RADIOISOTOPES

in

MEDICINE:

The potential of accelerators

Gerd-Jrgen BEYER
Cyclotron Unit University Hospital of Geneva, Switzerland gerd.beyer@cern.ch
XXXV EUROPEAN CYCLOTRON PROGRESS MEETING

Nice (France) November 1 4, 2006

ISOTOPES IN MEDICINE
DIAGNOSIS
in vitro 14C 3H 125I
99

THERAPY
internal external

in vivo

Mo-99mTc
201Tl 123I 111In 67Ga

systemic
131I,90Y 153Sm,186Re 188W-188Re 166Ho,177Lu,

sources

tele radio
60Co

others

sealed sources and applicators:

192Ir,
182Ta, 137Cs

gamma knife
137Cs

81Rb-81mKr

others
+ emitters for PET
18F, 11C,13N,15O 86Y, 124I

others a-emitters: 225Ac-213Bi 211At, 223Ra

149Tb

others

needles for brachytherapy:

103Pd, 125I

blood cell irradiation

68Ge-68Ga 82Sr-82Rb

e--emitters:
125I

microspheres
90Sr

or 90Y, others
G.J.BEYER, HUG Geneva, 2005

Future Demand for Isotopes in Medicine

Status 1998, USA only : Health care totally Surgery Radiation ca . 10 12 US$ (50 -100) 10 9 US$ (1-5) 10 9 US$

Roy Brown : 10 7 nucl . med . examinations per year Richard Reba : Isotope demand for therapy only 1996 48 10 6 US$ 2001 62 10 6 US$ 2020 6000 10 6 US$
R sum from the Medical Isotope Workshop, Dallas, May 2 3,-1998 2- 3, 1998

Status:
Diagnosis: (industrialized countries)
Boom PET only little increase (Mo-99) due to: better logistic (Europe, US), more efficient utilization no real need for new large scale production units for the classical cyclotron produced SPECT isotopes (201Tl, 123I, 67Ga and 111In)

Diagnosis: (Third World Region)

logistic problems, isolation growing demand and tendency to be independant from external supply, autonome solutions both directions: reactor and cyclotron based RI-products R&D delay over diagnosis, fast growing, main business field in the near future, very profitable

Therapy:

Change of the Role of Accelerator in RI-Production

Clear difference in the demand in industrialized and the third world region: - New isotope products Which ones? - New national RI production centres
This talk: Isotopes in Medicine: Overview on R&D activities in today Potential of accelerators for the future RI-production

ISOTOPES in Therapy =
surgery with radiation
Tissue surgery
131I, 90Y,

Cell surgery
212, 213

Molecular surgery
125I 165Er

ISOTOPE

153Sm,166Ho, 177Lu

Others E 1 3 MeV about 1 cm

Bi, 211At, 149Tb, 223, 224Ra Ea 48 MeV

Ee few eV 1 m Auger Knife

Range

30 80 m

-Knife

a-Knife

Rats with SSR-positive tumours in liver model mimics disseminated disease PRRT
(PRRT = Peptide Receptor Radionuclide Therapy )

177Lu-octreotate

Int J of Cancer

Control

2003

Wouter A.P. Breeman Erasmus MC Rotterdam The Netherlands

Questions to be answered:
Realtionship between radiation dose delivered to a lesion and the therapeutic response
In vivo dosimetry by quantitative PET imaging need for +-emitting metallic radionuclides

Relationship between beta energy and therapeutic response

Variation of radionuclides with different -energy need for metallic - -emitters with very different energy

emitter for therapy

10

Beta spectra

144Ce 144Pr

319 keV
2998 keV 351 keV 498 keV 600 keV 808 keV 934 keV 1855 keV 2300 keV

Intensity as % betas per 1 keV channel

169Er 177Lu

47Sc 153Sm 143Pr

166Ho 90Y

1000

2000

3000 keV

emitters for in vivo dosimetry

[111In]DTPAoctreotide SPECT

[86Y]DOTA-DPhe1-Tyr3- Scintigraphic abdominal images 5 & 24 h p.i. octreotide affected by PET carcinoid with
extensive hepatic and paraaortal metastases. Patients:
3 patients with metastases of carcinoid tumor (histologically confirmed) No therapy with unlabeled somatostatin > 4 weeks Age: 46 67 years, male All were candidates for a possible 90Y-DOTATOC therapy

5 h p.i.

24 h p.i.

F.Rsch et.al.

Radiation doses for [90Y]DOTATOC therapy

(based on [86Y]DOTATOC-PET)
25

86

20

111

Y-DOTATOC In-DTPA-octreotide

Dtumor (mGy/MBq)

15

Patient #1

Patient #2

10

Patient #3 Large discrepancies in tumor masses

Patient #1

Patient #2

Patient #3

H.Wagner Jr: A diagnostic dosimetric imaging procedure will be unevoidable a part of the protocoll for the F.Rsch et.al. radioimmuno therapy (individual in vivo dosimetry).

Rare Earth Elements:

Nuclide
43Sc

Positron Emitters
MeV
1.2 1.5

T
3.9 h 3.9 h

% +
88 94

MeV g / %

Production Route
43Ca 44Ti

(p,n) 43Sc,

44Ca

(p,2n) 43Sc

44Sc
85mY

decay (generator), 45Sc (p,2n) 44Ti V, Ti (p,spall)

86Sr

4.9 h
14.7 h

67
32

2.3
1.2

238

34

(p,2n) 85mY, ISOLDE

86Sr

86Y
134Ce 134Pr 138Nd 138Pr 140Nd 140Pr 142Sm 142Pm 152Tb

637 33 1077 83 No 605 No 789 4

No No No No Div

(p,n) 86Y ISOLDE

75.9 h 6.7 m 5.2 h 1.5 m

3.4 d 3.4 m 72.4 m 40.5 s 17.5 h

EC 64 EC 76
EC 50 6 78 20

2.7

Ta, Er, Gd (p,spall) 132Ba (a,2n) 134Ce Ta, Er, Gd (p,spall) 136Ce (a,2n) 138Nd, ISOLDE
Ta, Er, Gd (p,spall), ISOLDE 141Pr (p,2n) 140Nd, Ta, Er, Gd (p,spall), ISOLDE 142Nd (a,4n)142Sm Ta (p,spall) ISOLDE 152Gd (p,4n) 149Tb, 142Nd(12C,5n)149Dy

3.4

2.4

1.5 3.9 2.8

134Ce/La

140Nd/Pr

149Tb

Positron emitting radiolanthanides PET phantom studies

142SmEDTMP

in vivo study

138Nd/Pr

142Sm/Pm

152Tb

a-emitters for therapy

ALPHA EMITTERS FOR THERAPY

225Ac

10 d

decay chain 229Th (a-decay) 225Ra

228Th

233U

226Ra

(p,2n) 225Ac

224Ra
223Ra 213Bi 212Bi 211At 149Tb

3.66 d 11.4 d
45.6 m 60 m 7.2 h

(a-decay)

224Ra

decay chain 227Th (a-decay) 223Ra

225Ac

227Ac

226Ra

(n,g) 227Ac

decay chain decay chain

AcBi generator RaBi/Pb generator

209Bi

224Ra

(a,2n) 211At

4.1 h
20.1 h
255Ei

Ta (p,spall) (39.8 d)-decay (p,4n) 149Tb 255Ei -255Fm generator

152Gd

255Fm

Survival of SCID mice

100 90 80 % of survived mice 5 MBq
149

Tb, 5 g MoAb

70 60 50 40
30 20 10 0 0 20

no MoAb 300 g MoAb, cold

5 g MoAb, cold

40 60 80 Survival time, days

100

120

G.J.Beyer, M.Miederer, J.Comor et al. EJNM 2004, 31 (4), 547-554

AUGER electron emitters for therapy

Only very few radionuclides exists that decay exclusively by ECmode without any accompanying radiation 165Er is one of them All labeling techniques used for the three-valent radionuclides can be adapted without modifications. Generated in the EC-decay of the mother isotope 165Tm Production routes suitable for theTESLA accelerator:

165Er
105

KXHo
104
LXHo

165Er

10.3 h

200 mm2 x 5 mm Ge(Li)

Counts per channel

103

KXGe
KX + KX

102

101

100 0 1000 2000 Channel number

1000

3000

(p,2n)

(p,n)

Yield: 165Ho (p,n) 165Er 15 MeV p 50 A 5h 10 GBq

Cross section [mb]

100

10

1 6 8 10 12 14 16 18 20 Energy [MeV]

G. J. Beyer, S. K. Zeisler and D. W. Becker Radiochimica Acta 92 (4-6) , 219, 2004

Role of Accelerators in Medical RI Production

Isotope Production with Cyclotrons

The classical SPECT isotopes are produced via the (p,2n) process, the related penergy is ~25 MeV Because of the continuous high demand of 201Tl, the (p,3n) is usually considered as a main product. The upper p-energy for producing 201Tl is 30 MeV. The short-lived PET isotopes are based mainly on the (p,n) process, ~15 MeV is the preferable proton energy. Normally dedicated small cyclotrons are used for PET. However, due to the high standard of targetry and production technology a large scale FDG-production can be integrated economically today into the program of a larger cyclotron, because of the low beam time demand (high productivity). New trends in radioimmuno therapy require alpha emitting nuclides. The 211At needs to be produced via the (a,2n) Process. The related a-energy is 28 MeV. A cyclotron, that can accelerate alpha particles to 28-30 MeV can principally accelerate p to energies higher than 30 MeV. Consequently, higher reaction processes such as (p,4n) or generally (p,xn) or even (p,xn,yp) processes are possible. Such a multipurpose cyclotron with the option of high particle beam intensity and well developed tools for beam diagnosis and a certain variation of particle beam energy is an excellent universal instrument supporting commercial isotope production and R&D in the field of medical isotope application for diagnosis and therapy.

Commercial Isotope Production with cyclotrons ~30 MeV proton beam

201Tl: 203Tl

(p,3n) 201Pb

201Tl

most important SPECT isotope, commercialized by all radiopharmaceutical Co. The worldwide installed production capacity exceeds the demand 123I: 124Xe (p,2n) 123Cs 123I very important SPECT isotope, corresponding target design from Karlsruhe is installed worldwide. Batch size up to 10 Ci possible.

111In: 67Ga:

112Cd 68Zn

(p,2n) 111In

important for certain SPECT techniques, expensive because of low demand

(p,2n) 67Ga

easy to make, low and decreasing demand

IBA

with beam diagnosis elements and Automatic active target transport chain

Target station for the production of

201Tl

Isotope Production with Cyclotrons

(p,n) process with ~15 MeV protons
18O

18F:

(p, n) 18F

most important PET isotope, commercialized by many centers using dedicated small cyclotrons, however also done at 30 MeV or even at 65 MeV cyclotrons as well (Nice)

124I:

124Te

(p,n) 124I

very important PET isotope with commercial interest (in-vivo dosimetry), large scale production technology not yet available, same technology could be used for medium scale 123I production based on 123Te target material

86Y: 64Cu: 186Re:

186Re

86Sr

(p,n) 86Y (p,n) 64Gu

very important PET isotope with commercial interest (in-vivo dosimetry)

64Ni

therapeutic isotope for RIT, PET allows the measurement of the biodistribution during therapy.
186W(p,n) 186Re

(3.7 d) is one of the two important therapeutic isotopes of Re. The advantage over 188Re (16 h) is the longer half-life, the advantage over the reactor based 185Re(n,g)186Re process is the carrier free quality.

Remark:

The (p,n) process requires ~15 MeV only, and is performed normally at dedicated small PET cyclotrons. However, due to the high productivity of dedicated targets combined with a modern system for beam diagnosis allows to run these reaction under economical conditions at larger cyclotrons as well using only a small fraction of the available beam time.

Production of other useful isotopes with the PET induced reactions with < 20 MeV proton cyclotron
Isotope
45Ti 55Co 64Cu 67Cu 66Ga 76Br 81Rb/81mKr 86Y 89Zr 90Nb 94Tc 110In 120I 123I 124I 165Er 186Re

T 1/2 3.08 h 17.54 h 12.7 h 61.9 h 9.4 h 16 h 4.58 h 14.7 h 78.4 h 14.6 h 4.9 h 69.1 m 1.35 h 13.2 h 4.15 d 10.3 h 90.6 h

Reaction
nat.Sc natFe 64Ni 70Zn 66Zn 76Se 82Kr

Batch size 10-20 GBq 100 GBq 0.5-1 GBq 50 GBq 100 GBq 40 GBq 10-20 GBq 50 50GBq 10 GBq 10 GBq 2 GBq 0.5-1 GBq 20 GBq 5-10 GBq 50 20 10 GBq 20 10 GBq 20 10 GBq 5-10 GBq 20 10 GBq 20 10 GBq 2 1 GBq 40 20 GBq 20 GBq 5 GBq

Application PET: bioconjugates PET, encymes, vitamines PET & therapy, therapy, bioconjugates PET PET Generator, SPECT PET, bioconjugates PET, bioconjugates PET, bioconjugates PET PET PET SPECT PET Auger Therapy Therapy

(p,n) 45Ti

(p,2n) 55Co (p,n) 64Cu (p,a) 67Cu (p,n) 66Ga (p,n) 76Br (p,n) 86Y (p,n) 89Zr (p,n) 90Nb (p,n) 94Tc (p,n) (p,n) (p,n) (p,n)
110In 120I 123I 124I

The irradiation of solid materials requires much better beam quality parameters than gas targets. Consequently, beam homogenisation and beam manipulation is needed, ussually not possible at the PET cyclotrons. External beam lines, known from classical isotope production at cyclotrons, will take this function over. The new generation of multi-purpose cyclotrons will be equipped with hightech diagnostic tools and provide higher beam current than in the past.

(p,2n) 81Rb

86Sr 89Y 90Zr

94Mo 110Cd 120Te 123Te 124Te natHo 186W

(p,n) 165Er (p,n) 186Re

PET-isotope production at the IBA 30 MeV cyclotron: Target station

at the end of one beam line equipped with 5 target ports

18F:

IBA

H218O target 11C: N -target 2 15O: N -target 2 2 positions free

COSTIS : Test Installation in Belgrade

COSTIS and its constructors at the low energy beam line of the mVINIS ECR ion source at the TESLA Accelerator Installation in Belgrade, Yugoslavia

124I:

124TeO 2

(p,n) 124I
~13 MeV, 0.45 mCi/Ah 124I 123I = 0.1 % EOB + 2 d
R.J. Ylimaki, M.Y. Kiselev, J.J. omor, J. Beyer G.DEVELOPMENT OF TARGET DELIVERY AND RECOVERY SYSTEM FOR COMMERCIAL PRODUCTION OF HIGH PURITY IODINE-124

124I T 1/2
+ E
511

max

= 4.17 d = 22.8 % = 2.1 MeV

WTTC 10, Madison (USA), 2004

irradiation time: 1 h, 10 A, protons

124I
124 I

15 : (p,n) 250

13

MeV

150 MBq

Pt-disc with 124TeO2 after irradiation

100 500 1000 1500 [keV]

123 I:

(p,2n)

680
178 /

75 MBq
51 MBq

After 2 d:

123-IODINE PRODUCTION ROUTES

123Cs
1985 Karlsruhe,
124Xe

5.9 min EC/+

123Xe

2.08 h EC 1975 many

124Te

123I

Canada

1980 PSI Wrenlingen

127I

places

(p,2n)

(p,5n)

(p,2n)

20 30 MeV p
125I

75 MeV p
125I

22 28 MeV
124I

< 10-3 %

<1%

=1%

ALTERNATIVES: local 123 I production using PET cyclotrons 123Te (p,n) 123 I 15 MeV p, 150 MBq/Ah Fast, easy, reliable, clean product, suitable for direct labelin g,

86Sr

(p,n) 86Y

enriched 86SrO target, Pt-backing, ~15 MeV p electrochemical separation technology Yield: 3.2 mCi/Ah with 13 MeV, [Rsch, 1990 ZfK-728] 10 50 GBq possible
511 keV

Isotope Production with Cyclotrons The (p,4n) process

82Sr:
82Sr

85Rb

(p,4n) 82Sr
52Fe

% betas per 1 keV channel

generates the short-lived 82Rb (80 sec), which is an positron emitter. This generator nuclide is used for PET in nuclear cardiology. The low availability and the still relatively high price hampered a larger distribution so far. Produced at TRIUMF(Ca), Protvino (Ru), South Africa and LosAlamos. Liquid Rb-metal sealed in silver bodies is used as target. High beam intensity is used.

+,EC 8.3 h

52Mn

+,EC 52 Cr 21 m

2.0

+ from
1.5 1.0 0.5 0 0 200

52Fe

52Mn

55.0% 29.6%
52Fe

52Fe:
52Fe

55Mn

(p,4n) 52Fe

is an interesting radionuclide for PET, it generates the 20 min 52Mn daughter nuclide that can be used in PET.

149Tb:
149Tb

152Gd

(p,4n) 149Tb

52Mn

has shown its potential in TAT (targeted alpha therapy) as it is a partial alpha emitting nuclide and any bio-conjugate (monoclonal antibodies or peptides) can be easily labeled with this interesting nuclide

400 600 800 1000 energy in keV

Isotope Production with Cyclotrons The (a,2n) process

211At: 209Bi(a,2n) 211At

Among the very few suitable alpha emitting radionuclides for the 211At turns out to be the most suitable candidate for the medical application (targeted alpha therapy) presently a subject of intense international research activity. The 211At can be produced by irradiating of natural Bi targets with 28 MeV alpha particles. Newly developed targets allow a production on large scale: Production yield is ~ 40 MBq/Ah, production batches of 10 GBq are technically possible. A typical patient dose for therapy will range between 0.4 and 2 GBq.

211At
207Bi

(7.2h)
211At

28 MeV, ~20 MBq/Ah

106 105 104 103 102 101 100
0 4000 1000 2000 3000

(a,2n)

Channel number

Segment of the decay chain A = 149

indirect production routes direct production routes

+ ~ 7 % EC++= 83 %

Indirect production routes

4He

138Ce(16O,5n)149Dy 143Nd(12C,6n)149Dy 136Ce(16O,3n)149Dy 142Nd(12C,5n)149Dy 144Sm(9Be,4n)149Dy 152Gd 152Gd

p
10000

(a,7n)

149Dy

(p, 4n) 149Tb

9Be
1000

12C
16O

Saturated yield (MBq/m A)

100

10

1 20 40 60 80 100 120 Incident particle energy (MeV)

Higher Quality is required

Why is high specific activity that important?

The receptor density is low for peptide ligands The infusion speed is limited for certain therapeutical approaches We do not wont to dilute our biospecific ligands with inactive atoms

Influence of production mode for 177Lu 176Lu-route versus 176Yb-route

200 MBq 177Lu of NRG vs Nordion 100 75 50 25 0 0 0,5 1 1,5 nmol peptide 2 2,5 3
Wouter A.P. Breeman Erasmus MC Rotterdam The Netherlands

% incorporation

176Yb 176Lu

200 MBq 177Lu

incubation: pH = 4.5 T = 80 oC T = 20 min Peptide variation

Factor of 4

Low carrier shorter infusion time

Future Medical RI Production:

R&D needed for development of alternative technologies producing carrierfree radioisotope preparations for therapy.

Role of Accelerators in

Reactor versus cyclotron production routes: 185Re (n,g)186Re // 186W (p,n) 186Re 67Cu others Other alternatives: spallation reaction High energy proton induced fission isotope separation (of radioactive preparations)

Radiolanthanides at
spallation or fission 1 or 1.4 GeV protons pulsed beam, 3 1013 p/pulse (~1A) Ta-foil- or U-carbide target Surface ionization ion source 122 g/cm2 Ta (rolls of 25 m foils) at 2400 oC W-tube as ionizer at 2800oC Radioactive Ion Beams of 40 elements possible today mass number 149 150

148

151

152

Plasma Ion Source Surface Ionization Target Ion Source

Alteranative Production Routes:

high energy proton induced

Spallation
Fission
or

1 MW target for 1015 fissions per s

Hg-jet p-converter target

The SNS neutron source target station under construction

Operating pressure 100 Bar Flow rate 2 t/m Jet speed 30 m/s Jet diameter 10 mm Temperature - Inlet to target 30 C - Exit from target 100 C Power absorbed in Hg-jet 1 MW Total Hg inventory 10 t Pump power 50 kW

The MEGAPIE 1MW molten PbBi target under construction at PSI

Operation scheduled for 2006

Conclusion
Productin of Classiccal SPECT isotopes will also be produced with PET cyclotrons Classical PET isotope production will be organized with SPECT cyclotrons as well More attention will be paid to beam quality Intense R&D related to Solid target technique Multi-purpose cyclotron centers coming up High intensity p-beams of high energy will be available in the very near future, targetry, chemistry and the medical environment are not yet ready to use these new possilities