Biomedical cyclotrons for radioisotope production

0883-2897/86 $3.00+0.00 Pergamon Journals Ltd

Nucl. Med. Biol. Vol. 13, No. 2, pp.lOl-107, 1986 Int. J. Radiat. Appl. Instrum. Part B Printed in Great Britain

BIOMEDICAL

CYCLOTRONS

Dominique

Service France

Hospitalier

Frederic

Joliot,

FOR

COMAR

RADIOISOTOPE

and

Christian

DBpartement

de

PRODUCTION

CROUZEL

Biologie,

CEA,

HBpital

d’Orsay,

91406

Orsay,

INTRODUCTION Many well documented reviews published during the last few years describe the various aspects of medical cyclotrons for the production of radioisotopes (l-2). If one considers that short lived positron emitting radionuclides are now a necessary tool for medical research, the cyclotron as such should be regarded as part of the material necessary to provide medical teams with labeled probes which, administrated into patients, will quantitatively visualise metabolic and pharmacological parameters, using positron emission tomography. Taking into account economic parameters, industrial engineers and chemists have focused their efforts on the design of integrated material capable of automatically producing the most useful labeled compounds. These “black boxes” usually includes three parts: -

A cyclotron accelerating ionised particles when interacting with stable nuclei.

at

-

A set of targets

take

-

Chemistry units where and radiopharmaceuticals.

discussed 1.

where

A description in consideration

the nuclear the

reactions

radionuclides

are

an

energy

place

such

yielding

incorporated

that

they

radioactive

into

the

nuclear

reactions

nuclides.

desired

of the characteristics of these three components of the various commercially available machines.

radioactive

is presented

precursors

here

and

Cvclotrons

The most successful device for accelerating positive is the cyclotron proposed by E.O. Lawrence in 1929. A remarkable the fir& model which produced 80 KeV protons in 1930 to the giant synchrocyclotrons accelerating the same particles to energies of many hundreds of MeV needed by nuclear physicists. For radionuclide production in hospitals such high energies are not necessary but many technical developments were necessary for making reliable machines at reasonably low prices.

ions to millions of electron development has taken place

Energy

volts from

South pole

,

Ion source Deflector

A cyclotron accelerates ions by multiple applications of a radiofrequency field. A magnetic field constraines these ions to move in a special path consisting in a series of semi circles with increasing radii (3). a)

induce

Vacuum box Dees

of the particles

principle of The is operation shown in figure 1, ions are produced in an arc ion source near the centre of the machine between two semi circular

North pole

FIGURE

101

1:

Open View

of a Cyclotron

102

electrode boxes called “dees”. The dees and the source are enclosed in a vacuum box located between the poles of an electromagnet. A high frequency potential difference is applied between the dees. As the positive ions are produced by the ion source they accelerate toward the dee which is at a negative potential. When inside the dee box, ions do not accelerate any more but are submitted to the magnetic field constraining them into a semi circular path. If the frequency of the accelerating potential difference is such that the electric field has reversed its direction precisely when the ions again reach the gap between the dees, the ions are again accelerated: Their velocity increases and so does the radius of the semi circular path. The ions accelerate each time they cross the dees and describe a spiral path toward the periphery of the electromagnet where they are removed from their circular path by a negatively charged deflector allowing them to emerge through a window and strike the target. The equation of motion and the centrifugal force such as:

of an ion is given by the equality

of the centripetal

magnetic

force

mv* Bqv = -

(1) r

where m = particle mass, B = magnetic field, q = particle v = particle velocity and r = radius of path.

charge

mv* -

and Bqv being the centrifugal

The kinetic

energy of the particle

and centripetal

forces,

respectively.

is

E = k mv* substituting

(21

v in (2) by its value given by (1). the particle

energy becomes

r*B*q* E=-------

(3)

2m For a magnetic field of the energies cyclotrons, and EjHe = 30 MeV.

16 Kgauss and a radius of 40 cm, values of various particles are: Ep = 20 MeV,

commonly obtained in medical Ed = 10 MeV, E, = 20 MeV

b) Acceleration The frequency of the accelerating field cannot charge and mass of the particle and to the magnetic field. by turn, the relation for the frequency becomes

1 w Bq n = __- = ___-_ = ---_-T

2ll

be chosen arbitrarily. It is related When the particles are accelerated

to the twice

(4)

*am

V

where w = --r is the angular frequency and T is the period for a particle to make one revolution. B = 16 KCauss, n = 24,5 MHz for protons and 12.25 MHz for deuterons. cl

In our example

with

Relativity

One difficulty in the acceleration is presented by the relativistic mass increase of the particles as they reach high energies. This mass increase is for about 1 % for 10 MeV protons and 0.5 % for 10 MeV deuterons. It is clear from equation (4) that if the angular frequency is to be kept constant, the increase in mass must be compensated by a proportional increase in field strength at the periphery of the magnetic poles. d) Focusing An important feature of the cyclotron is the focusing action it provides for the particle beam. An electrostatic focusing at the dee gap exists at the centre of the cyclotron at low particle energies (figure 2). However, as the energy of the particle increases this effect becomes negligible.

103

focusing Fortunately, a magnetic effect becomes more pronounced as the particles travel toward the periphery. Near the edges of the pole faces the magnetic lines of force are curved (Figure 2) and the field therefore has a horizontal component which provides a restoring force toward the median plane. e) The azimuthally (AVF) cyclotron

varying

field

South pole

Particle path Dee

North pole A method for overenergy coming the limitation on cyclotron acceleration was proposed by Thomas (1938) who showed that an azimuthal variation of the magnetic field could result FIGURE 2: Focusing electrostatic and magnetic in axial focusing. lt was thus forces in a cyclotron possible to let the average field increase with radius, as required to compensate for the relativistic mass increase, and yet to achieve focusing by means of azimuthal field variations. These field variations are obtained by the use of pole faces that have alternative “hill” and “valley” sectors as shown on the south pole of figure 1. f)

External

beam

Once the particles have reached the desired energy they are extracted as indicated earlier and guided toward the target by means of a beam transport system. In some cases the target is placed directly at the output of the vacuum box. The beam section is usually elliptical and its area has to be modified in order to penetrate into the target holder. Sections of a few square centimeters are in most biomedical cyclotrons generally obtained by using magnetic lenses. Beam currents available are of the order of 50 to 100 VA depending on the particle. According to the maximum energy of the particle, cyclotrons have been classified in different levels (2) which presently are the most used for the production of radioisotopes. The low energy machines accelerating protons to 16-17 MeV and deuterons to 5-10 MeV are considered to be the best for the production of the commonly used llC, 150, 13N and 18F isotopes. TABLE Characteristics

I

of low and medium energy medical

cyclotrons

-----~-------_~------__------___--------_----______________-________---_____-----____-----PARTICLE

LOW ENERGY

*

MEDIUM

ENERGY

*

___________--______--__------___--------_---!~~~~__________-________---_____---~~~~~_-----_ protons

16-17

24-45

deuterons

5-10

15-24

Helium-4

26-40

Helium-3

31-53

____________________---____--___-___-_________--____------___------____-----______---______ extracted

beam currents

reach 50 PA for CLand 3He, 100 uA for protons and deuterons.

Scanditronix, Uppsala, Sweden; Japan Steel * maximum energy listed by the following manufacturers: Corporation, Muroran, Japan; CCR-MeV, But, France; Sumitomo, Tokyo, Japan and TCC, USA. By the end of 1986, 25 to 30 low energy cyclotrons will be installed in medical centres all entirely devoted to the production of positron emitting short lived isotopes. On the other hand, more than 40 medium energy cyclotrons are partly or totally used for medical radioisotope production (4). 2. Taraetry The second step in the preparation of radiopharmaceuticals is the production of the radioisotopes by bombardment of a stable element by the accelerated particles. Since we are mainly interested in low mass and low 2 isotopes the minimum energy of the particle required to overcome

104

the coulomb barrier is below 5 MeV for most nuclear reactions. However, in order to obtain high yields the bombarding energy should be higher than the threshold taking also into account the excitation function of the nuclear reaction. Other parameters to be considered when one is interested in production yields are intensity of the particle beam, thickness of the target material, ease with which the radioisotopes are recovered, dissipation of heat during bombardment and parasite nuclear reactions Most of these problems have been solved for low energy giving rise to undesirable radionuclides. cyclotrons used for making the simple molecules currently used as liquid or gas (5). A metallic cylinder closed by a thin metallic foil at the end through which the beam is generally used. The cooling of this cylinder is insured by cooled helium gas at the level and water circulating in a double envelope around the body of the target holder. Irradiation can be conducted in a stationnary mode, the pressure of the gas in the target holder being such as to dissipate most of the energy of the particles, or in a flow mode when the has such a short half life that it has to be used as it is produced.

penetrates of the foil of the gas calculated radionuclide

target

For irradiating holder as possible. Nuclear

liquids, 180 enriched water for example, it is important Vessels containing 1 ml or less are now available.

reactions

commonly

used with

a proton,

deuteron,

medical

to desigo the smallest

cyclotron

are

shown

in table II.

TABLE II

Nuclear

reactions for the production of some 6+ emitting using 16 MeV protons or 9 MeV deuterons

radionuclides

NUCLEAR REACTION RADIOISOTOPE HALF LIFE _______-_______--______--_____-----___------__~~~~---~~~~~~--~-~~~~~-~--~~~--~-~~~---~-~~~

Oxygen

Nitrogen

15

13

2 min

TARGET

MATERIAL

15N(p,n1150

enriched

14N(d,n)150

N2

10 min

gas

H20 CO2 CO2

Carbon 11

Fluorine

18

20.4 min

112 min

14N(p ,.)l’C

N2

11B(p,n)l 1C

B2O3

1OB(d,n)l 1C

B2°3

H20 (‘80) Ne

Multitarget holder facilities may be adapted in front of the extracted beam of the cyclotron which allows to automatically change by simple rotation the target holder in which the nuclear reaction is desired. Yields of production may be calculated in many ways. Manufacturers often give theoretical values using published data for excitation functions and times of irradiation corresponding to saturation. These values are only indicative and often very different from routine reality. Table III gives the experimental production yields for the main short lived 8+- emitting radiosotopes using a cyclotron accelerating protons to 16 MeV and deuterons to 8 MeV.

105

TABLE

111

Production yields for the main short lived radioisotopes using a cyclotron with Ep = 16 MeV and Ed = 8 MeV

NUCLEAR

CHEMICAL

REACTION

PRODUCTION

FORM

‘50 “Iso,

48 48 70 64

“Co2 “Co H”CN

60 mCi/min 54 mCi/min 54 mCi/min

c’50* c’50

At site and time

(2)

At equilibrium,

(3)

E.O.B.

+ 10 min for

(4)

E.O.B.

+ 20 min after

1 hour

(5)

E.O.B.

+ 10 min after

1.5 hour

(6)

E.O.B.

+ 10 min after

30 min irradiation

3.

of administration in 2 ml saline H”CN

(target

for

irradiation

(30 PA) (3) (30uA) (3) (30~A) (31

18F-

600 mCi

(15 PA) (5)

13NH40H

350 mCi

(30 PAI (6)

target

gas being

N2+C02

(2OlpA) (4)

or N2+02.

injection.

gas consists

irradiation

(1) (1) (2) (1)

90 mCi

(20 meters),

ready

(20~4) (20pA) (2OuA) (2OuA)

‘8~2

2Otde(d,a)18F

(1)

mCi/min mCi/min mCi/min mCi/min

YIELD

(carrier

of N2+H2). F2 is added

of H2180

to neon).

(no carrier

added).

of H2160.

Chemistry

The physical characteristics of the radionuclides involved dictate to the chemists two Rapidity, since half lives of the radioisotopes are short. conditions to be fulfilled: Rapidity and safety. It is generally accepted that the synthesis of the labeled compound including purification and sterilisation should not last more than two or three half lives of the nuclide (40 to 60 minutes for carbon-l 1). Safety, because high radioactivities of 511 KeV gamma emitting nuclides are involved. It must be recalled that the gamma dose rate at one meter from a point source of 1 Curie of carbon-11 is 0.5 rem/h. A 5 cm lead wall is necessary to decrease it by a factor of 1.000. It is thus inevitable to have radiosyntheses carried out in shielded areas and very early chemists have been interested in developing In order to avoid contamination by unwanted carrier frequently present remote control techniques. micro scale methods were studied adding complexity to the design. Three types of in reagents, increasing complexity automatic synthesis systems exist today and are available from various companies. The aim of the first level is the on line production of radioactive gases directly useful for patient Table IV indicates those for which automated black boxes administration or for chemical synthesis. exist.

106

TABLE Automatic

IV

synthesis systems for short lived radioisotopes

compounds

LABELED COMPOUNDS DESCRIPTION _____________________--____--__---__---___--__-____--___---___--__---__---___-_____-_______

“Co

Inorganic gas

COMMENTS

blood volume

“Co*

radiochemistry

13N2

pulmonary

ventilation

‘502

oxygen metabolism

cl50

blood bolume

c’50*

blood flow

Special attention has been paid to labeled which can be used for introducing the steps, radiopharmaceuticals.

precursors obtainable radionuclides in a

in one or two chemical given position of the

and phosgen all labeled with carbon 11 Hydrocyanic acid, methyl iodide, formaldehyde However, if high specific activity can now be made automatically with high yields within a few minutes. is needed, as for receptor studies, great care has to be taken in the choice and the purity of the reagents. No specification regarding this point is given yet by manufacturers. Fluorine-18 as F2 cannot be obtained carrier free and is mainly used for fluorodeoxyglucose labeling. F- of HF are available from gas targets (Ne+H2) or water targets (H180), Production yields are given in table IV-2. Table IV-2 lists the available precursors (level 2 compounds) and indicates their main uses.

TABLE Automatic

DESCRIPTION

precursors

IV-2

synthesis systems for short lived radioisotope

LABELED

COMPOUNDS

compounds

USE

amines, sugars

H”CN

amino acids “CHjl

methylation

H”CH0

methylation

13NH3

ring closures amino acids and cardiac

‘8~2

*

H18F (gas) H18F (liquid) 18F- (liquid)

studies

FDC FDG FDG receptor

__-___-_-__----_-----~~-~-~~--~-~~~-~-~~~-~-~~~-~~--__~~~--_~~--_~----__---___---___-_____ * carrier

added

ligands

107

The involving listed

all

those

third

steps already

level

of

necessary

automatic to

manufactured

synthesis

obtain

consists

a product

or under

ready

synthesis

DESCRIPTION

systems

LABELED

into

of

radiopharmaceuticals

patients.

In table

IV-3

are

IV-3

for short

lived

8+ emitting

compounds

COMMENTS ____-____--

COMPOUNDS

H2150

Radiopharmaceuticals

preparation

injection

preparation.

TABLE Automatic

in the

for

blood

*

13NH40H

’ 3N-amino

myocardium

* acids

llC-glucose

*

flow imaging

sugar

metabolism

sugar

metabolism

1 1 C -deosyglucose “C-methionine

’

lC-palmitic

protein

* acid

“C-acetate

*

*

metabolism

myocardium

metabolism

myocardium

metabolism

l1 C-octylamine

lung imaging sugar

‘*F-FDG

metabolism

_* manufactured

It can be seen that only a few of the numerous compounds the synthesis of which are in fact, it is reasonable to automate published have been subjected to automatic synthesis development. the tracers that are routinely used in PET centres such as “C-palmitic acid, ‘*F fluorodeoxyglucose, some llC-amino acids and perhaps in the next future a few ligands for receptor imaging. One of the big advantages given by automation is the reproducibility of the quality of the product allowing better However, standardisation of techniques intercentre comparisons of the measured biological parameters. must be achieved to obtain such a goal. A series of workshops and task groups sponsored by the European Communities was recently organized on this purpose. They should help improving the techniques and insuring the same quality all over the PET community (6).

REFERENCES

1.

2.

3.

A.P. Wolf and J.S. Fowler Positron emitter labeled radiotracers. In “Positron Emission Tomography”, A.P. Wolf and W. Barclay Cyclotrons for biomedical Radiochim. Acta.34. l-7

Chemical 1985. Alan

Jones radioisotope (1983)

considerations. R. Liss Inc., pp. 63-80

production.

Nuclear and Radiochemistry. C. Friedlander, J.W. Kennedy John Wiley, 1966.

and J.M.

4.

Tenth international conference East Lonsing, Michigan, USA,

on cyclotrons and their applications. April 1984 F. Marti Eds. cf. also previous conferences of this society.

5.

D. Comar, M. Berridge, B. Maziere and C. Crouzel Radiopharmaceuticals labeled with positron-emitting In Computed Emission Tomography, pp. 42-90 Oxford Press, 1982. Eli and Holman Eds.

6.

Workshop on Or-say, France,

Muller

radioisotopes.

Radiochemistry Methodology and Standardisation March 1985 (sponsored by the E.E.C.).

in

Positron

Emission

Tomography,