Radiopharmaceuticals

and
Radiopharmacy

Docente : Ângelo Jesus BPharm, PhD

Basics for Radiopharmacy
• The Atom
According to Bohr’s atomic
theory, an atom is composed
of a nucleus at the center and
one or more electrons
rotating around the nucleus
along different energy orbits.

The nucleus is primarily

composed of protons and
neutrons, collectively called
nucleons.

For an atom of a given element, the number of electrons

moving around the nucleus equals the number of protons,
balancing the electrical charge of the nucleus
Basics for Radiopharmacy
• The Atom
 Basics for Radiopharmacy
• Nuclides, Isotopes, Isobars…

Mesmo número de
Isótopo
protões (Z)

Mesmo número de
Isótono
neutrões (N)
Nuclideo
(caracterizado por A e
Z e estado de
energia)
mesmo número de
Isóbaro
massa (A)

mesma carga e o
mesmo número de
Isómeros
massa em estados
internos diferentes

The nuclides can be both stable or radioactive

Basics for Radiopharmacy
• Radioactive Nuclides…
If a nuclide is unstable or radioactive, it decays by spontaneous
fission, or alpha-particle, beta ( - and + )-particle, or gamma-ray
emission and the nuclide is termed a radionuclide
Basics for Radiopharmacy
• Radioactive Decay
Basics for Radiopharmacy
• Radioactive Decay
Basics for Radiopharmacy
• Radioactive Decay - ALPHA

In alpha decay, the atomic number of the parent nuclide

is therefore reduced by 2 and the mass number by 4

An alpha transition may be followed by beta

emission or gamma-ray emission or both.
Basics for Radiopharmacy
• Radioactive Decay – Beta (Minus and plus)
Basics for Radiopharmacy
• Radioactive Decay – Isomeric Transition

Radiação
Gamma

Transição
isomérica

A nucleus can remain in several excited energy states above the

ground state that are defined by quantum mechanics. All these
excited states are referred to as isomeric states and decay to the
ground state, with a lifetime of fractions of picoseconds to many
years
Basics for Radiopharmacy
 Production of Radionuclides

Para obtenção dos diferentes

radionuclídeos utilizados em
Medicina Nuclear/Molecular, torna-
se necessário proceder à sua
Reactor
produção artificial através de
mecanismos como a cisão nuclear,
a activação por neutrões e a
irradiação com partículas
Generator carregadas

Cyclotron

(Mettler and Guiberteau, 2006; Pedroso de Lima, J.J., 2008)

Production of Radionuclides
• Cyclotron

An example of a simple cyclotron-produced radionuclide is

111In, which is produced by irradiating 111Cd with 12-MeV
protons in a cyclotron.
 Production of Radionuclides
• Cyclotron- Produção de isótopos distintos
• The target material for irradiation must be pure and
preferably monoisotopic or at least enriched isotope in order
to avoid the production of extraneous radionuclides.

• The energy and type of the irradiating particle must be

chosen so that contamination with undesirable radionuclides
resulting from extraneous nuclear reactions can be avoided.

• Since various isotopes of different elements may be

produced in a particular irradiating system, it is necessary to
isolate isotopes of a single element; this can be
accomplished by appropriate chemical methods such as
solvent extraction, precipitation, ion exchange, and
distillation.
Production of Radionuclides
• Cyclotron- Galium 67
A pure natural zinc target or enriched zinc isotope in the form of
oxide is irradiated with 20-MeV protons, 8-MeV deuterons, or
23-MeV alpha particles in a cyclotron at a certain beam current
for a specified time.

After irradiation the target is dissolved in 7N hydrochloric acid

(HCl) and Ga 67 is extracted with isopropyl ether.

The organic phase is then evaporated to dryness in a water

bath and the residue is taken up in dilute HCl for supply as
gallium chloride.

It may be complexed with citric acid to form gallium citrate,

which is most commonly used in nuclear medicine.
 Production of Radionuclides
• Cyclotron- Short Lived Radionuclides

Carbon 11

• half-life of 20.4 min

• can be produced by Boron 10 ; Nitrogen 14

Nitrogen 13

• half-life of 10 min
• produced from Carbon 12

Oxygen 15

• half-life of 2 min
• produced from Nitrogen 14

Fluorine 18

• half life of 110 minutes

• produced from Oxygen 18
Production of Radionuclides
• Reactor

Fissionable heavy elements are 235U, 239Pu, 237Np, 233U,

232Th, and many others having atomic numbers greater than 90
Production of Radionuclides
• Reactor

These isotopes of different elements are separated by appropriate

chemical procedures that involve precipitation, solvent extraction,
ion exchange, chromatography, and distillation.
Production of Radionuclides
• Reactor

Iodine-131

Molybdenum-
99

.
Production of Radionuclides
• Generators

In a generator, basically a long-lived parent nuclide is

allowed to decay to its short-lived daughter nuclide and the
latter is then chemically separated.

.
Production of Radionuclides
• Generators

In a generator, basically a long-lived parent nuclide is

allowed to decay to its short-lived daughter nuclide and the
latter is then chemically separated.

.
Production of Radionuclides
• Generators

In a generator, basically a long-lived parent nuclide is

allowed to decay to its short-lived daughter nuclide and the
latter is then chemically separated.

.
Production of Radionuclides
• Generators

In a generator, basically a long-lived parent nuclide is

allowed to decay to its short-lived daughter nuclide and the
latter is then chemically separated.

.
RadioPharmaceuticals

• A radiopharmaceutical is a radioactive
compound used for the diagnosis and
therapeutic treatment of human diseases.

• In nuclear medicine nearly 95% of the

radiopharmaceuticals are used for diagnostic
purposes, while the rest are used for
therapeutic treatment.

.
RadioPharmaceuticals

• A radiopharmaceutical has two components: a

radionuclide and a pharmaceutical.

Radio-
Ligando Radiofármaco
nuclideo

.
RadioPharmaceuticals
Radiofármaco ideal
Methods of Radiolabeling

• In a radiolabeled compound, atoms or

groups of atoms of a molecule are
substituted by similar or different
radioactive atoms or groups of atoms.

• In any labeling process, a variety of

physicochemical conditions can be
employed to achieve a specific kind of
labeling
Methods of Radiolabeling
Methods of Radiolabeling
Isotope Exchange – Troca de Isótopos

In isotope exchange reactions, one or more atoms in a

molecule are replaced by isotopes of the same element
having different mass numbers.
Methods of Radiolabeling
Introduction of a Foreign Label– Introdução de um
grupo radioactivo diferente

Molecules 2014, 19(2), 2135-2165

Methods of Radiolabeling
Labeling with Bifunctional Chelating Agents –
Marcação com Agentes Quelantes

Need for appropriate chelation chemistry for adequate

sequestration of the metallic radionuclid

Brechbiel, M. W. (2008). Bifunctional Chelates for Metal Nuclides. The Quarterly Journal of Nuclear
Medicine and Molecular Imaging : Official Publication of the Italian Association of Nuclear Medicine
(AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society
Of., 52(2), 166–173.
Methods of Radiolabeling
Labeling with Bifunctional Chelating Agents –
Marcação com Agentes Quelantes
The utility of these metallic radionuclides has necessitated the
development of metal chelating agents to effectively provide a
handle over their behavior.

These chelating agents have been termed “bifunctional chelating

agents” since they have a metal binding moiety function and then
also possess a chemically reactive functional group.
T
he former then provides for the sequestration of the metallic
radionuclide while the latter aspect provides the requisite chemistry
for covalent attachment to a targeting vector of interest, such as a
small molecules peptides (octreotide),2 proteins (monoclonal
antibody, Zevalin),3 or nano-particles.4

Brechbiel, M. W. (2008). Bifunctional Chelates for Metal Nuclides. The Quarterly Journal of Nuclear
Medicine and Molecular Imaging : Official Publication of the Italian Association of Nuclear Medicine
(AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society
Of., 52(2), 166–173.
Methods of Radiolabeling
Labeling with Bifunctional Chelating Agents –
Marcação com Agentes Quelantes

Biological data for

some of these
ligands complexing
radionuclides of
medical interest, both
animal and human
use, is available in
the literature

Brechbiel, M. W. (2008). Bifunctional Chelates for Metal Nuclides. The Quarterly Journal of Nuclear Medicine and Molecular Imaging :
Official Publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology
(IAR), [and] Section of the Society Of., 52(2), 166–173.
Methods of Radiolabeling
Biosynthesis

In biosynthesis, a living organism is grown in a culture medium

containing the radioactive tracer, the tracer is incorporated into
metabolites produced.

For example, vitamin B12 is labeled with 60Co or 57Co

by adding the tracer to a culture medium in which the organism
Streptomyces griseus is grown.
Diagnostic and Therapy
Radiofármacos para diagnóstico
• Tempo de semi-vida curto

• Emissão de radiação gamma

• Mínima emissão beta ou alfa

• Energia do fotão emitido entre 80 e 300 KeV

Perfusão –
1ª Geração

Específicos
– 2ª geração
(Saha, 1998).
Diagnostic and Therapy
Radiofármacos para diagnóstico
• Dos radiofármacos utilizados para diagnóstico, os que
contêm na sua composição 99mTc representam cerca de
90% da totalidade:

• t1/2 de 6 h,

• E missão com energia adequada ao detector (140 keV)

disponível em gerador de baixo custo.

• 9 estados de oxidação (-1 a +7), o que lhe dá a

possibilidade de formar complexos com numerosos
agentes quelantes.

• Disponivel na forma de pertecnetato (TcO4−)

Diagnostic and Therapy
Radiofármacos para diagnóstico
Diagnostic and Therapy
Radiofármacos para diagnóstico

Brazilian Journal of Pharmaceutical Sciences vol. 42, n. 2, abr./jun., 2006

Diagnostic and Therapy
Radiofármacos para diagnóstico

Brazilian Journal of Pharmaceutical Sciences vol. 42, n. 2, abr./jun., 2006

Diagnostic and Therapy
Radiofármacos para Terapia

Radionuclídeos emissores de partículas β-

São os radionuclídeos mais utilizados em terapia. As
partículas β- permitem uma dose de radiação uniforme
apesar da sua deposição nos tecidos alvo (tumores) ser
heterogénea.

Radionuclídeos emissores de partículas α

Estes radionuclídeos são os escolhidos quando se
pretende que a radiação tenha um pequeno alcance.

Brazilian Journal of Pharmaceutical Sciences vol. 42, n. 2, abr./jun., 2006

Diagnostic and Therapy
Radiofármacos para Terapia

Brazilian Journal of Pharmaceutical Sciences vol. 42, n. 2, abr./jun., 2006

Diagnostic and Therapy
PET Radiopharmaceuticals

SPECT (Single Photon

Emission Computed
Tomography)
• Radiofármacos que emitem
radiação gamma

PET (Positron Emission

Tomography
• Radiofármacos emissores de
pósitrons (β+)

Brazilian Journal of Pharmaceutical Sciences vol. 42, n. 2, abr./jun., 2006

Diagnostic and Therapy
PET Radiopharmaceuticals
Name Diagnostic Tests
Fluorine-18 Bone scintigraphy.
18F-2-fluoro-2- study of metabolism in the brain and
deoxyglucose (2-FDG) heart and for the detection of epilepsy
and various tumors.
18F-fluorodopa Assessment of the presynaptic
dopaminergic function in the brain.
Oxygen-15 and Amonia- Myocardial and cerebral perfusion
13 studies
11C-L-methionine Detection of different types of
malignancies, reflecting the amino acid
utilization.
… …
Drug interactions / Adverse
reactions of
radiopharmaceuticals
Adverse Reactions /Interactions
Adverse Reactions /Interactions
EANM report 2001: an analysis
–Majority of reports were minor, unspecific and resolved quickly
without the need for treatment other than patient reassurance and
care

–Where treatment was given, this was symptomatic and commonly

involved antihistamine and/or steroid administration

–Diphosphonates continue to produce most reports, reflecting the

widespread use of these radiopharmaceuticals

–99mTc-MAA = vasovagal reaction +++

–131I-iodocholesterol: immediate and serious reaction (caused by

formulation component ?)

–Reaction to DMSA occured in children. This again reflects the

prevalence of use of this radiopharmaceutical in paediatric patients.
It is also possible that departments are more likely to be made
aware of and report reactions in children.
Adverse Reactions /Interactions
Adverse reactions to radiopharmaceuticals in
France - 2014
Five therapeutic radiopharmaceuticals ((131)I-sodium iodide, (131)I-
lipiodol, (89)Sr-chloride, (153)Sm-lexidronam, and (90)Y-
ibritumomab-tiuxetan) were involved in 48 reports
(97 adverse reactions: 86.6% serious, 9 deaths). Pulmonary
disorders represented 44.3% of ARRPs used for therapy, mainly
related to (131)I-lipiodol.

There were 34 diagnostic radiopharmaceuticals involved in 256

reports (451 adversereactions: 38.1% serious, 3 deaths); 8
diagnostic products ((99m)Tc-oxidronate, (18)F-fluorodeoxyglucose,
(99m)Tc-tin pyrophosphate, (99m)Tc-tetrofosmin, (99m)Tc-
dimercaptosuccinic acid, (201)Tl-chloride, (99m)Tc-sestamibi, and
(111)In-pentetate) accounted for two-thirds of ARRPs.

The most frequent adverse reactions were skin (34.4%), general

(18.2%), nervous (9.0%), and gastrointestinal disorders (7.0%).
There were 25 cases of altered images and 10 medication errors.
Adverse Reactions /Interactions
Adverse Reactions /Interactions
Drug interactions with radiopharmaceuticals

• Physico-chemical interaction (pharmaceutical

interaction)

•Pharmacokinetic interaction: interaction with

–Absorption (IV route for RP)
–Distribution
–Metabolism
–Elimination

•Competition of the RP with other drugs on its

target (tissue, receptor, transporters, enzyme,
etc…)
Adverse Reactions /Interactions

Physico-chemical interaction (pharmaceutical

interaction)

•Antiseptics
–Povidone iodine may release free 99mTcO4-
–Chlorhexidine gluconate can react to form Tc-gluconate
complex (kidney uptake)

•Interaction with syringe and catheter components

–Lipophilic compounds binding to plastic
–Need to measure empty syringe activity after administration
Adverse Reactions /Interactions

Pharmacokinetic interaction: interaction with

–Absorption (IV route for RP);

Não relevante

–Distribution
Acesso ao SNC ; bloqueio de transportadores

–Metabolism
Indutores e Inibidores enzimáticos

–Elimination
Alterações na filtração, reabsorção…
Adverse Reactions /Interactions

Interaction on the target

111In-pentetreotide (somatostatin analogue) with…

somatostatine analogues (sandostatin)

•123I /131 I-iodide thyroid uptake is influenced by

–Iodine containing medications (lugol, vitamin/mineral
supplements)

•Hepatobiliary imaging (99mTc-IDA) interact with

–Opiates (biliary tract spasm due to the contraction of the
sphincter of Oddi
Obrigado pela vossa atenção