3.1 INTRODUCTION

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Chapter 3

Production of Short Half-Life PET Radionuclides

Michael R. Kilbourn, Melissa E. Rodnick and Mara Clark

Department of Radiology, University of Michigan, Ann Arbor, MI, 48109, USA

3.1 INTRODUCTION

The number of positron-emitting radionuclides is remarkably large, with a signicant

number available using cyclotron irradiations of natural or enriched target materials

(Tables3.1 and3.2). However, routine applications of positron emission tomography (PET) imaging in humans has predominantly utilized the four short-lived positron emitters carbon-11, oxygen-15, nitrogen-13, and uorine-18, with growing use of the isotopes rubidium-82 and gallium-68. All six have half-lives under two hours and high theoretical molar activities (radioactivity/mass) (Table3.1). Signicant eorts have been expended in trying to optimize the production of these isotopes via the small

cyclotrons (E < 30 MeV) commonly used for radiopharmaceutical preparation. The cyclotron targets for production and the processing equipment for the isolation and

purication of radionuclides are readily available from commercial vendors, as are the

radionuclide generators for incorporating metal radionuclides into radiopharmaceuticals has resulted in an increasing

demand for a slew of novel positron-emitting isotopes (Table3.2) for use as diagnostic

or theranostic radionuclides for nuclear medicine, with some of them available from

low-energy (<20 MeV) medical cyclotrons[1]. None of the radionuclides in Table3.2 are

pure positron emitters, and the impact of other emissions on their imaging potential

has been reviewed[2]. Examples of the chemistry and applications of these newer PET

Rb and 68Ga. The development of many new methods for

Handbook of Radiopharmaceuticals: Methodology and Applications, Second Edition. Edited by Michael R. Kilbourn and Peter J.H. Scott. © 2021 John Wiley & Sons Ltd. Published 2021 by John Wiley & Sons Ltd.

radionuclides are discussed in later chapters of this handbook. This chapter discusses the production methods for the most commonly used short-lived PET radionuclides, with an emphasis on the methods used with the typical low- to medium-energy (15–30 MeV) cyclotrons used for the production of radiopharmaceuticals for PET imaging studies.

For a more thorough review of all positron-emitting radionuclides, a series of articles by

Qaim is recommended[3–6].

3.2 PRODUCTION OF COMMONLY USED PET

RADIONUCLIDES:

The characteristics of the group of most-used radionuclides (18F, 11C, 13N, 15O, 82Rb,

and

Ga) for human PET imaging studies are shown in Table3.1. The history of use of

positron-emitting isotopes in human studies now spans more than 50 years, but the

applications of these radionuclides in imaging studies have steadily increased, as has

the acceptance and regulatory approval of PET radiopharmaceuticals for use in clinical nuclear medicine. As a result, the nuclear reactions and target materials used to generate

them have in practice been reduced to a small number of well-understood, reliable

production strategies. Of the radionuclides in Table3.1, lives so short (<20 minutes) that their production very close to the site of use (the PET scanner) is required, most often by a cyclotron located very near the PET imaging suite. Fluorine-18, with a nearly two-hour half-life, can be shipped to imaging sites remote from the cyclotron production site. The radionuclides to their access from mother/daughter radionuclide generators[7–9], although recent

developments in direct cyclotron production of

equipment to an available cyclotron facility. The very short half-life of generator to also be placed in close proximity to the PET scanner.

A very thorough discussion of the theory, design, engineering, and operation of

cyclotron targets is available in the free publication from the International Atomic Energy

F, 11C, 13N, 15O, 82Rb, AND 68Ga

C, 13N, and 15O have half-

Rb and 68Ga are widely available due

Ga will require proximity of imaging

Rb requires the

Table 3.1 Com-

monly used radionuclides

forhuman PET

imaging studies.

Radionuclide T

Rubidium-82 1.25 Generator Ox ygen-15 2.03 Cyclotron

Nitrogen-13 9.98 Cyclotron Carbon-11 20.4 Cyclotron Gallium-68 67.71 Generator

Fluorine-18 109.8 Cyclotron

Only the most often used nuclear reaction or radionuclide generator for each is shown.

46 Handbook of Radiopharmaceuticals

(min) Method

1/2

Cyclotron

Max molar

Nuclear reac-

tion

Sr/82Rb 5564

O(p,pn)15O 3394

N(d,n)15O

O(p,α)13N 699.3

N(p,α)11C 341.1

Ge/68Ga 102.3

Zn(p,n)68Ga

O(p,n)18F 63.3

Ne(d,α)18F

activity

(TBq μmol−1)

Radionuclide T

Astatine-77 26 h Bromine-75 1 .6

Bromine-76 1 6 Cobalt-55 17. 6 Copper-61 3 .3

Copper-64 12 .7 Gallium-66 9.5 Iodine-122 3.6 Iodine-124 4 .18

Potassium-38 7.6

Manganese-52 5.6 Rubidium-81 4 .6 Scandium-44 3 .9

Technetium-94m 52 Titanium-45 3. 08 Yttrium-86 14 .7 Zirconium-89 78 .4

h min

min

d h h

min

Production method

Se/77As generator

Se(p,2n)76Br

Se(p,3n)76Br

Se(p,2n)76Br

Fe(p,2n)56Co

Ni(p,n)61Cu

Zn(p,α)61Cu

Ni(p,n)64Cu

Zn(p,n)66Ga

122

Xe/

124

I generator

124

Te( p,n) Te(d,2n)

124

Cl(α,n)35K As(p,3n)35K Cr(3He,t)52Mn Kr(p,2n)82Rb

Ti/44Sc generator

Ca(p,n)44Sc

Mo(p,n)

94m

Sc(p,n)45Ti Sr(p,n)86Y Y(p,n)89Zr

Table 3.2

common cyclotron-produced

PET radionuclides used foranimal or human PET

imaging studies.

Agency[10]. In the following sections are brief descriptions of the methods typically used to produce the common PET radionuclides for present-day radiopharmaceutical preparation.

3.2.1 Fluorine-18

Fluorine-18 (T largely due to the widespread use of the radiopharmaceutical 2-deoxy-2-[ glucose ([18F]FDG) for both research and clinical care. Not surprisingly, the long history of interest in this PET radionuclide encouraged exploration of a variety of methods for its production using both nuclear reactors and particle accelerators (Table3.3), but today it is almost exclusively done using the producing uorine-18 were crucial to the introduction of human PET imaging and remain viable, if seldom used.

[

F]Fluoride ion was rst used for patient studies in the 1960s: the method of

preparation at that time was using the neutron ux of a nuclear reactor to irradiate

powder, yielding [18F]uoride ion from the nuclear reactions 6Li(n,4He)3H and

2CO3

16O(3

H,n)18F[11]. The [18F]uoride ion from reactors was used for the original synthesis

of 5-[

F]uoroDOPA in 1973[12]. [18F]Fluoride ion was also obtained at cyclotron

=109.8 minutes) is the single most-used PET radionuclide in the world,

1/2

O(p,n)18F reaction. However, other methods of

F-labeled compounds into

F]uoro-d-

Chapter 3: Production of Short Half-Life PET Radionuclides 47

Inlet/Outlet

Foil

Table 3.3 Nuclear

reactions used

forcyclotron

production

ofuorine-18.

Particle energy

Nuclear reaction

Ne(d,4He)18F 0 –15

16O(3

He,p)18F 1–15

18O(p,n)

16O(4

16O(3

16O(4

Li(n,4He)3H, 16O(3H,n)18F Reactor

F 4–14

Ne(3He,4He p)18F 10–40

He,np)18Ne: 18F 10–52 He,n)18Ne: 18F 15– 40 He,np)18F 20–40

Ne(p,2pn)18F 30–40

range (MeV)

installations by using large-volume (10–15 ml) water targets and the 16O(α,np)18F reaction[13]. At present, [

F]uoride ion used for clinical PET studies (bone imaging) and

radiopharmaceutical syntheses is most eciently produced using the proton irradiation

of [

O]water targets. This choice is a combination of the much higher yields obtained

with the

radiochemistry using [

O(p,n)18F reaction[14] and the ever-increasing diversity of methods for

F]uoride[15–17].

The proton irradiation of small-volume oxygen-18 enriched water targets yields

aqueous solutions of [

for subsequent syntheses to form useful

F]uoride ion, the chemical form of the radionuclide most useful

F radiopharmaceuticals. The design of such

targets has not really changed from that reported years ago[18, 19]: either a small-

volume cavity is created by machining a cavity into a solid metal target and covered with

a thin metal foil (Figure3.1) or, alternatively, a double-foil design with a central spacer is used to create the target volume[20, 21]. Ports into the cavity allow the introduction and removal of the target water, as well as the potential for pressurization (often used to minimize cavitation during beam irradiation). The target is then lled with enriched

[

O]water (usually less than 3 ml to conserve the enriched water) and irradiated with

Figure 3.1 Sche-

matic diagram of

Ta rget

Vent

a small-volume water target.

rticle

Beam

Beam Line

Flange

Ta rget Water

48 Handbook of Radiopharmaceuticals

Ta rget Wate

Cavity

Cooling

water

protons: the cross-section for the nuclear reaction is in the 2–15 MeV range, which is easily reached by low-energy cyclotrons. Water targets having many dierent cavity sizes and shapes have been utilized with various metal compositions, among them Ag, Ti, Nb, Ta, and Au[18–26]. Although the conceptual design of a small-volume [

O]water target was quite simple, extensive eorts to improve these targets were expended to achieve three goals: (i) improve the chemical reactivity of the [

F]uoride from [18O]water targets by decreasing ionic impurities; (ii) increase yields from such targets, important for the development of distribution systems for the uorine-18 radiopharmaceuticals and in particular [

F]FDG; and (iii) improve molar activities (radioactivity/mass) of [18F]uoride

for use in syntheses of organic radiopharmaceuticals.

The particle irradiation of [

O]water targets produces metal ions in the water, with both nonradioactive and radioactive ions present at the end of bombardment. The target body and foil are potential metallic ion sources, and much eort was spent in understanding the impact of the foil material. For example, many targets were initially equipped with Havar foils, an alloy with high tensile strength and a high melting point. It is an alloy of eight metals (Co, Cr, Ni, W, Mb, Mn, Be, and Fe), and numerous long-lived radioactive species (isotopes of Ni, Co, Mn, Cu, and Cd) have been observed in protonirradiated water[18, 27]. Lower concentrations of metal ion impurities were found by replacing Havar with materials such as silver, titanium, or niobium[20]: using Nb, Pt, Ta, Ti, or Zr-sputtered Havar foils provided a better inert surface with the tensile strength of the Havar foil[28]. The potential for the target body being a source of metal ions in solution can be minimized by target designs that reduce or eliminate the proportion of the particle beam hitting the rear metal surface of the target cavity.

The formation of anionic contaminants of proton-irradiated [

O]water has been

less well studied, but the presence of nitrate, nitric, and chloride ions at concentrations

3–20 times that of the uoride ion have been reported[29]. The impact of such anions on subsequent radiochemical syntheses has also not been fully examined, but with the development of better methods for uorine-18 radiochemistry, the impact of both anion and metal ion contaminants on the reactivity of the [

F]uoride ion from water targets

has been minimized. The processes used for radiochemical syntheses of, for example,

[

F]FDG also eectively remove the trace amounts of the metallic radioisotopes[30].

The increasing importance of [

F]FDG in clinical medicine undoubtedly was the

stimulus in the development of target systems capable of producing very large amounts

of [

F]uoride ion, a necessary step for the widespread geographic distribution of

[

F]FDG. The high-level production has been addressed in target design by modications

of target materials, foil composition and thickness, target thickness, particle beam

prole, and/or target cooling and over-pressurization. Those eorts achieved [

O]water targets capable of withstanding high-beam currents (80–150 μA)[31] with a report of production of as much as 1 TBq of [

In contrast to the need to produce such high quantities of [

F]uoride ion using dual-target irradiations.

F]uoride ion, which is not necessary for non-commercial uses (most hospital-based research or clinical PET imaging programs), the molar activity of all users. The theoretical maximum molar activity for uorine-18 is 63.3 TBq μmol

F obtained from [18O]water targets is very important to

−1

, but

Chapter 3: Production of Short Half-Life PET Radionuclides 49

that has not yet been reported for [18F]uoride from any cyclotron target. The metals of the targets and foils, and the [

O]water used as target material, are likely not the source of signicant carrier uoride ions, but numerous studies have identied that using uorinated tubing, valves, and ttings resulted in measurable dilutions of the molar activity[32, 33]. A particularly poor early choice of materials was Teon (polytetrauoroethane [PTFE]). The elimination of any target components constructed with uorine-containing polymers, and the use of, for example, polypropylene or polyether ether ketone (PEEK) plastic lines for the lling and emptying of the target, signicantly improves the molar activity for

[

F]uoride with reported values as high as 43 TBq μmol−1[34], although routine molar

activities are probably in the 2–10 TBq μmol

The production of

F can also be done using an [18O]O2 gas target. The interest in this

−1

range.

target design was mostly as an option to the production of the radionuclide in neon gas

targets (discussed shortly) for the formation of

F-labeled uorine gas. As with water targets, a variety of metal surfaces were investigated (Ni, Al, Ag, Au, Cu), with the best result using aluminum targets. Upon irradiation of

the

F is found attached to the inner target surface (chemical species undened).

Removal of the gas content allows recovery of the enriched

re-lling with a 1% F produces [

F]F2, which can then be swept out of the target with an inert gas ow. This procedure produces [ activities (<1000 GBq mmol

Before the advent of the small-volume [

in krypton gas mixture followed by a short proton irradiation

F]F2 in a necessarily carrier-added fashion, with much lower molar

−1

)[35].

O-enriched oxygen gas with protons,

O-oxygen, and subsequent

O]water targets, most of the production of uorine-18 for radiopharmaceutical chemistry was done using the deuteron irradiation of neon-20 gas targets (

Ne(d,α)18F nuclear reaction). The major interest in these targets was the production of uorine-18 labeled uorine gas for use in electrophilic uorination reactions, an important need (at the time) for the syntheses of such important radiopharmaceuticals as [ radiopharmaceuticals can be made in much higher yields from [

F]FDG and 6-[18F]uoroDOPA: today, both of these

F]uoride ion. The deuteron irradiation of a gas target lled with neon-20 containing a trace amount (0.1%) of uorine gas produces carrier-added [

F]F2 suitable for radiochemical syntheses. A

variety of metal target materials, target gas compositions, and irradiation conditions

were explored in attempts to improve yields and increase the yields and molar activities

of the [

F]F2 produced[36–38], but the best results were obtained with nickel, Inconel (Ni-Cr alloy), and aluminum target materials. The targets were routinely passivated with cold uorine gas to improve recovery of the radionuclide, but that also resulted in the formation of low-molar-activity, carrier-added [

The neon gas targets can also be used to provide

F]F and [18F]uoride ion. Irradiation of a hydrogen-neon gas mixture produces [18F]HF,

F]uorine gas.

F in two other chemical forms:

and the product can be swept out of the target using a recirculating gas system[39, 40] or after irradiation by heating the target (>370 °C)[40] and using a gas purge: the [

F]HF is trapped at low temperature or by, for example, solid-supported cesium hydroxide. When done in targets that have not been passivated with cold uorine gas (in contrast to targets intended for [

F]F2 production), such H[18F]targets can yield very high molar activity 18F for

50 Handbook of Radiopharmaceuticals

radiochemical syntheses, as exemplied in the synthesis of [18F]uoroethanol with a value

Foil

Flange

ooling

of 4.6 TBq μmol

−1

[41]. The production of aqueous [18F]uoride ion from a neon target is also possible: irradiation is done using a neon gas target that is constructed such that the uorine-18 that is “stuck” on the inner target surface at the end of irradiation can be removed by washing with a small volume (e.g. 4.5 ml) of water. This method of aqueous [ production may produce fewer metal ion impurities compared to a [

O]water target, but it

F]uoride ion

also requires much longer beam times to produce far less radionuclide.

3.2.2 Carbon-11

The 20.4 minute half-life radionuclide carbon-11 can be produced by nuclear reactions using cyclotron-produced proton, deuteron, or helium-3 beams (Table3.4), but the

common method for producing this isotope for radiopharmaceutical syntheses uses

the

N(p,α)11C nuclear reaction and irradiation of a nitrogen gas target[42]. The

design for

congurations[42, 43]: a metal cylinder is tted with a thin metal foil at one end to allow

entry of the irradiating protons, a cooling system to remove heat from the target body,

a gas cooling ow for the entry window, and ports for pressurization of the cylinder

with the desired target gas and post-irradiation removal of the irradiated gas (a simple diagram of a typical

is aluminum, but targets take many dierent shapes and sizes depending on the energy of the proton beam, the beam current, and the desired length of irradiation. Targets

C gas targets is conceptually simple and has not changed much from early

C gas target is shown in Figure3.2). A common target body material

rticle

Beam

Beam Line

Particle energy

Nuclear reaction

B(d,n)11C 3–12

B(p,n)11C 5–20

N(p,α)11C 7–15

12(3

He,4He)11C 7–15

(d,n4He)11C 10–15

C(p,pn)11C 20–50

Inlet Outlet

range (MeV)

Water

Table 3.4

Nuclear

reactions used

forcyclotron

production

ofcarbon-11.

Figure 3.2 Sche-

matic diagram

of a carbon-11

gas target.

Chapter 3: Production of Short Half-Life PET Radionuclides 51

are operated at high pressure to provide sucient gas density to allow the use of the

entire cross-section for the

N(p,α)11C reaction (5–20 MeV) available to typical low-energy

(<30 MeV) cyclotrons.

Two forms of carbon-11 are readily available from nitrogen gas targets. In the

presence of a trace amount of oxygen, the product from irradiation is [

C]carbon dioxide, which can be simply trapped upon release of the target gas and then used directly for radiochemical syntheses. Under reducing conditions, done via the proton irradiation of nitrogen-hydrogen gas mixtures, the product obtained is [ 44, 45] which can also be trapped after the release of the target gas. Both [

and [

C]CH4 can be converted using rapid online systems to a variety of useful single-

carbon reagents including [

[

C]formaldehyde, [11C]phosgene, [11C]cyanide ion, or [11C]uoroform[17, 45, 46].

Both the [

C]CO2 and [11C]CH4 targets produce sucient amounts of radioactivity

C]CO, [11C]methyl iodide, [11C]methyl triate, [11C]methanol,

C]methane[42,

C]CO2

(>74 GBq) for radiopharmaceutical syntheses, and thus most of the eort over the years has been devoted to improving the molar activity (radioactivity/mass) of the nished

radiopharmaceuticals. The general design of targets has not changed. However, to obtain

high molar activities, close attention must be paid to the quality of target gas materials

(typically, using nitrogen gas of 99.9999% purity) and using materials and connection ttings that minimize the possibility of dilution of the molar activity by environmental carbon dioxide. To obtain ultra-high specic-activity

C-labeled radiopharmaceuticals

from the subsequent radiochemical synthesis step, the target system needs to be coupled with a radiochemical synthesis system that has also been rigorously designed

and maintained to prevent unintentional addition of carbon-12. A few institutions have devoted the time and resources to building such systems using either [

[

C]CH4 targets, and molar activities of radiochemicals with specic activities in the

4–20 TBq μmol

−1

have been reported[47, 48]. It is likely, however, that commercially

C]CO2 or

available carbon-11 target systems and synthesis systems are not routinely operated to produce radionuclide with molar activities matching these select few examples: molar

activities of

in the range of 400–4000 GBq μmol

C radiopharmaceuticals typically used for human PET studies are more often

−1

3.2.3 Nitrogen-13

The formation of nitrogen-13 (T Curie demonstrated the a variety of additional nuclear reactions (Table3.5), but the predominant method used currently for nitrogen-13 production for radiopharmaceuticals is via the on ordinary [ cases, identical to those used for F-18 production, except that larger volumes might be used as the target material is obviously of essentially no cost. A small-volume water target, such as that shown in Figure3.1, for example, can be used for both

The chemical form of nitrogen-13 from

oxides ([

52 Handbook of Radiopharmaceuticals

O]water. The water targets used for N-13 production are similar or, in many

N]NOx) and [13N]NH3[49], which is not particularly useful. However, they can

=9.98 minutes) dates back to 1934 when Joliot and

1/2

B(α,n)13N nuclear reaction[48]. Nitrogen-13 can be produced by

O(p,α)13Ν reaction

F and 13N production.

O-water is mostly a mixture of nitrogen

Particle energy

Nuclear reaction

C(p,n)13N 1–6

10B(4

H,n)13N 4–6

C(p,n)13N 4–9

11B(4

He,2n)13N 6–10

O(p,4He)13N 8–15

N(p,pn)13N 14 –30

range (MeV)

be rapidly reduced by chemical means (DeVarda’s alloy) to form the useful species

[

N]ammonia, which in itself is used as a radiopharmaceutical (cardiac blood ow

imaging) or as a synthetic precursor (e.g. amino acid syntheses). As an alternative,

[

N]NH3 can be formed by in-target methods, using either over-pressurization of the water target with hydrogen or methane gas[50] or the irradiation of water containing a small amount of ethanol[49]. The nitrogen-13 from water targets can also be processed into such small chemical species as nitric oxide or molecular nitrogen, both used for in vivo ventilation studies. The production of nitrogen-13 in water targets is subject to the

same concerns for contamination by metallic radionuclides as discussed for

O-water

targets. In those instances where the radioactivity is volatized, such as during DeVarda alloy reduction and distillation of [

N]NH3 or conversion to a volatile gas ([13N]N2, [13N]

NO), metal ions are of no further concern. However, when in-target production methods

of [

N]ammonia are employed, removal of the metal ions by select ion-exchange col-

umns may be necessary.

The production of nitrogen-13 is also possible using several other nuclear reactions (Table3.5) and used to prepare [ years. Interestingly, the formation of [

proton irradiation of nitrogen (

N]NH3, but none of them are routinely used in recent

N]N2 occurs simultaneously during a typical

N(p,n)13N) for production of carbon-11 but is discarded

during the subsequent processing and synthesis steps; if desired, it can be isolated and

puried for independent use[51].

Most reports of nitrogen-13 production and use did not address, and in many cases did not even report, the molar activity for the radionuclide. This was due to little interest in it when nitrogen-13 was used to prepare such radiolabeled compounds as [

or [

N]amino acids, where molar activity is not important for in vivo biological studies.

N]ammonia

However, if an attempt is made to carefully exclude sources of nitrogen-15, then molar activities as high as 6200 GBq mmol

−1

have been reported, making the 13N potentially

useful for the syntheses of radiopharmaceuticals (e.g. receptor ligands) that require such high values.

Table 3.5

Nuc

reactions used

forcyclotron

production

nitrogen-13.

lear

3.2.4 Oxygen-15

Oxygen-15 is a very short-lived radionuclide (T nuclear reactions for production (Table3.6). When made using a low-energy cyclotron

Chapter 3: Production of Short Half-Life PET Radionuclides 53

=2.04 minutes) with a few potential

1/2

Table 3.6

Nuc

reactions used

forcyclotron

production

ofoxygen-15.

lear

Particle energy

Nuclear reaction

N(d,n)15O 2–10

N(p,n)15O 4–10

12C(4

He,n)15O 12–18

O(p,pn)15O 20–26.5

range (MeV)

(E < 20 MeV), this is done by deuteron irradiation of nitrogen gas containing a small amount (1%) of oxygen (

[

O]O2 obtained to other small molecules ([15O]CO2, [15O]CO, [15O]H2O) is done using

N(d,n)15O nuclear reaction)[52, 54]. Rapid conversions of the

ow-through processing systems (e.g. furnaces, lters, traps)[53]. An example of the incorporation of oxygen-15 into an organic molecule is the reaction of [ organoborane[54] to form [

O]butanol, an alternative to [11C]butanol that had been

O]O2 with an

previously introduced as a blood ow agent.

When a higher-energy cyclotron (>25 MeV) is available, oxygen-15 can also be

produced by proton irradiation of oxygen-16 gas or water using the

O(p,pn)15O nuclear

reaction (the cross-section starts at 15 MeV and is very high at >20 MeV). Water targets

are constructed in a similar fashion to that used for volume is not restricted as the target material is of no cost (

activity of the [

O]water formed is of no consequence. The high yields of this nuclear

reaction were particularly useful for the rapid sequential production of [

N or 18F production, except that the

O-water) and the molar

O]H2O for brain activation PET studies[55]. The short half-life of oxygen-15 places severe restraints on its use, as the cyclotron production system must be located very close to the PET scanner[56] or a very fast and ecient transfer system must be employed.

3.2.5 Tandem Targets andDual-Use targets

A wide variety of cyclotrons have been utilized for the production of the common PET

radionuclides

often include the ability to perform dual-target irradiations. That makes feasible the simultaneous production of two dierent radionuclides for independent uses.

In past years, simultaneous dual-isotope production was simply not possible as only

single external beamlines were available: the best that was done was rapid sequential production of two isotopes through the use of target-switching systems or the utilization of a single target for production of more than one radionuclide. As examples of the

latter approach, small-volume water targets can obviously be used for either production depending on the target material loaded ( and a gas target can be employed for the production of two radionuclides as done for

oxygen-15 ( also worked best when changing particles (e.g. protons to deuterons) was not necessary, as that often required a time delay.

54 Handbook of Radiopharmaceuticals

C, 18F, 15O, and 13N, and low-energy medical cyclotrons currently available

O(p,n)15O) and uorine-18 (20Ne(p,2pn)18F)[57]. Target-switching or dual use

N or 18F

O- or 18O-water, respectively),

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