation process was performed with HCl solution using a concentration gradient elution process Starting HCl solution is of 6.5 M

concentration The elution profile was monitored by a radioactivity recording

instrument Samples were also taken from each elution fraction for the gamma

spectrometric evaluation

Solid Target Digestion Equipment

240 V

012007.slv

• 64

Cu separation process

Chromatographic diagram of the 64Cu separation using a HCL

concentration gradient elution technique HCl concentration gradient was from 6.5M to 2.0 M

Chromatographic column: A glass column of 1.0 cm in diameter x 15 cm length loaded with anion exchange resin AG1-X4

Elution profile of 64Cu separation from 64Ni target solution

HCl concentration gradient for 64Cu separation from 64Ni target solution

Elution time, Minutes

64Cu radioisotope separation equipment

3 Automation

This procedure is
ecommended for automation at a cyclotron of 11-18

MeV proton energy with a reserved beam line

Cu is analysed using an ICP-MS instrument

The radiochemical purity of the 64Cu solution is evaluated by thin layer

chromatography using ITLC/SG (Gelman Sciences Inc.,USA)

Quality assurance

QA procedure is not available yet For this procedure the documents

(Standard premises, facility set-up, SOP-s, SP-s for both production and quality control, starting material control, in-process control, …) should be finalized

5 Non-decayed yield, final specific activity, maximum theoretical SA

Production yield calibrated on delivery date ( 36 hours after E.O.B) :

1.2 Ci 64Cu per batch (80 % of radioactivity achievable from NMC cyclotron activation)

Specific radioactivity of 64Cu on delivery date:

Around 55.6 % atom or 2143.0 Ci 64Cu / mg Cu

Maximum theoretical specific radioactivity of 64Cu : 3853.0 Ci 64Cu / mg Cu

6 Time required each process and total

Cyclotron bombardment and cooling time: 33 hours

Radiochemical processing time : 8.0 hours

Preparation work : 2.0 hours

Quality control : 2.0 hours

Product dispensing : 1.0 hour

Product autoclaving &packing : 1.0 hour

Sub-total : 14 hours

Total production time: 47 hours

7 Estimated cost on the NMC cyclotron bombardment basis

Total 16651.0 Cost per mCi 64 Cu ( at shipping

time)

13.87

II. 64Cu preparation based on the 68Zn target

(From the waste of 67Ga process)

1 Target & irradiation

 Target:

Isotopically enriched 68Zn metal target material is purchased from

Trace-Sciences International Inc.USA

The target isotopic compositions are 68Zn (>99.4 %), 67Zn (0.43 %), 66Zn

(0.08 %), 64Zn (<0.01 %), 70Zn (0.09 %) and other chemical impurities (< 10 p.p.m)

 Targetry

Optimisation of 68 Zn target thickness and assessment of 64 Cu yield for NMC proton beam

- Excitation function of the 68Zn nuclide for 68Zn (p, 2n) 67Ga,

 Target design

The target assembly cross-section and the radionuclides induced in the improved 68Zn target optimised for the 67Ga and no-67Cu contaminated 64Cu production

 The 68Zn thickness: 120.66 µm

 Target material weight: 800 mg 68Zn (99 % enrichment)

 The Nat Au thickness: 30.0 µm

 The Nat Ni thickness: 10.0 µm

The Copper substrate thickness: 4.5 mm

 E.O.B yield : 2.2 Ci 64Cu

 Delivery yield (36 hours after E.O.B): 275 mCi 64Cu

New 68 Zn target for 64 Cu & 67 Ga production

This improvement in target design, compared with that currently used in NMC (see figure below) , results in a 64Cu product free of longer lived 67Cu radionuclide impurity It offers also a preferable production process in view of treatment of less overall target radioactivity

The target assembly cross-section and the radionuclides induced in the target currently used

for the 67 Ga and 64 Cu production at NMC

The 68 Zn, Nat Ni and Nat Cu layers were of 120.66 µm, 26.2 µm and 4.5 mm, respectively

Target preparation by electroplating

 68Zn target bombardment

Nuclear reaction: 68Zn (p, α n)64Cu

Proton beam 23.5 MeV and 200 microamperes for activation

Bombardment time: 24 hours

Cooling time: 23 hours

 Target dissolution & processing

Digestion solution: 60 ml 8M HCl at 50 oC temperature

Digestion process and apparatus (seen below)

Solid Target Digestion Equipment

2 Finished product processing ( 64 Cu radiochemical separation from 68 Zn target solution)

Anion-exchange chromatographic separation of 64Cu from 68Zn target solution is performed as shown below

A glass column of 1.0 cm in diameter x 15 cm length loaded with anion exchange resin AG1-X4 was used for the chromatographic separation of different radionuclides (64Cu,

Cu separation process

Chromatographic diagram of the 68Zn target solution separation using a concentration gradient elution technique (a) and HCl concentration gradient (b)

 Chromatographic column: A glass column of 1.0 cm in diameter x 15 cm in length loaded with anion exchange resin AG1-X4

This procedure is not recommended for automation

4 QA & QC procedures

Quality controls

The radionuclidic impurities (especially 67Ga) in 64Cu solution are assessed

by gamma ray spectrometry

Chemical contamination in the completely decayed (at least for > 10 half-life)

64

Cu are analysed using an ICP-MS instrument and polarography

The radiochemical purity of the 64Cu solution are evaluated by thin layer

chromatography using ITLC/SG (Gelman Sciences Inc.,USA)

Quality assurance

QA procedure are not yet available

5 Non-decayed yield, final specific activity, maximum theoretical SA

Production yield calibrated at delivery date ( 36 hours after E.O.B) :

250 mCi 64Cu per batch (80 % of radioactivity achievable from NMC cyclotron activation)

Specific radioactivity of 64Cu at delivery date:

Around < 50 % atom or < 2143.0 Ci 64Cu / mg Cu

Maximum theoretical specific radioactivity of 64Cu : 3853.0 Ci 64Cu / mg Cu

6 Time required each process and total

Cyclotron bombardment and cooling time: 47 hours

Radiochemical processing time : 8.0 hours

Preparation work : 2.0 hours

Quality control : 2.0 hours

Product dispensing : 1.0 hour

Product autoclaving &packing : 1.0 hour

Total 9440.0 Cost per mCi 64 Cu ( at shipping

time)

37.76