Ojima I. (ed.) Fluorine in Medicinal Chemistry and Chemical Biology

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358 Fluorine in Medicinal Chemistry and Chemical Biology

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Fluorine - 18 Radiopharmaceuticals

Michael R. Kilbourn and Xia Shao

14.1 Introduction

PET (positron emission tomography) is a powerful in vivo imaging technique capable of

providing dynamic information on biochemical processes in the living human subject.

Applications of PET in oncology, neurology, psychiatry, cardiology, and other medical

specialties continue to grow each year, and this modern imaging technique has become an

important part of medical care. PET has also emerged as an important tool in drug research

and development, where it is increasingly used to measure pharmacokinetics and pharma-

codynamics. The use of PET is driven by the characteristics and availability of appropri-

ately labeled radiopharmaceuticals that are speciﬁ cally designed for measurement of

targeted biochemical processes. Of the handful of positron - emitting radionuclides that

have been utilized for PET imaging, ﬂ uorine - 18 has particularly appealing properties.

Addition of a ﬂ uorine atom to a large molecule can often (but not always) be accomplished

without signiﬁ cant changes to the physiochemical or biological properties of the com-

pound. Fluorine - 18 is a positron - emitting radionuclide (97% positron emission, 0.635 MeV

maximum energy, mean range 2.39 mm in water) with a relatively long half - life (109.6 min)

compared to the other often - used positron - emitting radionuclides (e.g., carbon - 11, 20.4 min;

nitrogen - 13, 9.96 min; oxygen - 15, 2 min). The half - life permits both longer synthesis times

(typically 1 – 2 half - lives, or nearly 4 hours), thus opening up possibilities for multistep

radiolabeling procedures, as well as the option of preparation of the radiopharmaceutical

at a location remote from the site of use.

A large number of

F - labeled organic molecules have now been synthesized, ranging

from the simplest ([

F]ﬂ uoromethane) to quite large (radiolabeled proteins). A thorough

review of compounds that have now been synthesized in ﬂ uorine - 18 form is impossible.

Fluorine in Medicinal Chemistry and Chemical Biology Edited by Iwao Ojima

362 Fluorine in Medicinal Chemistry and Chemical Biology

In 1982, a comprehensive review by Fowler and Wolf listed 88 ﬂ uorine - 18 radiochemicals

[1] ; by 1990, a subsequent review [2] had listed over 280 compounds in a similar table,

and although there are no more recent attempts to compile a comprehensive listing of such

radiochemicals, at the most recent International Symposium on Radiopharmaceutical

Chemistry, there were over 140 individual abstracts involving ﬂ uorine - 18 alone [3] , indica-

tive of the continued growth in the ﬁ eld of ﬂ uorine - 18 radiochemistry. A few recent

reviews are available for ﬂ uorine - 18 radiopharmaceuticals [4 – 9] , and the reader is directed

to modern literature - searching methods to obtain a more complete listing of currently

available radiochemicals.

The labeling methods for

F - ﬂ uorination reactions, described in the following sec-

tions, have been continuously expanded and improved upon through the years, leading to

the proliferation of useful new

F - labeled compounds for in vivo studies of biochemistry

in animals and humans. A few

F - labeled radiochemicals will be presented as examples

of the issues involved in their design and synthesis. Due to the growing importance of

PET, and the unrelenting need for new and better radiopharmaceuticals, continued devel-

opment of new and improved methods for

F - labeling has been pursued and some of the

most recent developments in that area will also be reviewed.

14.2 Fluorine - 18 Chemistry

14.2.1 General Considerations

Fluorine - 18 is a short - lived (109.6 min) radionuclide that has to be generated anew for

each synthesis. Production of the radionuclide is these days almost exclusively by the use

of a small cyclotron (typical energies of 11 – 30 MeV for protons), a particle accelerator

which can often be accommodated within a medical center or other research facility,

although the concept of producing and shipping the radionuclide to distant sites for use in

radiochemical syntheses has been accomplished. The majority of ﬂ uorine - 18 is produced

via the proton irradiation of an oxygen - 18 - enriched water target (

O(p,n)

F) with the

radionuclide product obtained as [

F]ﬂ uoride ion in aqueous solution. A variety of rapid

and sometimes ingenious means have been developed to convert the aqueous [

F]ﬂ uoride

ion to both reactive nucleophilic ﬂ uoride (usually in an organic solvent; but see recent

developments described below) or electrophilic ﬂ uorination reagents. Fluorine - 18 can be

generated by a number of other nuclear reactions (Table 14.1 ), and radiolabeled ﬂ uorine

gas ([

F]F

) is generated directly in gas cyclotron targets, but these methods are of less

utility in the ﬁ eld of ﬂ uorine - 18 radiochemistry.

For the synthesis of high - speciﬁ c - activity radiopharmaceuticals (speciﬁ c activity is

deﬁ ned as radioactivity per unit mass) the use of [

F]ﬂ uoride ion is preferred if not

required. The theoretical speciﬁ c activity for ﬂ uorine - 18 is 1.71 × 10

Ci/mol, but that

value has never been achieved and in practice the speciﬁ c activity of

F - labeled radio-

chemicals has been signiﬁ cantly lower. Typically, ﬁ nished radiochemicals are produced

with speciﬁ c activities in the 1000 – 10 000 Ci/mmol. Some of this difference has

been attributed to physical dilution of the ﬂ uorine - 18 by the presence of ﬂ uorine - 19 in

Fluorine-18 Radiopharmaceuticals 363

reagents and equipment (e.g., glassware); in other instances the lower speciﬁ c activities

may better represent the ability of analytical methods such as high - pressure liquid chro-

matography (HPLC) to identify and quantify cold mass associated with a radiochemical

product peak. Thus, the production of true “ carrier - free ” ﬂ uorine - 18 radiopharmaceuticals

has not been achieved, but in current practice speciﬁ c activities of 1000 – 10 000 Ci/mol

(37 – 370 GBq/mmol) are routinely achieved, and such speciﬁ c activities are suitable for

even the most demanding in vivo applications of the radiolabeled compounds.

The availability of ﬂ uorine - 18 from high yield oxygen - 18 - enriched cyclotron water

targets, the development of automated or remotely controlled synthesis apparatus capable

of yielding hundreds of milliCuries to Curies of products, and the desire to produce new

radiopharmaceuticals with the potential for widespread (and even commercial) distribution

from the point of synthesis has resulted in a problem not often seen in earlier days of ﬂ uo-

rine - 18 chemistry: radiolytic decomposition. Syntheses can now be done using multi -

Curie amounts of the radionuclide, often in small reaction volumes (commonly several

hundred microliters of solvent, but sometimes even much lower than that), resulting in

very high rates of irradiation of chemical components by both the positrons and the

511 keV gamma rays produced by their annihilation. Yields and radiochemical purities

of reactions runs using low amounts of radionuclide, as is commonly done in development

of new radiotracers, may not necessarily translate into high - level production runs.

Radiolytic decomposition can also occur when high amounts (levels of several hundreds

of milliCuries) of ﬁ nal products are formulated for injection, leading to the need in

many cases to add an antioxidant or free - radical scavenger, such as ethanol or ascorbic

acid, to the formulation to reduce decomposition of the radiochemical. This represents a

unique problem not encountered in the usual use of ﬂ uorine in medicinal or bioorganic

chemistry.

In the following sections are examples of typical methods for

F - ﬂ uorination using

nucleophilic and electrophilic reaction mechanisms, with selected examples of their use

in preparation of PET radiopharmaceuticals.

14.2.2 Radiochemistry: Yields and Speciﬁ c Activities

In the ﬁ eld of radiochemistry, and particularly with the use of high - speciﬁ c - activity radio-

nuclides, syntheses are almost uniformly done with an excess of unlabeled precursor and

reagents with respect to the radionuclide, in this review ﬂ uorine - 18. For that reason the

efﬁ ciencies of reactions are generally given in terms of radiochemical yields instead of

Table 14.1 Nuclear reactions used to produce ﬂ uorine - 18

Ne(d, α )

Ne(p,2n)

He,p)

O( α ,pn)

O(p,n)

Ne(

He,n)

Ne,

Ne -

364 Fluorine in Medicinal Chemistry and Chemical Biology

chemical yields. However, radiochemical yields in the literature are deﬁ ned in many

different ways: as ﬁ nal product (amount of radioactive product) divided by the amount of

radioactivity produced in the cyclotron target; as that perhaps rendered reactive by an

intermediate preparation in the solvent of choice (e.g., preparing [

F]ﬂ uoride ion in

organic solvent); or even relative to a small - molecule intermediate prepared for the radio-

labeling reaction (e.g., yields based on electrophilic ﬂ uorination reagents prepared from

the product from the cyclotron target, [

F]ﬂ uorine gas or [

F]ﬂ uoride ion). Furthermore,

radiochemical yields can be expressed either decay - corrected or without decay correction,

depending on whether the investigator chooses to correct the yield for the time of synthesis.

Because radiochemical yields can be expressed in so many different ways, and certainly

are in the literature, in this review yields will not be routinely discussed unless they are

signiﬁ cantly higher (or lower) than usually found, or where a single publication has

reported multiple yields all calculated the same way such that comparisons can be properly

made.

In the synthesis of ﬂ uorine - 18 radiochemicals an important attribute of the ﬁ nal

product is also the measured speciﬁ c activity. Unfortunately, the literature is also replete

with different means of estimating or measuring speciﬁ c activity. The majority of ﬂ uorine -

18 radiochemicals are today analyzed by some means of chromatography, such as gas or

high - pressure liquid chromatography, leading to a speciﬁ c activity measurement relating

the observed mass in the chromatographic spectrum (often UV absorbance) relative to

injection of standard solutions of known mass. Speciﬁ c activity measurements can thus

vary between investigators, for reasons relating to the quality of the radionuclide used in

the synthesis but also depending on the precision and accuracy of the chromatographic

analyses. In this review there are general discussions of the importance of no - carrier - added

versus carrier - added ﬂ uorine - 18 radiochemical syntheses: with a few exceptions, most

radiopharmaceuticals are best if prepared in no - carrier - added form, which does not mean

they are free of the presence of any ﬂ uorine - 19 but simply that no cold carrier ﬂ uorine

has been deliberately added either during the generation of the radionuclide or during the

radiochemical synthesis.

14.3 Nucleophilic

F - ﬂ uorination: General Aspects

By far the majority of ﬂ uorine - 18 radiotracers are synthesized using some type of nucleo-

philic ﬂ uorination reaction. As ﬂ uorine - 18 is most widely produced by cyclotrons as an

aqueous solution of [

F]ﬂ uoride ion, considerable effort was expended in the development

of rapid methods to convert this to a source of reactive [

F]ﬂ uoride in organic solvents

appropriate for subsequent radiochemical syntheses. This was accomplished by removal

of water, most often by azeotropic evaporation in the presence of a cationic counterion;

to enhance solubility of metallic cation – ﬂ uoride ion salts, often a cryptand is included,

with the most popular pairing being the aminopolyether 8 - crown - 6 (Kryptoﬁ x) and potas-

sium ions [10] . Other metal salts such as cesium and rubidium salts, or organic cations

such as tetraalkylammonium salts, have been employed as alternatives. Finally, [

F]ﬂ uoride

ion can be efﬁ ciently trapped on anion exchange resins, which can be directly used for

on - column nucleophilic reactions [11] . In general the reactions using [

F]ﬂ uoride ion are

Fluorine-18 Radiopharmaceuticals 365

conducted in aprotic dipolar organic solvents, such as dimethyl sulfoxide or acetonitrile,

although recently a novel solvent system has been applied (see Section 14.5 ).

14.3.1 2 - [

F ]Fluoro - 2 - deoxy - d - glucose: Two - step Aliphatic

Nucleophilic Substitution

For both basic science animal research, clinical medical research, and clinical medical

care, 2 - [

F]ﬂ uoro - 2 - deoxy - d - glucose ([

F]FDG) is the single most used PET radiophar-

maceutical in the world. As an analogue of glucose, the major energy source of biological

systems, it has found applications in nearly every area of nuclear medicine imaging, with

exceptionally widespread application in imaging of the location and characterization

of tumors.

The synthesis of [

F]FDG has been very well developed and reﬁ ned since its intro-

duction by Ido and co - workers in 1978 [12] . Whereas the original synthesis of [

F]FDG

was done using electrophilic ﬂ uorination of an alkene precursor, yields were limited

by the maximum 50% possible from an electrophilic reagent (see later discussion on

electrophilic

F - ﬂ uorinations), and much higher - yield nucleophilic ﬂ uorination methods

were subsequently developed [13] and have been adopted by virtually every investigator

at present.

The commonly used synthesis of [

F]FDG (Figure 14.1 ) involves two steps: reaction

of [

F]ﬂ uoride ion with an appropriately substituted mannose derivative, followed by

removal of the hydroxyl - protecting groups. Use of the tetraacetate esters of the hydroxyl

groups, present in the sugar structure but also found in the hydroxyl or amino groups of

many compounds of interest for radiolabeling with ﬂ uorine - 18, is sometimes necessary

as otherwise the reactive [

F]ﬂ uoride ion acts as a strong base to extract the acidic

hydrogen to form H[

F]F, and prevents reaction of the [

F]ﬂ uoride ion in a nucleophilic

reaction. As nucleophilic ﬂ uorination to displace the 2 - triﬂ ate leaving group proceeds

Figure 14.1 Synthesis of 2 - [

F]ﬂ uoro - 2 - deoxy - D - glucose ([

F]FDG) using two - step proce-

dure of nucleophilic substitution of [

F]ﬂ uoride ion for a triﬂ ate ester leaving group followed

by base - catalyzed hydrolysis of acetyl protecting groups.

366 Fluorine in Medicinal Chemistry and Chemical Biology

by inversion of stereochemistry at the C - 2 carbon center, a suitably protected mannose

precursor rather than one derived from glucose itself becomes the substrate. Although

syntheses using different cationic counterions and even solid - phase supported

F -

ﬂ uorinations have been applied to [

F]FDG syntheses, the state of the art utilizes the

potassium ion/Kryptoﬁ x in acetonitrile system for

F - ﬂ uorination followed by acid or base

hydrolysis of the protecting groups (base hydrolysis has been found to be faster and

milder). The synthesis of [

F]FDG is so well worked out, and so reliable, that relatively

simple entirely computer - controlled automatic apparatus is marketed for the production

of this important radiopharmaceutical. Puriﬁ cation of the ﬁ nal product is accomplished

using a series of disposable bonded - phase chromatographic columns, neutralization of the

base with an appropriate buffer solution, and sterilization; automated equipment to make

[

F]FDG is now available which produces the radiopharmaceutical in high yields ( > 60%

corrected for decay) and overall synthesis times of less than 26 minutes (starting from end

of cyclotron target irradiation). [

F]FDG is clearly the most reﬁ ned ﬂ uorine - 18 synthesis

yet developed.

14.3.2 [

F ]Fluoropropyldihydrotetrabenazine ( FP - DTBZ ): One - step Aliphatic

Nucleophilic Substitution

For the in vivo imaging of the vesicular monoamine transporter type 2 (VMAT2), a mono-

amine - neuron speciﬁ c protein in the brain and other organs, the clinically used drug tet-

rabenazine and several derivatives were labeled with carbon - 11 leading to a ﬁ nal widely

used radiopharmaceutical, (+) - α - [

C]dihydrotetrabenazine (DTBZ) [14] , which is in fact

a single enantiomer (tetrabenazine is used clinically as a racemic mixture) of the predomi-

nant metabolite of tetrabenazine formed in the human body. Numerous studies have uti-

lized this radiopharmaceutical in a variety of neurological and psychiatric diseases [15] .

Although useful, the 20 - minute half - life of the radionuclide carbon - 11 signiﬁ cantly limited

the application of this radiopharmaceutical to institutions possessing an on - site cyclotron

and radiochemistry expertise in carbon - 11 syntheses. The development of [

F]ﬂ uoro-

propyldihydrotetrabenazine ([

F]FP - DTBZ) represents an excellent example of how a

F - labeled alternative can be readily designed and implemented by building on the carbon -

11 experience. [

F]FP - DTBZ also represents an example of a radiopharmaceutical that

can be prepared in a single step but which requires much more effort in puriﬁ cation and

quality control.

As the in vivo imaging application of [

F]FP - DTBZ requires a high - speciﬁ c - activity

radiopharmaceutical, due to the limited capacity of the high - afﬁ nity VMAT2 binding sites

in the brain, a synthesis starting with [

F]ﬂ uoride ion was deemed necessary. The stereo-

chemical requirements of the ligand had been evaluated in the syntheses of the carbon - 11

radiopharmaceuticals, and thus a straightforward synthesis of 9 - O - ﬂ uoroalkyl derivatives

of (+) - α - 9 - desmethyldihydrotetrabenazine provided high - afﬁ nity radioligands with excel-

lent in vitro properties and with binding afﬁ nities equal to or better than the parent tetra-

benazine [16, 17] . Radiolabeling of the ﬂ uoroalkyl groups could then be readily achieved

by a one - step aliphatic nucleophilic substitution, with [

F]ﬂ uoride ion substitution of a

mesylate ester leaving group (Figure 14.2 ). Puriﬁ cation of the desired [

F]ﬂ uoroalkyl -

DTBZ requires application of high - pressure liquid chromatography (HPLC) to effectively

Fluorine-18 Radiopharmaceuticals 367

remove unreacted mesylate precursor as well as any hydroxyl derivative formed by hydro-

lysis of the sulfonate ester. There are actually few radiochemical impurities in many simple

nucleophilic

F - ﬂ uorination reactions: the unreacted [

F]ﬂ uoride ion is often rapidly

removed using relatively simple column chromatography (bonded - phase chromatography,

such as Sep - Paks) and the HPLC puriﬁ cation is mostly necessary to obtain the required

chemical purity. The radiolabeling strategy for [

F]FP - DTBZ is an example of that used

for many ﬂ uorine - 18 radiopharmaceuticals and utilizes the displacement of a sulfate ester

(mesylate, tosylate) group by [

F]ﬂ uoride ion. Interestingly, this is an example where the

free hydroxyl group in the molecule did not have to be protected as an ester or ether to

allow reactivity of the [

F]ﬂ uoride ion with the mesylate leaving group. Syntheses of

radiopharmaceuticals incorporating [

F]ﬂ uoroalkyl groups have mostly been limited to

[

F]ﬂ uoromethyl, [

F]ﬂ uoroethyl and [

F]ﬂ uoropropyl groups, likely due to the increas-

ing lipophilicity of longer alkyl chains, which can lead to undesired in vivo

pharmacokinetics.

[

F]FP - DTBZ is an example of a

F - labeled radiopharmaceutical where high speciﬁ c

activity is a requirement because of the limited capacity of the in vivo binding site, and

the desire for any in vivo radiotracer to occupy a negligible number of such sites. For other

radiopharmaceuticals, the need for high speciﬁ c activity is not only rooted in this desire

for minimal occupancy but is also due to potential unwanted pharmacological or toxico-

logical effects of the higher masses of radioligand if administered at a low speciﬁ c activity.

This is exempliﬁ ed by such radiotracers as [

F]ﬂ uoroethoxybenzovesamicol [18] and

F - labeled nicotinic acetylcholinergic receptor agonists [19 – 22] , two classes of com-

pounds with signiﬁ cant peripheral pharmacological effects that severely limit the allowed

Figure 14.2 Synthesis of 9 - (3 - [

F]ﬂ uoropropyl) - 9 - desmethyl - (+) - ( α ) - dihydrotetrabenazine

([

F]FP - DTBZ) by a single - step nucleophilic aliphatic substitution of a mesylate ester leaving

group.

368 Fluorine in Medicinal Chemistry and Chemical Biology

administered mass of compound to prevent such physiological effects. Fortunately, sufﬁ -

ciently high speciﬁ c activities can now be attained routinely with ﬂ uorine - 18 radiotracers

such that human studies of these compounds are quite feasible.

14.3.3 Aromatic Nucleophilic Substitution: Activated Aryl Rings

A large number of compounds containing aromatic rings have now been radiolabeled with

ﬂ uorine - 18. Most often, nucleophilic substitutions of [

F]ﬂ uoride ion is done using a

suitable leaving group (e.g., halogen, nitro, or trimethylammonium group) on a benzene

ring bearing an electron - withdrawing substituent (e.g., nitro, ketone, aldehyde, ester,

nitrile), through a classical aromatic nucleophilic substitution reaction. Syntheses of

[

F]ﬂ uoroheterocyclic rings proceeds in a similar fashion. Nucleophilic substitution by

[

F]ﬂ uoride also proceeds successfully with aryl rings bearing both electron - withdrawing

and electron - donating substituents [23] .

In using simple

F - ﬂ uorination of an activated benzene ring, radiotracers are usually

designed such that the activating group is easily incorporated into the ﬁ nal radiotracer

design, converted rapidly into a functional group needed in the ﬁ nal product, or even

removed entirely. An example of incorporating the activating group into the ﬁ nal desired

radiopharmaceutical is 4 - [

F]ﬂ uorobenzoyl hexadecanoate ([

F]HFB), a long - chain ester

developed for radiolabeling of stem cells as it is rapidly and simply absorbed and retained

in the lipid bilayer of a cell [24] . Synthesis of [

F]HFB was accomplished by reaction of

[

F]ﬂ uoride ion, using the potassium/Kryptoﬁ x system in dimethyl sulfoxide, with a

4 - trialkylammonium - substituted benzoyl ester precursor (Figure 14.3 ). The synthesis is

thus one - step: the desired

F - labeled ester is easily separated from the cationic precursor

as well as unreacted [

F]ﬂ uoride ion by simple column ﬁ ltration. As an alternative, a

synthesis of a long - chain fatty benzoic acid ester with the ﬂ uorine - 18 on the alkyl chain

could also have been employed, by utilizing an appropriately placed leaving group as in

the synthesis of ﬂ uorine - 18 fatty acids such as 16 - [

F]ﬂ uorohexadecanoic and 14 -

[

F]ﬂ uoro - 6 - thiaheptadecanoic acid [25] . This exempliﬁ es how ﬂ uorine - 18 chemistry

often offers several options for incorporation into different positions of desired target

molecules.

Nucleophilic aromatic

F - ﬂ uorination has also been used in the synthesis of small

prosthetic groups which are then incorporated into larger molecules, or attached to very

large molecules such as peptides or proteins. This approach is often taken if the larger

organic compound is unsuitable for direct

F - ﬂ uorination reactions (for example, due to

Figure 14.3 Synthesis of the long - chain ester 4 - [

F]ﬂ uorobenzoylhexadecanoate ([

F]HFB)

using [

F]ﬂ uoride ion in a nucleophilic aromatic substitution of a trimethylammonium leaving

group, with the ring activated by the ester function.