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,