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A signicant application of HTS methods has been in the design of radiotracers for
the proteinopathies, particularly those associated with neurological diseases: β-amyloid,
tau, and synuclein. As there are no endogenous “ligands” for these proteins that accumulate in the brain, and protein structural information is very limited, the screening of
chemical libraries with a diversity of molecular structures has been a useful mechanism
in the search for possible radiotracer structures. The use of HTS is often more dicult
for academic research groups, simply due to the lack of access to the chemical libraries
and the equipment needed for performing the tedious in vitro assays, or the cost of
performing the assays, or both. This has not, however, totally prevented its use, as exemplied by the eorts of the Tohoku University research group[54], who screened over
2000 chemicals in the search for a chemical scaold suitable for the development of tau
imaging agents. Their eorts resulted in the development and evaluation of [
18
F]THK5351
as one of the several new radiochemicals that have now been investigated for PET
imaging of tau in Alzheimer’s disease subjects.
The encouraging studies with [
18
(e.g.[
F]1451, [18F]MK-6240, [11C]PBB3, and others) provided insights into the some of
18
F]THK5351 and other proposed tau radioligands
the structural features needed for tau selectivity and binding, allowing chemists at
Janssen Pharmaceutica[55] to employ a mini-HTS of only 4000 compounds to identify
a compound (Figure1.5) with high anity (K
β-amyloid binding (K
=134 nM). Structural explorations involving syntheses of deriv-
i
=14 nM) and encouraging selectivity over
i
atives with varying ring nitrogen numbers and positions, and placement of a uorine
substituent in a position with potential for radiolabeling with
didate molecule (Figure1.3) with an improved anity (K
β-amyloid binding (K
> 4 4 00 nM ).
i
18
F, yielded their best can-
=7.9 nM) and selectivity over
i
These examples demonstrate the potential power of HTS for radiopharmaceutical
design, but challenges remain. At the start, what is the correct (or needed) library size
of chemical compounds[56]? Should searches be restricted to smaller focused libraries,
or would searches of the vast virtual libraries (now containing billions of structures[57])
provide the lead structures needed for the development of new radiotracers for the
plethora of biochemical targets (receptors, transporters, enzymes, ion channels) that are
being identied by advances in genetics and biochemistry, but for which there are currently no known ligands? It must also be recognized that HTS screens most often identify
lead structures with anities for the target that may be far lower than needed for an in
vivo radiotracer, and signicant time and eort may be needed to achieve a new chemical
entity with the needed anities and ADME (absorption, distribution, metabolism, and
excretion) properties for in vivo imaging applications.
1.6 LABEL ANATURAL PRODUCT OR
DERIVATIVE
Natural products have for many years been a source of chemical structures for drug
development[58], and there are important examples of in vivo radiopharmaceuticals that
are derived from natural products.
Chapter 1: Targeted Diagnostic Radiopharmaceuticals 15
Cocaine is the neuroactive alkaloid isolated from leaves of the coca plant (Erythroxyla-
H
CH
CH
Morphine
ceae family). It is pharmacologically active at a number of transporters and receptors in
the human brain, but the most signicant eect of cocaine is at the neuronal membrane
DAT. In 1989, Fowler etal. isotopically radiolabeled cocaine with carbon-11[59], but applications of [
11
C]cocaine for studies of the DAT in neurodegenerative diseases proved challenging due to its very rapid pharmacokinetics in the human brain. Fortunately, an earlier
interest by medicinal chemists in developing cocaine antagonists had led to the syntheses
of a very large number of compounds based on the 3-phenyltropane structure[60, 61],
and that provided chemical leads useful for syntheses of a large number of analogs and
derivatives labeled with radioiodine, carbon-11, and uorine-18[5]. These eorts led to
radiotracers selective for the neuronal membrane dopamine (DAT), serotonin (SERT), and
norepinephrine (NET) transporters [62]. Several of these radiolabeled 3-phenyltropanes
have been used in human studies, and the radioiodinated compound DaTscan (Ioupane
I123, Figure1.6) has been approved for clinical studies of Parkinson’s disease and related
conditions.
A second example of natural products used as radiopharmaceuticals comes from the
opiate receptors. Morphine is a high-anity opiate receptor agonist rst isolated from
plant sources (e.g. opium poppy) in the rst decade of the 1800s and marketed for human
use since 1827. The extensive synthetic eorts of medicinal chemists produced numerous
synthetic opioids that act as agonists or antagonists with varying selectivity for the three
receptor subtypes (μ, δ, and κ receptors). Two such synthetic opioids, diprenorphine
(μ receptor) (Figure1.6) and naltrindole (δ receptor), were selected for carbon-11 or
uorine-18 labeling and have been used for opiate receptor PET studies in the human
Figure 1.6 Tar-
geted radiopharmaceuticals based
on structures of
O
N
C
3
3
O
O
O
N
3
O
123
I
natural products.
O
Cocaine
HO
O
HO
CH
3
N
Ioflupane I123 (DaTscan
HO
O
11
CH
3
O
[11C]diprenorphine
TM
)
N
16 Handbook of Radiopharmaceuticals
brain[63, 64]. Morphine and cocaine are, of course, somewhat unique examples of plantderived natural products. Both compounds have been or are in use as medicines, but both
are also addictive and included on regulatory lists as controlled substances: development
and use of radiolabeled forms of such compounds can at times be challenging from a
regulatory standpoint.
There are times when natural products have been simply too complex for
radiolabeling, had physical or metabolic properties inconsistent with use as an in vivo
radiotracer, or had no obvious site for radiolabeling: examples are reserpine (a potent
inhibitor of vesicular monoamine transporters), tetrahydrocannabinol (THC: one of the
many alkaloids active at the cannabinoid receptor), and colchicine (binding to microtubules). Fortunately, for each of these targets, smaller and simpler chemical structures
were pursued to yield useful in vivo imaging radiotracers[39, 65, 66].
1.7 SUMMARY
As described in the previous sections, there are multiple routes to new radiopharmaceutical design, and all have yielded radiotracers useful for human imaging studies. For all of
these approaches, radiotracer development has drawn from known chemical structures,
although often with small to very signicant modications required to achieve the
desired attributes of specicity, biodistribution, pharmacokinetics, and metabolism
needed for in vivo radiopharmaceuticals. The design and evaluation of new radiopharmaceuticals remains an exciting but challenging eld, and one with a tremendous potential
impact on our understanding of physiology and disease.
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Chapter 1: Targeted Diagnostic Radiopharmaceuticals 19
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20 Handbook of Radiopharmaceuticals
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Chapter 1: Targeted Diagnostic Radiopharmaceuticals 21
Chapter 2
Concepts andIssues
forTherapeutic
Radiopharmaceuticals
Alexandra R. Sowa Dumond and Peter J.H. Scott
Department of Radiology, University of Michigan, Ann Arbor, MI,
48109, USA
2.1 INTRODUCTION
The time since the publication of the rst edition of the Handbook of Radiopharmaceuticals has seen enormous growth in radiotherapy applications within nuclear medicine
and the radiopharmaceutical sciences. Radiotherapy is an overarching term that can refer
to dierent applications of radiation toward the treatment of disease. Types of radiotherapy include: (i) external beam radiation, the use of single or multiple beams of radiation produced by a linear accelerator and aimed at a tumor; (ii) brachytherapy, which
involves implanting a radiation source near a tumor; and (iii) targeted radiotherapy (also
referred to as radioimmunotherapy or radioligand therapy [RLT]), which involves targeting
radiation to a tumor through the use of pharmaceuticals labeled with radionuclides that
decay via Auger, alpha (α), beta (β), or gamma (γ) emission. Clinically, the growth in radiotherapy has been in the use of targeted radiotherapeutics for the treatment of cancer,
as shown in this chapter, but other emerging applications are also highlighted, including
preclinical treatment of infections. Due to the selective nature of radiotherapeutics,
targeted radiotherapy oers precise treatment of dierent subtypes of cancer such as
prostate cancer (PC), neuroendocrine tumors (NETs), and lymphoma, while limiting otarget radiation toxicity eects that can be caused by other therapies such as external
beam radiation[1]. In the United States, targeted radiotherapeutic protocols are typically
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.
outpatient procedures, and depending on the mode of decay of dierent radionuclides,
A
C
safety precautions must be taken after a patient receives therapy. These include a patient
not using public transportation, using a single set of dishes and silverware that is washed
separately, and limiting contact with other household members, including recommended
use of a separate bathroom.
In its simplest form, a radiotherapeutic is a radionuclide coupled with a targeting
moiety such as a monoclonal antibody (mAb), peptide, or smaller drug-like molecule.
Depending on the radionuclide of choice, the radionuclide can either be bonded to
the targeting moiety directly (e.g.
chelating group in the case of radioactive metal ions (e.g.
131
I; Figure2.1a,b) or complexed with an appropriate
177
225
Lu,
Ac; Figure2.1c,d).
The disease-targeting moiety can be directly coupled to the radionuclide, creating a
one-step radiotherapeutic that is administered to the patient (Figure2.1a–d). Alternatively, therapy can also involve a two-step biorthogonal process where an antibody for
a particular target is administered rst, followed by a radiolabeled small molecule that
attaches to the antibody in vivo (Figure2.1e). The latter biorthogonal approach is benecial when the biological equilibration of the primary antibody, which can take days,
is much longer than the half-life of the therapeutic radionuclide of choice. Letting the
antibody reach the target rst, and then treating with radiolabeled small molecules that
have faster kinetics and quickly associate with a pre-targeted antibody, increases the
eectiveness of the therapy and reduces o-target eects. The most common pre-targeted radiotherapy approach exploits the anity of biotin for streptavidin or avidin, and
recent reviews discuss the ability of pre-targeted radiotherapy to treat systemic malignancies[2, 3].
Nomenclature for targeted radiotherapy is fairly complex, with multiple terms frequently used interchangeably. Radioimmunotherapy (RIT), for example, targets diseased
cells with mAbs complexed with a radionuclide. RLT is another commonly used term.
MAb
MAb
B
D
Small Molecule
Small Molecule
= Chelator
E
1.2.Strepavidin
MAb
Biotin
Figure 2.1 (a) Radioisotope bonded directly to a monoclonal antibody. (b) Radio-
isotope bonded directly to a small molecule. (c) Monoclonal antibody bonded to a
chelator that complexes a radiometal. (d) Small molecule bonded to a chelator complexed with a radiometal. (e) Example of a two-step radiotherapeutic approach. Step
1: Tumor-targeting mAb linked to Streptavidin. Step 2: Biotin linked to a chelated
radiometal.
24 Handbook of Radiopharmaceuticals