production of radioisotopes for medical applications at riamantica/radio-ria/ruth_radioria.pdf ·...

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

Production of Radioisotopes for Medical Applications at RIA

Thomas J. RuthTRIUMF

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

The advances in Nuclear Medicine during the next decade will be in the use of radiotoxic nuclides for therapy.

To make the best use of these isotopes they must be prepared in high specific activity.

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

What role can RIA play?

• Source for unique radiotoxic nuclides for radioisotope therapy (RIT).

• Demonstrating the efficacy of high specific activity radioisotopes.

• Implantation of radiotoxic nuclides.

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

Cell killing and DNA damage

• Tumor control and normal tissue injury by IR both depend on cell killing.

• Cell killing is caused primarily by damage to genomic DNA.

4

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

Radiation therapy (XRT)•A number of approaches to therapeutic radiation delivery:Regional: External beam (EB-XRT)

Sealed source (brachytherapy)Systemic: Unsealed source (radionuclide therapy)

Targeted radioisotope therapy, e.g., with antibodies (radioimmunotherapy).

•The ideal agent for systemic XRT would localize uniformly in tumor cells and carry isotopes that emit radiations with penetration of cellular dimensions, thereby minimizing dose to normal tissue.

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

Regional versus systemic XRT•Systemic therapy differs from EB-XRT in 2 major ways:1. Dose rate [high dose rate (HDR) and constant, versus low dose rate (LDR) and declining.2. Heterogeneity of dose distribution (especially in large tumors with poor vascularization and hypoxic regions). This makes tumor control more difficult because of cold regions of radionuclide deposition.•Most of our radiobiological understanding has come from homogeneous exposures to large single doses or fractionated doses of ionizing radiation (IR).

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

IR induces clusters of ionizations and of DNA-damaging events

α

β

•The complexity of the cluster depends strongly on the LET of the incident ionizing species.

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

Isotopes commonly used in systemic therapy

•Important features : half time, penetration (type and LET of emission).

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

Which Isotope?

range [mm]

10-2 10-1 100 101 102

1.7 MeV β-

0.15 MeV β-

5.3 MeV α

AUGER-electrons

64Cu

131I

90Y

64Cu

211At

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

Candidate radionuclides forradioimmunotherapy: 47Sc 64Cu 67Cu

90Y 105Rh 103Pd

111Ag 124I 142Pr

149Pm 153Sm 159Gd

166Ho 177Lu 186/188Re

194Ir 193m,195mPt 211At

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

Yields from direct bombardment of UC2 with 500 MeV p

193m,195mPt

186Re, 188W

142Pr10-3

10-6

atoms p-1

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

Direct production yields are probably too low!

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

Typically, high energy reactions favor the proton rich isotopes. However these spallation type reactions are accompanied by large amounts of secondary protons and neutrons.

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

2º Proton spectrum from from 500 MeV p on Ta

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

Neutron spectrum from 500 MeV p on Ta

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

Therefore, how can we take advantage of this additional source of isotope production?

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

2 Stage Concept

1º Target

Cooling water2º Target

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

A 2 stage target may be able to be operated in parasitic mode and can be tailored to the radioisotopes of interest. Many of the radioisotopes of interest are only a few neutrons off the line of stability.

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

S. Katcoff, BNL

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

Some examples...

• 51V(n,2p3n)47Sc (99.75% nat. abund.)• 69Ga(n,2pn)67Cu (60% nat. abund.)• 107Ag(n,2pn)105Rh (52% nat. abund.)• 169Tm(n,2p2n/α)166Ho (100% nat.

abund.)• 181Ta(n,2p3n)177Lu (99.988% nat. abund.)

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

S. Katcoff, BNL

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

S. Katcoff, BNL

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

Perhaps a route to the highly sought after platinum isotopes…

197Au(n,pxn)193m,195mPtx = 2,4

While additional isotopes of Pt are formed such as 194,196Pt, the SA is still better than

from n-capture.

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

And what about co-production of isotopes?

On-line isotope separators!

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

ISOL produced RadionuclidesUniversality:

Spallation reaction provides the access to any radionuclide we want, with respect to of type and energy of radiation and half-life

Purity:isotopically separated and carrier free

Ion Energy:ion energy is usually between 30 and 60 kV, implantation technique opens a new field of application

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

Reactor produced radionuclides that potentially could be prepared via on-line

isotope separator system:

105Rh 109Pd 111Ag

142Pr 149Pm 153Sm

159Gd 166Ho 177Lu

186Re 188Re 194Ir

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

Production of Selected Isotope

Isotope ISOLDE Yield(atoms/µA /s)

Projected ISAC YieldmCi/100 µA day

105Rh 1.5 x 108 190 109Pd 2.4 x 109 790 142Pr 1 x 107 23

149Pm 4.3 X 105 0.4 153Sm 8.7 x 107 83

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

What about in-situ production and release?

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

211At Production t1/2 = 7.2 h

• Possible reactions– 209Bi(α,2n) @ 28 MeV– 209Bi(7Li,5n)211Rn @ 60 MeV– 232Th(p,spall.)211Rn @ >200 MeV

• 211Rn t1/2 = 14.6 h

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

Decay of 211Rn and growth of 211At

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

Estimated Production of 211Rn

• Target - UO2/C - 3.4 g• Yield of 211Rn - 1.5 x 107nuclei/s/µA• Translates to 0.027 mCi/h

Conclusion - Need at least 3 orders of magnitude improvement to have any clinical utility.

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

• 100 µA provides 2 orders of magnitude,• thicker target/beam optics gains a factor

of 2 or 3 (or more),• better transport system from target to

ECR gains a factor of 2 at most,• better ionization efficiency could

provide another factor of 2 or 3.

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

Implantation Research• + ions implanted with 60 keV into

different backings:• - Mylar foils• - filter paper• - polyethylene foil• - aluminum foil• - Other metals and shapes

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

Implantation

ION BEAM

60 keV

Implantation into plastic material open channelsmetal foils channels closedII

P l a s t i c – f o i l (PE, polyether, MYLAR, KAPTON …)

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

max implantation density: 2x1013

Rb+cm-2

2x1013 81Rb-ions = 1 GBq 81Rb

A 5 mm long tip of a Catheter with d = 3.5 mm can stable carry 0.5 GBq 81Rb.

Blood acts as eluting agent!

for in vivo use

Implantation Type 18Rb / 81mKr Generator

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

Feasibility of 125Xe Implantation at TRIUMF for the Preparation of 125I Brachytherapy Sources

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

Critical Factors on 125I Implantation

• Production rates of 125Xe• Implant system efficiency• Stability from losses of implanted species • Radiobiological effectiveness

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

Conclusions

• System efficiency = 23%• Cs target has high production rate• Estimated yields = 2 mCi/hour• Stable implant

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

Many clinically relevant therapeutic nuclides can not be produced in high specific activity from reactors and the accelerators can not produce sufficient quantities for large scale usage.

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

Problem

• Reactor production - Low Specific Activity.• National Lab Accelerators - Capacity for

large scale production insufficient.

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

Possible Solution:

Production in reactors or spallation sources with off-line isotope separation.

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

Conclusions

• Many radionuclides can be produced at low energy cyclotrons distributed throughout NA, Europe and Asia.

• High Energy facilities can not be relied upon for the bulk of clinically relevant radionuclides.

• Alternative methods of production and isolation need to be explored.

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

Conclusions continued…

RIA can help define these methods through access to radioisotopes, in high specific activity, that are not readily available elsewhere.

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

However, as is the situation today, RIA will face the same issues that existinghigh energy radioisotope sources in itsability to serve as a source of radiotracers.

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

Limitations of High Energy Facilities

• Availability• Scheduling• Range of products (not an issue for RIA)• Sp. Act. affected by co-production of

isotopes (not an issue with ISOL)• Reliability

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

In spite of these limitations RIA radioisotopeproduction capacity will make it an importantcomponent in both Biomedical Research butalso in bringing radiotracers to the Health Care of North Americans and beyond.

27 March 2003 RIA, DNCT, New Orleans ACSTJ Ruth

Acknowledgements

I wish to thank the many colleagues have contributed to the work, ideas and/or slides presented here, especially Gerd Beyer, Geneva, Lutz Moritz, TRIUMF, Suzanne Smith, ANSTO and John Vincent, TRIUMF.

• This work supported by the TRIUMF Life Science Program. TRIUMF is funded through a contribution from the National Research Council of Canada.