1. RADIOISOTOPES in MEDICINE: The potential of accelerators
Gerd-Jürgen BEYER
Cyclotron Unit
University Hospital of Geneva, Switzerland
XXXV EUROPEAN CYCLOTRON PROGRESS MEETING
Nice (France)
November 1 – 4, 2006

2. ISOTOPES IN MEDICINE a-emitters: 149Tb 14C 3H 201Tl sealed sources
DIAGNOSIS
THERAPY
in vitro
in vivo
internal
external
systemic
sources
tele radio
14C 3H
125I
others
201Tl
123I
111In
67Ga
81Rb-81mKr
others
ß+ emitters
for PET 18F, 11C,13N,15O
86Y, 124I
68Ge-68Ga
82Sr-82Rb
sealed sources
and
applicators:
192Ir,
182Ta,
137Cs
others
needles for
brachytherapy:
103Pd,
125I
microspheres
90Sr or 90Y, others
131I,90Y
153Sm,186Re
188W-188Re
166Ho,177Lu,
others
a-emitters:
225Ac-213Bi
211At, 223Ra
149Tb
e--emitters:
125I
60Co
gamma
knife
137Cs
blood
cell
irradi-
ation
G.J.BEYER, HUG Geneva, 2005

3. Future Demand Isotopes in Medicine Future Demand Demand for for
Status
1998, USA
only :
Health
care
totally ca
. 10 12
US$
Surgery
(50 -
100) • 10 9
Radiation (1 5)
Roy Brown
: 10 7
nucl .
med
examinations per year
Richard
Reba
: Isotope
demand
for
therapy only
1996 48 6
2001 62
2020
6000 R é
sum
from the Medical
Isotope Workshop, Dallas, May 2
3, 1998
Future
Demand
Isotopes in
Medicine
Future
Demand
Demand
for
for
Isotopes in
Isotopes in
Medicine
Medicine .
examinations per year
Richard
Reba
: Isotope
demand
for
therapy only
S 5: In order to determine the general trend I wish to refer to the Medical Isotope workshop 1998, because in this workshop the top scientists of the US from the isotope business and the medical application site discussed the future needs and tried to find an answer to the question whether it would be useful to join a large LINAC project foreseen for the accelerator driven production of tritium as an alternative to the reactor mode.
In this discussion a growth of the medical isotope demand by a factor 100 was estimated for the period 2001 to While in 1998 the PET studies were of the order of 1 % of the total nuclear medical studies, in 2003 this value reached in the US already about 20 %, mainly FDG. The main increase in the isotope demand comes clearly from the need for therapy.
1996 48 • 10 6
US$
2001 62 • 10 6
US$
2020
6000 • 10 6
US$ R é
sum é
from the Medical
Isotope Workshop, Dallas, May 2-
3, 1998

4. 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
Therapy:
R&D delay over diagnosis,
fast growing,
main business field in the near future,
very profitable

5. 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

6. ISOTOPES in Therapy = surgery with radiation
Tissue
surgery
Cell
Molecular surgery
ISOTOPE
131I, 90Y, 153Sm,166Ho, 177Lu
Others
Eß 1 – 3 MeV
212, 213 Bi, 211At, 149Tb,
223, 224Ra
Ea 4–8 MeV
125I
165Er
Ee few eV
Range
about 1 cm
30 – 80 µm
1 µm
ß-Knife
a-Knife
Auger
Knife
S 7: Radiation in cancer treatment is often compared with the scalpel of the medical Dr.. Thus, gamma radiation focused form outside the head on a tumor inside the brain is performed using the „gamma knife“. In analogy we can name beta emitting radiopharmaceuticasl, that are injected into the patients as „beta knife“, that performs a tissue surgery. If we target smaller objects, for instance individual cancer cells, than we may use the „alpha knife“ and consequently the “Auger knife” can make a surgery on molecules directly.

7. Rats with SSR-positive tumours in liver
model mimics disseminated disease  PRRT
Int J of Cancer 2003
(PRRT = Peptide Receptor Radionuclide Therapy )
177Lu-octreotate
Control
Wouter A.P. Breeman
Erasmus MC Rotterdam
The Netherlands
S 10: This is another example for the Peptide Receptor Radionuclide Therapy, the study was perfomred by Dr.Breeman, Rotterdam. In this case the radiolanthanide 177Lu was used for the therapy.

8. 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 ß+-emitting metallic radionuclides
Relationship between beta – energy and therapeutic response
Variation of radionuclides with different ß-energy
need for metallic ß- -emitters with very different
energy
S12: There is a great progress and high expectations for the new techniques in systemic therapy, however some questions are still waiting for an answer:
Relationship between radiation dose and the therapeutic response, and in addition the radio toxicity,
And the relationship between beta-energy and the therapeutic response (and also in addition toxicity)
In order to get an answer to these questions we need to mace available metallic positron emitting radionuclides, that are preferable homologues of the nuclides used in therapy and to make available other suitable metallic beta-emitting nuclides.

9. ß- emitter for therapy
S 13/14: This slide shows a selection of suitable beta-emitting isotopes for RIT sorted along the beta energy (starting from very soft radiation – 169Er) to very hard beta energy (90Y). Most of them are produced with reactors. However, some of them need to be produced with a cyclotron (67Cu as example). Others can be produced with a cyclotron in much better quality (186Re).

10. S 13/14: This slide shows a selection of suitable beta-emitting isotopes for RIT sorted along the beta energy (starting from very soft radiation – 169Er) to very hard beta energy (90Y). Most of them are produced with reactors. However, some of them need to be produced with a cyclotron. Others can be produced along both lines, while the cyclotron route provides usually the better quality (67Cu, 186Re), what needs to be demonstrated in practice.

11. Beta spectra 144Ce 319 keV 144Pr 2998 keV 169Er 351 keV 177Lu 498 keV10 8 6 4 2
Beta spectra
144Ce keV
144Pr keV
169Er keV
177Lu keV
47Sc keV
153Sm keV
143Pr keV
166Ho keV
90Y keV
Intensity as % betas per 1 keV channel
S 15: The effect of beta emitting nuclides with different energy should be demonstrated in this slide. For a constant activity that is injected, higher radiation doses is adsorbed in a certain small region for low energetic beta emitter. High energetic beta emitters have a longer range: that is needed to create the so called „cross fire effect“. On the other hand it creates dosimetric problems in the healthy tissue (bone marrow for example). Thus, it is clear that optimization is requested: dedicated beta isotope for dedicated patient situation.
keV

12. ß+ emitters for in vivo dosimetry
S 17: In the following it should be illustrated, that metallic positron emitter are of high practical relevance for the future RIT.

13. [86Y]DOTA-DPhe1-Tyr3- octreotide PET [111In]DTPA- octreotide SPECT
Scintigraphic abdominal
images 5 & 24 h p.i.
affected by
carcinoid with
extensive hepatic and
paraaortal metastases.
[111In]DTPA-
octreotide
SPECT
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.
S 18: A comparative study 111In Octreoscan/SPECT versus 86Y DOTA TOC/PET was performed under F.Rösch, Uni Mainz, Germany. The slide illustrates, that control images supporting the 90Y-peptide therapy, should be done with PET and preferable a homologue PET isotope. In this case it is clearly seen, that the 86Y-DOTATOC provides the much better image compared to the 111In Octreoscan (SPECT). The quantification of the PET images allows obtaining individually dosimetric data and in this way, one can determine for each patient the optimal therapeutic dose of the radionuclide.
A dosimetric imaging procedure will be an unavoidable component in future RIT (H.Wagner, SNM 1999).
24 h p.i.
F.Rösch et.al.

14. Radiation doses for [90Y]DOTATOC therapy (based on [86Y]DOTATOC-PET)
Large discrepancies in tumor masses
S 19: The quantification of the PET images allows performing individually a dosimetry and in this way, one can determine for each patient the optimal dose for the therapy. This slide demonstrates that there can be significant differences in the uptake behavior between different patients, but may not be as well. A factor 2 difference was measured! (note: a difference of about 20-30% can decide to cure a patient or not.)
Thus, a dosimetric imaging procedure will be an unavoidable component in future RIT (H.Wagner, SNM 1999). Presently the techniques for producing those metallic PET isotopes are under development.
H.Wagner Jr: A diagnostic dosimetric imaging procedure will be unevoidable a part of the protocoll for the radioimmuno therapy (individual in vivo dosimetry).
F.Rösch et.al.

15. Rare Earth Elements: Positron Emitters
Nuclide T ½ % ß+ MeV MeV g / % Production Route
43Sc
3.9 h 88
1.2
43Ca (p,n) 43Sc, 44Ca (p,2n) 43Sc
44Sc 94
1.5
44Ti decay (generator), 45Sc (p,2n) 44Ti
V, Ti (p,spall)
85mY
4.9 h 67
2.3
86Sr (p,2n) 85mY, ISOLDE
86Y
14.7 h 32
86Sr (p,n) 86Y
ISOLDE
134Ce
134Pr
75.9 h
6.7 m EC 64
2.7 No
605
Ta, Er, Gd (p,spall)
132Ba (a,2n) 134Ce
138Nd
138Pr
5.2 h
1.5 m 76
3.4
136Ce (a,2n) 138Nd, ISOLDE
140Nd
140Pr
3.4 d
3.4 m 50
2.4
Ta, Er, Gd (p,spall), ISOLDE
141Pr (p,2n) 140Nd,
142Sm
142Pm
72.4 m
40.5 s 6 78
3.9
142Nd (a,4n)142Sm
152Tb
17.5 h 20
2.8
Div
Ta (p,spall) ISOLDE
152Gd (p,4n) 149Tb, 142Nd(12C,5n)149Dy
S 20: This slide contains a selection of suitable metallic positron emitters, that can support the future RIT. All these nuclides can be produced with the TESLA cyclotron.

16. Positron emitting radiolanthanides
134Ce/La
140Nd/Pr
149Tb
Positron emitting radiolanthanides
PET phantom studies
142SmEDTMP in vivo study
S 21: Examples of phantom PET Images performed with the Geneva Siemens PET scanner and poitron emitting radionuclides produced at CERN ISOLDE facility.
138Nd/Pr
152Tb
142Sm/Pm

17. a-emitters for therapy

18. ALPHA EMITTERS FOR THERAPY
225Ac 10 d U decay chain Ra (p,2n) 225Ac Th (a-decay) 225Ra
224Ra 3.66 d Th (a-decay) 224Ra
223Ra d Ac decay chain Ra (n,g) 227Ac Th (a-decay) 223Ra
213Bi m Ac decay chain Ac–Bi generator
212Bi 60 m Ra decay chain Ra–Bi/Pb generator
211At 7.2 h Bi (a,2n) 211At
149Tb 4.1 h Ta (p,spall)
152Gd (p,4n) 149Tb
255Fm h Ei (39.8 d)-decay 255Ei -255Fm generator

19. 10 20 30 40 50 60 70 80 90
100
120
Survival time, days
% of survived mice
Survival of SCID mice
5 MBq
149
Tb, 5 µg MoAb
no MoAb
5 µg MoAb, cold
300 µg MoAb, cold
S 25:
G.J.Beyer, M.Miederer, J.Comor et al. EJNM 2004, 31 (4),

20. AUGER electron emitters for therapy

21. 165Er Yield: 165Ho (p,n) 165Er 15 MeV p 50 µA 5 h 10 GBq
Only very few radionuclides exists that decay exclusively by EC-mode 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:
(p,2n)
(p,n)
Yield:
165Ho (p,n) 165Er
15 MeV p
50 µA
5 h
10 GBq
S 29:
G. J. Beyer, S. K. Zeisler and D. W. Becker
Radiochimica Acta 92 (4-6) , 219, 2004

22. Role of Accelerators in Medical RI Production

23. Isotope Production with Cyclotrons
The classical SPECT isotopes are produced via the (p,2n) process, the related p-energy 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 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.
S 30: After this introduction illustrating the strategy and the scientific background we shall now discuss the more technical and practical aspects.
The classical SPECT isotopes are produced via the (p;2n) process, the related p-energy 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.
New trends in radio-immune therapy require alpha emitting nuclides, thus 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 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. Combined with the option of high particle beam intensity (500 µA p beam intensity should be requested) and well developed tools for beam diagnosis and a certain variation of particle beam energy makes such a multipurpose cyclotron to an excellent universal instrument supporting commercial isotope production, research and university education and modern trends in medical isotope application for diagnosis and therapy.

24. Commercial Isotope Production with cyclotrons ~30 MeV proton beam
201Tl: Tl (p,3n) 201Pb Tl most important SPECT isotope, commercialized by all radiopharmaceutical Co. The worldwide installed production capacity exceeds the demand
123I: 124Xe (p,2n) 123Cs I very important SPECT isotope, corresponding target design from Karlsruhe is installed worldwide. Batch size up to 10 Ci possible.
111In: 112Cd (p,2n) 111In important for certain SPECT techniques, expensive because of low demand
67Ga: 68Zn (p,2n) 67Ga easy to make, low and decreasing demand
S 31: The (p;2n) process is the standard reaction in classical medical isotope production with cyclotrons. Most important are 123I, 111In and 67Ga. There are many other radionuclides of commercial interest that can be produced via this reaction. However, the 201Tl dictates the parameters of a production cyclotron:

25. for the production of 201Tl
IBA
Target station
for the production of 201Tl
with beam diagnosis elements and
Automatic active target transport chain
S 32: The slide illustrates an external beam line including an automated transport system, dedicated exclusively to the routine 201Tl production (IBA, one of the 30 MeV cyclotron installations).

26. Isotope Production with Cyclotrons (p,n) process with ~15 MeV protons
18F: 18O (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: 86Sr (p,n) 86Y
very important PET isotope with commercial interest (in-vivo dosimetry)
64Cu: 64Ni (p,n) 64Gu
therapeutic isotope for RIT, PET allows the measurement of the biodistribution during therapy.
186Re: 186W(p,n) 186Re
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.
S 33: As said before, today the highly developed standard in target technology for 18F production as well as modern diagnostic tools allow the production of 18F in a 10 Ci level within about 2 hours. Thus, one can practically obtain up to 5 Ci batches of [18F]FDG for a national clinical PET program. Due to the high productivity today transport times of up to 6 hours are accepted. The bottle neck in FDG utilization is not the productivity of a cyclotron center, it is clearly the scanning capacity and the patient flow. Under this consideration it is justified to day spending few hours beam time of a large cyclotron per day aiming producing large quantities of FDG for commercial purpose (done in Nice, France since many years using the 65 MeV cyclotron, see next slide)
Alternatively one can also consider other (p;n) processes to be performed with a large multipurpose cyclotron because of the following motivation: R&D, development of new technologies, education (university type) and training of personal. Results of those activities are qualified personal for the isotope work in the medical environment, new production technologies and new radiopharmaceuticals.

27. Production of other useful isotopes with the PET cyclotron
with < 20 MeV proton induced reactions
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 high-tech diagnostic tools and provide higher beam current than in the past.
Auger Therapy
20 GBq
nat
Ho (p,n)
165 Er
10.3 h
SPECT
10 GBq
123
Te (p,n) I
13.2 h
PET
1 GBq
124
4.15 d
Therapy
5 GBq
186
W (p,n) Re
90.6 h
120
1.35 h 5 -
110
Cd (p,n) In
69.1 m 94
Mo (p,n) Tc
4.9 h
PET, bioconjugates 90
Zr (p,n) Nb
14.6 h 89
Y (p,n) Zr
78.4 h 86
Sr (p,n) Y
14.7 h
Generator, SPECT
0.5 82
Kr (p,2n) 81 Rb
4.58 h
Rb/
81m Kr
2 GBq 76
Se (p,n) Br
16 h 66
Zn (p,n) Ga
9.4 h
therapy, bioconjugates 10 70
Zn (p, a ) 67 Cu
61.9 h
PET & therapy,
40 GBq 64
Ni (p,n)
12.7 h
PET, encymes, vitamines
Fe (p,2n) 55 Co
17.54 h
PET: bioconjugates
nat.
Sc (p,n) 45 Ti
3.08 h
Application
Batch size
Reaction T
1/2
Isotope
50 GBq
50GBq
100 GBq
S 35: This table contains a selection of interesting isotopes that can be made with some PET cyclotrons or with a low energy beam at a multipurpose cyclotron. The pink-colored nuclides are PET isotopes, the blue ones are used in therapy, the green are SPECT nuclides and the gray is a nice Auger electron emitter.
A universal solid target technology is required for this application.

28. PET-isotope production at the
IBA 30 MeV cyclotron:
Target station
at the end
of one
beam line
equipped with
5 target ports
18F: H218O target
11C: N2-target
15O: N2-target
2 positions free
S 36: This slide shows the irradiation position for the production of the basic positron emitting isotopes at an IBA 30 MeV cyclotron. The message is that one can adapt several targets on one beam line. This provides much more flexibility and allows installing dedicated target units designed individually for a dedicated isotope.
IBA

29. 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
S 34

30. R.J. Ylimaki, M.Y. Kiselev, J.J. Čomor, G.-J. Beyer
124I: 124TeO2 (p,n) 124I
~13 MeV, 0.45 mCi/µAh 124I
123I = 0.1 % EOB + 2 d
R.J. Ylimaki, M.Y. Kiselev, J.J. Čomor, G.-J. Beyer
DEVELOPMENT OF TARGET DELIVERY AND RECOVERY SYSTEM FOR COMMERCIAL PRODUCTION OF HIGH PURITY IODINE-124
WTTC 10, Madison (USA), 2004
irradiation time: 1 h, 10 µA, protons
MeV
124
I : (p,n) MBq
123
I: (p,2n) MBq
S 38
After 2 d: / MBq

31. IODINE PRODUCTION ROUTES
123 -
IODINE PRODUCTION ROUTES Cs Xe I
5.9 min
2.08 h
EC/ß + EC
124
I = 1 %
125
I < 1 %
I < 10
3 % 22 – 28
MeV 75 p 20 30
Te (p,2n)
127
I (p,5n)
Xe (p,2n)
1985
Karlsruhe
, Canada
PSI
Würenlingen
1975
many places
ALTERNATIVES:
local
I production using PET cyclotrons
Te (p,n) 15
p, 150
MBq
/µAh
Fast, easy, reliable, clean product, suitable for direct labelin g,
S 37: This slide illustrates the development in 123I production techniques over the last 25 years.
In the 70-th the basic reaction was the (p;2n) process on enriched 124Te. The drawback was the unavoidable contamination by >1 % 124I at end of irradiation. The 124I disturbed the imaging quality because of its high energy gamma radiation, in addition the dose for the patients becomes increased.
The (p;5n) process introduced from Würenlingen in the 80-th (using 72 MeV cyclotron) overcame this problem, however generating another unavoidable 1 % 125I contamination. 125I does not negatively influence the imaging quality of the 123I preparation. The dose consideration remained as a problem.
As spin-off from the gas target developments in PET in the 80-th Karslruhe invented the Xe-gas target technology for the production of high purity 123I via an (p;2n) process. Neither 124I nor 125I can be directly produced in this reaction.
As an alternative one can predict that the world-wide installed PET cyclotrons can be used for local production of 123I via the (p;n) process, in order to meet the local demand. Today high purity enriched 123Te target material is available for reasonable price. The Te-technology is simple and cheap, however cannot be seen so far as a competition to a large scale production based on the Xe-technology.

32. 86Sr (p,n) 86Y enriched 86SrO target, Pt-backing, ~15 MeV p
electrochemical separation technology
Yield: 3.2 mCi/µAh with 13 MeV,
[Rösch, 1990 ZfK-728]
10 – 50 GBq possible
511 keV
S 40

33. Isotope Production with Cyclotrons The (p,4n) process
82Sr: 85Rb (p,4n) 82Sr
82Sr 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.
52Fe: 55Mn (p,4n) 52Fe
52Fe is an interesting radionuclide for PET, it generates the 20 min 52Mn daughter nuclide that can be used in PET.
149Tb: 152Gd (p,4n) 149Tb
149Tb 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
S 41: Higher proton induced reaction than (p;3n) require higher proton energy. 70 MeV is somehow a reasonable figure, because this energy range allows as well other important application (p-therapy).
The most important isotopes of commercial interest in this concern is the 82Sr. It generates the 82Rb, a short-lived positron emitter, that could gain serious practical relevance in nuclear cardiology and PET. The combination 82Rb (available from a generator) and FDG (available from a large scale production center) would be ideal for many applications and the centers would not need to run an own cyclotron. Today the larger distribution of the 82Sr/Rb generator is hampered due to the high price.
High tech targetry, modern high intense beam facilities and consequently cheaper production costs can overcome this drawback. A new exotic isotope, suitable for targeted alpha therapy is the 149Tb (4.1 h half-live). This isotope can be produced with the (p,4n) process or an heavy ion induced reaction, if this option would be available at the cyclotron.
52Fe is an interesting nuclide, that allows to measure Fe-metabolism in vivo. The other advantage is the generation of a short-lived 52Mn, which is a very useful positron emitter for PET.
The 149Tb (4.1 h half-live) is a new exotic isotope, suitable for targeted alpha therapy. This isotope can be produced with the (p,4n) process or an heavy ion induced reaction, if this option would be available at the cyclotron.

34. Isotope Production with Cyclotrons The (a,2n) process
211At: Bi(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.
S 42: 211At is seen as the most realistic candidate for TAT in the future. Presently activities are seen creating new beam facilities that can produce reasonable quantities of this important isotope for the future TAT. In the last 20 years most of the existing positive ion cyclotrons that could make 211At have been decommissioned. Thus, there is a lack of alpha-beam capacity presently in the world.
Any multi-purpose cyclotron, now under consideration, shall be able to accelerate alpha particles, at least, eventually even heavy ions for research, dedicated to medical isotope production (149Tb) and nano technology.

35. 211At (7.2h) 207Bi (a,2n) 211At 28 MeV, ~20 MBq/µAh 106 105 104 103
Channel number
106
105
104
103
102
101
100
Counts per channel
S 43: This alpha spectrum demonstrates two main alpha energies in the decay of the 211At:
About 50 % of the 211At goes via 5.9 MeV alpha emission into 207Bi (33 years), the other half of the 211At decay via EC into 211Po (513 ms), which than emits the 7.5 MeV alpha decaying into the 207Pb. Thus, each 211At atom delivers one alpha particle for the therapy. The range in biological tissue is about 80 µm which corresponds to three cell diameter.

36. Segment of the decay chain A = 149
ß+ ~ 7 %
EC+ß+=
83 %
indirect production routes
direct production routes
S 44

37. Indirect production routes
138Ce(16O,5n)149Dy
143Nd(12C,6n)149Dy
136Ce(16O,3n)149Dy
142Nd(12C,5n)149Dy
4He
144Sm(9Be,4n)149Dy p
152Gd (a,7n) 149Dy
152Gd (p, 4n) 149Tb
9Be
12C
S 45
16O

38. Higher Quality is required

39. 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
S 47

40. Influence of production mode for 177Lu 176Lu-route versus 176Yb-route
Wouter A.P. Breeman
Erasmus MC Rotterdam
The Netherlands
176Yb
200 MBq 177Lu
incubation:
pH = 4.5
T = 80 oC
T = 20 min
Peptide variation
Factor of 4
176Lu
S 50
Low carrier – shorter infusion time

41. Role of Accelerators in Future Medical RI Production:
R&D needed for development of alternative technologies producing carrierfree radioisotope preparations for therapy.
Reactor versus cyclotron production routes: 185Re (n,g)186Re // 186W (p,n) 186Re Cu others
Other alternatives: spallation reaction
High energy proton induced fission
isotope separation (of radioactive preparations)
S 51

42. Radiolanthanides at spallation or fission 1 or 1.4 GeV protons
pulsed beam, p/pulse (~1µA)
Ta-foil- or U-carbide target
Surface ionization ion source
122 g/cm2 Ta (rolls of 25 µm foils)
at 2400 oC
W-tube as ionizer at 2800oC
Radioactive Ion Beams of
40 elements possible today
mass number
S 55
Plasma Ion Source
Surface Ionization
Target Ion Source

43. Alteranative Production Routes: high energy proton induced Spallation or Fission

44. 1 MW target for 1015 fissions per s

45. Hg-jet p-converter target

46. target station under construction
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

47. The MEGAPIE 1MW molten PbBi target under construction at PSI
Operation scheduled for 2006

48. 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