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target tissues due to the action of eux transporters such as p-glycoprotein (PGP) and
breast cancer resistance protein (BCRP). If the data is available, selection of compounds
with more rapid in vivo pharmacokinetics may be favored: when using short-lived radionuclides, prolonged tissue retention is not useful; and for many applications of in vivo
imaging, the ability to determine both the uptake and washout of a radiotracer in a
dynamic fashion provides information useful for pharmacokinetic modeling. Finally, the
development of radiotracers for imaging in the central nervous system (CNS) faces the
additional requirement of passing the blood-brain barrier (BBB), a membrane system
that eciently excludes many compounds: CNS entry can be achieved using an active
transport process or through passive diusion, with the latter requiring consideration
of the molecular size and lipophilicity.
In the following chapters of this Handbook of Radiopharmaceuticals, methods for producing radionuclides and radiopharmaceuticals, methods for evaluating new candidate
radiotracers, and the many exciting applications of radiolabeled compounds for in vivo
nuclear medicine imaging are discussed in detail. If radiopharmaceuticals are indeed the
“future of nuclear medicine,” where do the ideas for new radiotracer structures come
from? Although often the origins of a radiotracer are not clear, there are nevertheless
a variety of sources of chemical structures that can be identied as useful for targeted
radiotracer design (Table1.1), and this chapter will focus on the early step of identifying
appropriate chemical structures suitable for development into small-molecule radiotracers (for discussion purposes, small molecules are considered to have MW <600).
Many of the examples arise from the eld of positron emission tomography (PET) radiopharmaceutical chemistry, simply because it has often proven easier to radiolabel small
molecules with carbon-11 or uorine-18. There are, however, important examples of
radioiodinated single-photon emission computed tomography (SPECT) agents–e.g.
123
[
I]Ioupane (DaTscan®), [
iodobenzamide ([
123
99m into relatively small molecules with some success ([
123I/131
I]meta-iodobenzylguanidine ([
123I/131
I]MIBG), and [
123
I]IBZM)–and eorts have been made to incorporate technetium-
99m
Tc]TRODAT-1). Although
I]
the sources for radiotracer development listed in Table1.1 are discussed separately, it
should be understood that combinations of the methods are often used to arrive at a
molecule that can be successfully employed for in vivo imaging of biochemistry in living
human subjects.
Endogenous compounds
Established therapeutic drugs
Pharmaceutical industry
In vitro assay reagents
High-throughput screening
Natural products (plant derived)
Table 1.1
So
urces
ofleads for
chemical matter
fordesign
anddevelopment
ofnew invivo
imaging radiopharmaceuticals.
Chapter 1: Targeted Diagnostic Radiopharmaceuticals 5
1.2 LABEL ANENDOGENOUS COMPOUND
ORDERIVATIVE
The radiolabeling of an endogenous chemical species is perhaps the simplest and oldest
concept in radiotracer design: one of the earliest syntheses with carbon-11 was that of
11
[
C]acetic acid[6]. If the radiolabeling is done at a suciently high specic activity, then
there should be no concerns regarding pharmacological eects or toxicology, as the
mass of compound injected is likely far below normal physiological concentrations. It is
also likely that the metabolism of an endogenous compound is very well known. A large
number of endogenous compounds and derivatives have been radiolabeled and used for
imaging studies: an incomplete listing of such radiopharmaceuticals is given in Table1.2.
The labeling of endogenous compounds has been primarily done using PET radionuclides
11
(
C, 13N, 18F), simply because of the simplicity in isotopic substitutions (e.g. 11C for 12C) or
the observation that incorporation of the small uorine atom is often well tolerated[7].
For example, many natural and non-natural amino acids have been synthesized with
13
N, or 18F radiolabels, using a variety of approaches to prepare radiotracers in a regiospecic or stereospecic fashion. Incorporating SPECT radionuclides into endogenous compounds is more challenging but has in some cases been successful with radioiodinated
aromatic or non-natural amino acids[8].
Radiolabeled endogenous compounds may not seem to t the simple concept of targeted radiotracers, as the biochemical processes they address are often ubiquitous, but
they have proven useful when the target is enhanced or reduced in a pathophysiological
condition. The best-known and most-used radiopharmaceutical based on an endogenous
compound is 2-deoxy-2-[
tical used daily in clinical medicine, [
18
F]uoro-d-glucose ([18F]FDG). As the PET radiopharmaceu-
18
F]FDG can be considered to target a specic
biochemical process: the metabolism of glucose. The localization of radioactivity is, however, dependent on the action of one of the family of glucose transporters followed by
enzyme-mediated phosphorylation to form 2-deoxy-2-[
That metabolite is eectively retained in cells, and [
metabolic trapping radiotracer. The powerful applications of [
18
F]uoro-d-glucose-6-phosphate.
18
F]FDG is a classic example of a
18
F]FDG are the result of
11
C,
Table 1.2
Exa
mples
Type of molecule Radiotracer example
ofendogenous molecules andderivatives used asinvivo
imaging radiopharmaceuticals.
Amino acids [11C]methionine
Fatty acids [
Sugars [
Nucleosides [
Carboxylic acids [
Choline [
Steroids [
Biogenic amines [
Arachidonic acid [
6 Handbook of Radiopharmaceuticals
11
C]palmitate
11
C]glucose, 2-[18F]uoro-2-deoxyglucose (FDG)
11
C]thymidine, [18F]uorothymidine
11
C]pyruvic acid, [11C]ascorbic acid
11
C]choline, [18F]uorocholine
18
F]uoroestradiol
11
C]epinephrine, [18F]uorodopamine
11
C]arachidonic acid
the localized changes in glucose metabolism, with both increases (in tumors) or decreases
(in the brain in degenerative diseases) providing valuable information about physiology.
The tissue localization of radioactivity from [
18
F]FDG represents the action of a transporter and an enzyme, in that order. For endogenous compounds, the involvement of
multiple biochemical steps in radiotracer uptake and localization is very common[9].
18
[
F]Fluorothymidine ([18F]FLT) has been successfully used for tumor imaging, with the
mechanism of tumor retention proposed as trapping following phosphorylation by thymidine kinase, but the uptake of the radiotracer is also dependent on the equilibrative
nucleoside transporter 1 (ENT1, SLC29A1 ). The successful accumulation and imaging of
a radiotracer can also represent the actions of two transporters: for retention of the
SPECT radiotracer [
11
tracer [
C]hydroxyephedrine ([11C]HED) into presynaptic adrenergic neurons of the heart,
123
I]MIBG into neuroendocrine tumors or the uptake of the PET radio-
it is a combination of transport by the neuronal membrane norepinephrine transporter
(NET, SLC6A2 ) and the vesicular monoamine transporter type 2 (V MAT 2 , SLC18A2 ). The
use of either radiotracer in the heart provides a measure of the integrity of the adrenergic innervation[10]. The brain radiotracers [
18
and 6-[
F]uorodihydroxyphenylalanine ([18F]FDOPA) are examples where the specic
11
C]dihydroxyphenylalanine ([11C]DOPA)
localization of radioactivity in the synaptic vesicles of presynaptic dopaminergic neurons
results from a combination of actions by, in order, the large amino acid transporter 1
(LAT1, SLC7A5 ) in the BBB, an intra-neuronal enzyme (dihydroxyphenylalanine [DOPA]
decarboxylase) that converts the radiotracers to radiolabeled neurotransmitters ([
dopamine and 6-[
VMAT2) that moves those species inside neuronal storage vesicles. Thus, [
18
and [
F]FDOPA target dopamine biosynthesis but represent a combination of three
18
F]uorodopamine), and a second intra-neuronal transporter (the
11
C]DOPA
11
C]
biochemical processes. Furthermore, the radioactivity distribution and retention from
11
[
C]DOPA and [18F]FDOPA are also dependent on the actions of two metabolic enzymes,
COMT (catecholamine O-methyl transferase) and MAO (monoamine oxidase). Despite
this complexity, [
18
F]FDOPA remains a useful radiotracer for human PET studies.
Many of the endogenous amino acids have been isotopically radiolabeled with
nitrogen-13 or carbon-11, and numerous amino acid derivatives have been radiolabeled using uorine-18 (incorporation of a single uorine atom or a small uorinated
substituent) or radioisotopes of iodine[11–14]. The complex biochemical fates of the
amino acids nicely demonstrate the potential–and diculties–in the design and use of
endogenous molecules as imaging agents. The movement of radiolabeled amino acids
into and within cells is accomplished by no less than 51 transporters[15], and amino acids
are involved in protein synthesis, neurotransmitter synthesis, redox balance (formation
of glutathione and NADH/NADP+ coupling)[16], and energy-producing metabolism[17].
For the purposes of in vivo imaging, the natural amino acids may be not optimal, as their
tissue localization reects their multiple metabolic pathways; but that has not prevented their use in human studies, as exemplied by tumor imaging with [
11
C]methionine
(Figure1.2) as a purported marker of protein synthesis. The design of a derivative of a
natural amino acid such as (2-[
amino acids such as [
11
C]ACHC (aminocyclohexanecarboxylic acid)[19] or [18F]FACBC
18
F]uoroethyl)-l-tyrosine ([18F]FET)[18] or non-natural
Chapter 1: Targeted Diagnostic Radiopharmaceuticals 7
11
O
OO
F
F]FACBC
Figure 1.2 Targeted
radiopharmaceuticals based
on structures of
amino acids.
S
CH
3
A: [11C]methionine
HO
18
C:[
NH
18
F]FSPG
OH
OO
2
B: (2S,4R)4-[
OH
H2N
18
F
18
F]Fluoroglutamine
O
H2N
18
F
D: [
NH
OH
OH
2
18
(1-amino-3-[18F]uorocyclobutanecarboxylic acid: Fluciclovine, Axumin®, Figure1.2)[20]
provides radiotracers that cannot be incorporated into proteins and are resistant to
metabolism: such radiotracers target only the transporters primarily involved in their
movement into tissues or tumors. The application of radiolabeled amino acids to probe
tumor metabolism is exemplied by the synthesis of 4-[
which is transported via the cysteine/glutamate antiporter (X
18
F]uoroglutamine (Figure1.2),
−
, SLC 7A11 ) into tumor
C
cells where it is can be subject to further metabolism or incorporation into macromolecules[21]. Finally, the potential use of an amino acid derivative to study cellular redox
status is suggested for the radiotracer [
18
F]FSPG (S-4-(3-[18F]uoropropyl)-l-glutamic acid,
Figure1.2)[22].
Most of the radiopharmaceutical examples in Table1.2 are radiolabeled substrates
for enzymes or transporters but are not radioligands that image specic binding to
receptors. Why? The endogenous ligands for receptors usually have binding anities too
low for imaging specic binding in vivo: as an example, the anity of dopamine for dopamine receptors is micromolar and does not match the <10 nM binding anities of successful in vivo dopamine D2/D3 receptor imaging agents. One exception to this general
limitation of receptor binding agents is the radiopharmaceutical [
18
F]uoroestradiol ([18F]
FES). In vivo studies with radiolabeled estradiol started as early as 1967, with attempts to
construct compartmental models for the specic binding of tritiated estradiol following
intravenous administration and ex vivo tissue distribution studies[23]. The potential
use of radiolabeled estrogens for breast cancer imaging stimulated years of eort to
radiolabel estradiol, both with SPECT isotopes (16α-[
123
I]iodoestradiol[24] and 16α-[77Br]
iodoestradiol[25]) and subsequently with uorine-18 for PET imaging. Those eorts
culminated in 16-α-[
receptor (reported K
18
F]uoroestradiol as a high-anity radioligand for the estrogen
as low as 0.13 nM in cell studies[26]) that has subsequently been
i
used by numerous institutions to image and characterize the receptor status of primary
breast tumors[27]. The story of estrogen receptor imaging does not, however, end with
18
[
F]FES. The recent identication of two types of estrogen receptors (ER-α and ER-β) may
prompt research into radiotracers that show subtype specicity: whether these will be
estradiol derivatives, derived from therapeutic agents, or newly designed xenobiotics
cannot be predicted. Estradiol can be considered an endogenous compound that was
8 Handbook of Radiopharmaceuticals
slightly modied to become an in vivo imaging agent targeting a specic receptor, but it
could just as well have been used as an example of a clinically used drug successfully converted into an in vivo imaging agent, as discussed in the next section.
1.3 LABEL APHARMACEUTICAL OR DERIVATIVE
The radiolabeling of a candidate drug molecule with a long-lived radionuclide (3H or
14
C) to evaluate its disposition and metabolism has long been part of pharmaceutical
development programs. The in vivo distribution of such new molecules can also be
directly studied using isotopic substitutions with PET isotopes (e.g.
In recent years, many of the large pharmaceutical companies have added capabilities
for radiochemical syntheses with PET or SPECT radioisotopes, allowing them to develop
radiotracers useful as in vivo biomarkers for preclinical evaluation of new drug candidates. Those eorts have yielded a number of radiotracers with impact on their drug
development programs and led some investigators to form generalized concepts for
successful biomarker development[28, 29]. The decades of eort by medicinal chemists in the pharmaceutical industry have resulted in the syntheses of many thousands
of compounds, of which only a very small fraction have been eventually developed into
marketable drugs. Whereas such libraries of compounds are used by in-house radiotracer
development programs at pharmaceutical companies, they often remain inaccessible
to academic researchers interested in radiopharmaceutical development: increased
access to such chemical matter would be highly desired but will require more extensive
industry-academia collaborations[30]. A number of clinically used drug molecules or
compounds reported by pharmaceutical companies have, however, been the basis for successful radiopharmaceutical development in several dierent fashions, as exemplied in
Figure1.3 and discussed in this chapter.
In a few cases, it has been possible to radiolabel a therapeutic drug molecule using
isotopic substitutions with carbon-11 or uorine-18 (a large proportion of drugs have
uorine substituents[31]). Examples of drugs directly converted to in vivo imaging
agents include [
benzodiazepine binding site), [
antagonist), [
11
[
C]l-DOPA (levodopa, a dopamine precursor), [11C]erlotinib (Tarceva®: epidermal
growth factor receptor [EGFR] inhibitor), [
11
[
C]verapamil (Verelan®: calcium channel blocker). The monoamine oxidase inhibitor
deprenyl (Selegiline
11
C or 18F]umazenil (Romazicon®: antagonist of the GABAA receptor-
11
C]methylphenidate (Ritalin®: dopamine transporter [DAT]
18
F]altanserin (5HT2A receptor antagonist), [11C]elacridar (PGP inhibitor),
11
C]metomidate (Hypnodil®: hypnotic), and
®
) was rst radiolabeled by isotopic substitution with carbon-11 and
then underwent a second isotopic substitution with deuterium to improve human brain
imaging pharmacokinetics[32]. Radiotracers based on drugs that have been discontinued
from therapeutic human use, such as [
which are only used as veterinary drugs, such as [
11
C]rolipram (phosphodiesterase-4 inhibitor), or
11
C]carfentanil (Wildnil®: opiate agonist
used as an animal tranquilizer), have also found applications in human studies.
In other cases, the molecular structure of a clinical drug molecule needed to be
slightly modied to accommodate the radionuclide, to improve pharmacokinetics or
11
C for 12C, 18F for 19F).
Chapter 1: Targeted Diagnostic Radiopharmaceuticals 9
N
O
N
Cl
(B)
(C)
(D)
Figure 1.3 Tar-
geted radiopharmaceuticals
based on structures of known
therapeutic drugs.
(A)
N
N
F
O
O
N
CH
3
Isotopic
substitution
N
18
F
O
O
O
N
11
CH
3
Flumazenil
COOH
N
N
O
Candesartan
HO
H
N
N
N
Minor
N
change
COOH
N
H
N
N
N
N
O
11
CH
3
HO
Major
N
N
OCH
3
change
N
N
Misonidazole
NO
2
NO
2
FMISO
18
F
OCH
IBZM
N
3
H
O
N
HO
H
O
N
N
123
I
Choose
H2NO2S
OCH
Sulpiride
3
analog
O11CH
N
3
H
O
N
Raclopride
Cl
metabolism or to simplify its radiochemical synthesis. To design a radiotracer for SPECT
imaging in epilepsy, the uorine in umazenil was replaced with radioiodine, yielding the
compound [
123
I]iomazenil. The heart drugs candesartan (Cilexetil®) and losartan (Cozaar®)
are angiotensin II receptor antagonists where small changes in structure (substitution
10 Handbook of Radiopharmaceuticals
of methyl groups for ethyl or propyl substituents) were necessary to accommodate easy
radiochemical labeling with [
11
C]methyl iodide; but the slight molecular modication (e.g.
ethyl to methyl group) did not result in signicant loss of in vitro anities, and the resultant molecules proved useful as in vivo radioligands for cardiac imaging[33]. As discussed
earlier, 16-α-[
18
F]uoroestradiol is a simple uorinated derivative of the clinical drug
estradiol.
A larger, more signicant change in molecular structure might be needed, however, as
exemplied for the hypoxic radiosensitizer misonidazole: to provide for incorporation of
the radionuclide, the methoxy group of misonidazole was replaced by a uorine atom in
the synthesis of [
18
F]FMISO (uoromisonidazole) that is widely used in PET imaging[2].
Even more fortuitous was the discovery of a substituted diphenylsulde (403U76) as
an inhibitor of neuronal serotonin reuptake; that molecular structure provided the
lead to a large number of carbon-11, uorine-18, and radioiodine labeled diphenylsuldes that have been developed for in vivo imaging of the serotonin transporter (SERT,
SLC6A4)[34].
Sometimes an analog of the clinical drug is chosen for radiolabeling and evaluation
as an in vivo imaging agent: this may be due to the dierent pharmacokinetics required
for an in vivo imaging agent intended for intravenous injection as compared to a chronic
orally administered drug. Examples are the numerous substituted benzamides that
were synthesized by medicinal chemists in the pharmaceutical industry[35]. These were
investigated as potential antipsychotics based on pharmacological activity as dopamine
receptor antagonists, and sulpiride (Dogmatil
®
) was developed into the clinical drug.
It was, however, not chosen for development as a radioligand for in vivo brain imaging
studies of dopamine receptors. Instead, an iodobenzamide ([
123
I]IBZM) and [11C]raclopride
were synthesized as analogs of sulpiride, and both have been used for more than 30 years
for SPECT and PET imaging of the D2/D3 receptor in the human brain[36, 37]. Numerous
other benzamides have subsequently been radiolabeled, but only recently has sulpiride
been carbon-11 labeled[38]: not as a dopaminergic radioligand, but rather as a substrate
for organic cation transporters OCT1 (S LC22 A1 ) and OCT2 (SLC22A2), and multidrug and
toxin extrusion-type transporters MATE1 (SLC47A1 ) and MATE2 (SLC47A 2 ).
There is also the possibility of “rening” an old drug into a new, useful in vivo radio-
pharmaceutical. The benzoisoquinoline tetrabenazine (Xenazine
®
) was invented in the
late 1950s as an atypical antipsychotic, and in recent years it has been used in clinical
care for treating selected movement disorders. In 1990, isotopic substitution was used
to synthesize [
11
C]TBZ; and in vivo PET imaging of its intended target, the VMAT2 in the
brain, was successfully achieved in humans[39]. Signicant improvements in the imaging
of the VMAT2 were achieved when it was recognized that the brain pharmacokinetics
actually represented a mixture of four stereoisomeric metabolites: application of modern
methods for chiral chromatographic resolution allowed for the isolation, identication
(absolute conguration), and carbon-11 labeling of a single high-anity stereoisomer
11
(+)- α-[
C]dihydrotetrabenazine ((+)-α-[11C]DTBZ)[40]. This radiotracer optimization illustrates two useful concepts: understanding the metabolism of a drug (the metabolites
may actually be higher anity for the target site!) and using only single diastereomers of
Chapter 1: Targeted Diagnostic Radiopharmaceuticals 11
drugs with multiple chiral centers. Furthermore, the eorts in radiotracer development
may have impacted the design of a new VMAT2 inhibitor (valbenazine, Ingrezza), a prodrug form of the single isomer (+)-α-DTBZ, which has been recently introduced into
clinical use.
The radiolabeling of a class of clinical drugs does not always work, however. The
selective serotonin reuptake inhibitors (SSRIs) such as uoxetine (Prozac), citalopram
(Celexa), and related compounds constitute an important and highly successful group of
clinical drugs in psychiatry. The radiolabeling of such drugs with carbon-11 or uorine-18
failed to produce useful in vivo imaging agents for human PET studies of the SERT largely
due to the high non-specic binding of those lipophilic drugs[41, 42].
Established clinical drugs and the pharmaceutical industry are thus a rich source of
chemical matter for potential development into an in vivo imaging agent. One advantage
of a clinical drug is that the pharmacology, toxicology, and metabolism are already
established in humans, and the doses in clinical use are likely orders of magnitude
higher than the trace mass doses present in radiopharmaceuticals: this makes obtaining
regulatory approvals much simpler. However, in many cases, a clinically used therapeutic
drug does not work as a radiotracer, as the desired pharmacokinetics in blood and target
tissues from an oral drug dose[43] usually do not match the relatively rapid pharmacokinetics desired for an in vivo imaging radiotracer labeled with short-lived radionuclides.
1.4 FROM INVITRO REAGENTS
TOINVIVO IMAGING
The compounds synthesized as part of drug development represent only a portion of the
vast numbers of chemical structures that have been synthesized. There are examples of
the development of in vivo imaging radiotracers based on chemicals that were useful for
in vitro purposes but were never developed as drugs (Figure1.4).
Two examples of radiotracers used for in vivo brain β-amyloid imaging have origins in
the chemical compounds used for in vitro tissue staining. The neutral uorescent probe
DDNP (1,1-dicyano-2-[6-(dimethylamino)napthalen-2-yl]propene) was developed by
Jacobsen etal.[44] as a reagent for microscopy studies but was then later radiolabeled
with uorine-18: the resultant radioligand [
amyloid and tau in human brains[45]. Thioavin-T, a dye used in histochemistry to selectively stain amyloid in post-mortem brain tissues, was selected by Mathis and Klunk as the
starting point for the design of a brain-penetrant amyloid imaging agent[46]. The structure of thioavin-T includes a positively charged quaternary heterocyclic nitrogen, which
prevented its use directly as a brain imaging agent (it would not penetrate the BBB).
The syntheses of a series of derivatives was thus undertaken, with the most important
step being the removal of the methyl group on the quaternary nitrogen, eventually yielding several candidate compounds for radiolabeling; the best compound then chosen for
labeling with carbon-11 was designated 6-Me-BTA-1, or more commonly known as PIB
(Pittsburgh compound B) (Figure1.3). [
used for many thousands of human PET studies.
18
F]FDDNP was used for in vivo PET imaging of
11
C]PIB ([N-methyl-11C]6-Me-BTA-1) has now been
12 Handbook of Radiopharmaceuticals
H3C
HO
[11C]PIB [18F]FEOBV
S
+
N
CH
3
Thioflavin-T
Figure 1.4 Tar-
CH
3
N
CH
3
N
geted radiopharmaceuticals
based on structures of in vitro
chemical probes.
OH
Vesamicol
11
CH
NH
3
O
S
N
18
F
N
OH
Two further examples of compounds that became radiotracers but not drugs come
from studies of the cholinergic system in the brain. Quiniclidinyl benzilate (QNB) was
synthesized by chemists at Homan-La Roche in the 1950s and is useful as an in vitro tritiated radioligand for studies of the muscarinic cholinergic receptor, but QNB only drew
human use interest as, unfortunately, a possible chemical war agent. However, when
labeled with radioiodine, QNB was converted to radiotracers ([
123
I]QNB) successfully
used for in vivo imaging, including one of the earliest examples of receptor-targeted
human SPECT imaging[47]. Another example is vesamicol, a potent neuromuscular
blocking agent[48] subsequently identied as a high-anity inhibitor of the vesicular
transporter for acetylcholine (VAChT, SLC18A3 ). Multiple research groups pursued the
radiolabeling of vesamicol and derivatives with radioiodine, carbon-11, and uorine-18
with the goal of identifying in vivo imaging biomarkers for presynaptic cholinergic
neurons[49], and the radiotracer [
18
F]FEOBV (Figure1.3) is in current use in human PET
studies[50, 51].
Finally, there are the recently reported radiolabeled substrates for MAOs that
function as in vivo metabolic trapping agents[52]. These radiotracers can be considered
as derived from the neurotoxin MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine),
but with a structural modication (insertion of an ether oxygen between the phenyl
and tetrahydropyridine rings) that retains the reactivity with MAO but removes the
neurotoxicity concerns. The radiotracers derived from QNB, vesamicol, and MPTP are
examples of successful use of highly toxic chemicals as starting materials for radiotracer
development, which is only possible because the structural modications or high
specic activities of the radiopharmaceuticals allow their administration at very low and
safe mass doses.
Chapter 1: Targeted Diagnostic Radiopharmaceuticals 13
1.5 DO HIGH-THROUGHPUT SCREENING
O11CH
(B)
OFACHEMICAL LIBRARY
High-throughput screening (HTS) is a technique that screens a chemical library (often
many thousands of compounds) against an in vitro assay in the search for “hits”: that
is, chemical structures that appear to interact with the target. In the pharmaceutical
industry, the structures identied as hits provide leads for the development of new
chemical matter, where structural renements are then made to obtain optimal candidate drug molecules. HTS has been used by PET research groups in both industry and academia to identify scaolds for successful in vivo imaging agent development.
The phosphodiesterase 10A (PFD10A) enzyme was discovered in 1999 and has become
of signicant interest for the development of drugs useful in a variety of psychiatric diseases. The research group at Merck undertook the development of a PDE10A radioligand
useful for clinical studies of new candidate drug molecules[53] and employed HTS to
identify a scaold (Figure1.3) with encouraging properties of moderate ligand binding
(K
=130 nM), lipophilicity (clogP=3.9), and polar surface area (PSA=75). Syntheses of a
i
series of derivatives of that scaold identied four compounds with high anity for the
PDE10A binding site, each of which was then radiolabeled with carbon-11 and studied in
rat and rhesus monkey brains. The result was the selection of [
as a high anity (K
=0.15 nM), highly selective in vivo radioligand for the PDE10A
i
binding site.
11
C]MK-8193 (Figure1.5)
Figure 1.5 Tar-
geted radiopharmaceuticals based
on structures
derived from
high-throughput
screening.
(A)
O
N
N
O
HTS “hit”
PDE10A K
N N
H
tau Ki = 14 nM
b-amyloid Ki = 134 nM
O
N
= 130 nM
i
O
N
N
11
C]MK-8193
[
PDE10A K
N
F
N N
tau Ki = 8 nM
b-amyloid Ki > 4400 nM
O
i
O
N
= 0.15 nM
H
3
O
N
14 Handbook of Radiopharmaceuticals