Radio Pharmacy

5/10/2018 Radio Pharmacy - slidepdf.com

http://slidepdf.com/reader/full/radio-pharmacy 1/44

Introduction to

Radiopharmacy & Nuclear Medicine

or Molecular Imaging

Muh Yanis MusdjaDepartment of Radiopharmacy

BATAN Indonesia



History of Radiopharmacy

Medicinal applications since the discovery of Radioactivity

Early 1900’s Limited understanding of Radioactivity and dose



1912 — George de Hevesy

Father of the “radiotracer”

experiment.

Used a lead (Pb) radioisotope to

prove the recycling of meat by his

landlady.

Received the Nobel Prize inchemistry in 1943 for his concept of

“radiotracers”



Early use of radiotracers in medicine

1926: Hermann Blumgart, MD injected 1-6 mCi of “Radium C” to monitor blood flow (1st clinical use of a radiotracer)

1937: John Lawrence, MD used phosphorus-32 (P-32) to treat leukemia (1st use of artificial radioactivityto treat patients)

1937: Technetium discovered by E. Segre and C.Perrier



Early Uses continued

1939: Joe Hamilton, MD used radioiodine (I-131) for

diagnosis

1939: Charles Pecher, MD used strontium-89 (Sr-89) fortreatment of bone metastases.

1946: Samuel Seidlin, MD used I-131 to completely cureall metastases associated with thyroid cancer. This was thefirst and remains the only true “magic bullet”.

1960: Powell Richards developed the Mo-99/Tc-99m

generator

1963: Paul Harper, MD injected Tc-99m pertechnetate forhuman brain tumor imaging



What is a radiopharmaceutical?

A radioactive compound used for thediagnosis and therapeutic treatment of human diseases.

Radionuclide + Pharmaceutical

Part 1: Characteristics of a

Radiopharmaceutical



Radioactive Materials

Unstable nuclides

Combination of neutron and protons

Emits particles and energy to become a morestable isotope

N →

↑

Z

Chart of the Nuclides

http://sutekh.nd.rl.ac.uk/cgi-bin/imagemap/nuchart










Radiation decay emissions

Alpha ( a or 4He2+ )

Beta ( b- or e- )

Positron ( b+

) Gamma ( g )

Neutrons (n)






























Interactions of Emissions

Alpha ( a or4

He) High energy over short linear

range Charged 2+

Beta ( b- or e- ) Various energy, random

motion negative

Gamma ( g ) No mass, hv

Positron ( b+ ) Energy >1022 MeV, random

motion

Anihilation (2 511 MeV ~180°)

Negative

Neutrons (n) No charge, light elements

















































Half Life and Activity

Radioactive decay is astatisticalphenomenon

t1/2

l= decay constant

Activity

The amount of radioactive material

l

693.0=

t

el -

= *AA o
































Why use radioactive materials anyway?

Radiotracers

High sensitivity

Radioactive emission (no interferences) Nuclear decay process

Independent reaction

No external effect (chemical or biochemical)

Active Agent

Monitor ongoing processes




















Applications in Nuclear Medicine Imaging

Gamma or positron emitting isotopes

99m Tc, 111In, 18F, 11C, 64Cu

Visualization of a biological process

Cancer, myocardial perfusion agents

Therapy

Particle emitters

Alpha, beta, conversion/auger electrons

188Re, 166Ho, 89Sr, 90 Y, 212Bi, 225 Ac, 131I

Treatment of disease

Cancer, restenosis, hyperthyroidism
















































Ideal Characteristics of a

Radiopharmaceutical

Nuclear Properties

Wide Availability

Effective Half life (Radio and biological) High target to non target ratio

Simple preparation

Biological stability

Cost



















Ideal Nuclear Properties for

Imagining Agents

Reasonable energy emissions. Radiation must be able to penetrate several

layers of tissue.

No particle emission (Gamma only) Isomeric transition, positron ( b+ ), electron

capture

High abundance or “Yield” Effective half life

Cost

























Detection Energy Requirements

Best images between 100-300 KeV

Limitations

Detectors (NaI)

Personnel (shielding)

Patient dose

What else happens at higherenergies?

Lower photoelectric peak abundance, due

to the Compton effect

Cs-137 decay (662 KeV)

Energy →























Gamma Isotopes

Radionuclide T1/2 g (%) Tc-99m 6.02 hr 140 KeV (89)

Tl-201 73 hr 167 KeV (9.4)

In-111 2.21 d 171(90), 245(94)

Ga-67 78 hr 93 (40), 184 (20),300(17)

I-123 13.2 hr 159(83)

I-131 8d 284(6), 364(81),

637(7)

Xe-133 5.3 d 81(37)


















Positron Emission Tomography

b+ slows to thermal energiestwo 511KeV gammas raysemitted approximately 180° to each other

Coincidence detection

b+ travel some distance fromthe initial site

Cyclotron produced

Sharp images

Quantitative

Short Half Lives




























PET Isotopes

Nuclide T1/2 Production

Carbon-11 20.4 min 10B(d,n)11C

Nitrogen-13 9.96 min 12C(d,n)13N

Oxygen-15 2.05 min 14N(d,n)15O

16O(p,pn)15O12C(a,n)15O

Fluorine-18 110 min 18O(p,n)18F

Copper-64 12.7 hrs 64Ni(p,n)64Cu









































Imaging:

PET vs. SPECT

Biologically usefulisotopes

11C, 13N, 15O, 18F

More Quantitative ( b+ )

Very short T1/2

Very expensive

On site cyclotron

More complex andlarger molecules

Less quantitative

Longer half lives

Available world wide

Less expensive

No special productionequipment needed













































Radiopharmaceuticals for Therapy

Similar to imaging requirements Effective half life, high abundance, availability etc.

Particle emittersa, b, auger, amd conversion electrons

Particle energy Is higher better? Linear Energy Transfer (LET)

Additional g rays help with determining localization via imaging methods.























Some Radionuclides for Therapy

Radionuclide T1/2 Particle (MeV)Re-186 3.8 b- (1.07)

Re-188 17 hrs b- (2)

I-131 8 d b- (2)

P-32 14.3 d b- (1.7)

Sr-89 50.6 d b- (1.43)

Sm-153 1.9 d b- (0.81)

Bi-212 1 hr a (6.051)

































Therapeutic Radiation Dose

External cell receptors vs. DNA binding agents

Distance does matter Ionization and angle of interaction

Probability of DNA damage increases as distance decreases










http://micro.magnet.fsu.edu/cells/animals/animalmodel.html



DNA Damage in Radiotherapy Ionization

Direct and Indirect Alpha, beta, Auger electron, internal

conversion

Free Radical Induction

(R ., OH., HOO. ) Irreparable damage to DNA through

strand cleavage Double and single strand breaks

Base pair mutation

Therapy Goal: Induce cellular apoptosis































How do you prepare radioisotopes?

Site produced

Reactor or cyclotron

Limited by half life, facilities, Limited Shipping distance

Generator system Portable system

Reusable


















N →

↑

Z

Chart of the Nuclides

Reactor

Cyclotron













Production of Radionuclides

Nuclear Reactor (neutrons) Fission of U-235

Produces neutron richradioisotopes

Alpha, Beta, gamma decay (n, g ) reaction

Cyclotron (charged particles) Proton rich Positron, electron capture

(p,n), (d,n) reaction

most common

WSU Reactor

Washington University

St. Louis, MO





























A generator facilitates the separation of two radionuclides

(parent and daughter) from each other to yield a useable

radioisotope (daughter) for nuclear medicine studies.

Transient equilibrium

T1/2 daughter is less than 10 half lives than the parent

Ad= ld Ap e-lpt/( ld-lp)

Secular equilibrium

T1/2 of the parent much greaterthan 10 half lives of the daughter.

Activity at equilibrium (Ap = Ad ) Cs-137 (T1/2 = 30 y) and Ba-137m

(T1/2 = 2.5 min)


















































Ideal Characteristics for a Generator

Utilizes chemical characteristics of

the parent and the daughterradionuclide.

Output sterile and pyrogen free

Biological pH

Low radiation dose (Shielding)

Inexpensive.

Easy to produce.

Simple elution method

Reasonable half life of parent anddaughter

Radionuclide

Mixture

Column

Material

Desired Radionuclide

Eluant

Parent+

Daughter

Daughter

99mT “Th kh f N l M di i



































99m Tc “The workhorse of Nuclear Medicine

Industry”

Imaging Radionuclide

>90% FDA approve imagining agents are 99m Tc

Versatile chemistry

Ideal Nuclear characteristics

T1/2= 6.02 hr

Gamma, 140 KeV (89%)

Internal conversion (11%)

Energy vs. effectiveness of the

decay

Availability (generator)

99Mo→99m Tc




































Mallinckrodt/Tyco 99m Tc Generator

High specific activity 99Mo from 235U fission

Solid phase

Alumina

Liquid phase

0.9% saline

Generator easy to use Reliable separation


























Common radiochemical generators

Column Materials

1. Alumina (99Mo 99m Tc)

2. Zirconia(113Sn 113mIn)

3. Cation exchange resin(81Rb 81mKr)

4. Anion exchange resin(62Zn 62Cu)

5. Stannic Oxide(82Sr 82Rb)

Eluants

1. 0.9% NaCl(99Mo 99m Tc)

(82Sr 82Rb)

2. 0.05 N HCl(113Sn 113mIn)

3. O2 (81Rb 81mKr)

4. 1 N HCl 68Ge 68Ga)




















































































Effective Half life

(Radio and biological) Nuclear Decay (T1/2 )

Inherent statistical decay of the nuclide

Biological T1/2 Uptake/washout of the radiopharmaceutical

Equilibration

Decomposition

Pairing of biological and radionuclidic half lives is imperative to

optimize effectiveness of the drug.























High target to non target ratio

Lower activity require for detector statisticsand visualization of target tissue.

Low dose to non target tissues

Bone Marrow, gastro intestine

Decreased probability of organ overlap













How do agents localize at target tissues?

Method of Localization Active transport

Phagocytosis (Liver uptake)

Capillary blockade Simple/Exchange diffusion

Compartmental Localization

Chemisorption Antigen/Antibody reaction

S l T f R di h i l





















Several Types of Radiopharmaceuticals

1) Radioactive atom131I- ,201 Tl+, 81mKr

2) Radioactive compound I, C, or transition metals.

Covalent or coordination bond.

Radionuclide Chelate

+

Radioactive Comlex

I

N

O

O

H3C O

O

O

HN

O

H3C

Cocaine

Ritalin











































Methods of Labeling

Direct labeling Non specific binding

Antibodies, red blood cells

Site specific

Iodination (Tyr) , Methylation (amine, cys)

Chelate Metal Ligand coordination complex

Bifunctional Chelate

Normal chelate with biological targeting agent

Non specific

Chelate

Bifunctional Chelate


























Chelate Groups

Mixture of coordination donor atoms

N, O, S, P, etc.

Geared to metal and oxidation state

Monodentate to multi-dentate

1-8 coordination donors

Variety of coordination modes

Fac, mer, planar, equatorial, tetrahedral,asymmetric

E l Ch l S




















Example Chelate Systems

Various denticity (1-8) Variations of donor atoms

(N,S,O,P) Metal chelate ring size Complex stability Combination of multiple

ligands 2+2, 3+1,3+2

SH

NH HN

HN

O

O

O

OH

O

MAG3

NH HN

N N

OH OH

HMPAO

N N

OOH

OH

O

OH

O

DTPA

N

HO

O

HO

O

N N

O

OH

OH

O

OH

O

HO

O

EDTA

P

P

EtO

EtO

EtO OEt






























































Biological Target Design

Target a specific biological function

Biological TargetRadionuclide

Targeting Agent

T S ifi










Target Specific

Radiopharmaceuticals

Linker

TargetingMolecule

Radionuclide

BifunctionalChelate

Biological target

Targeting Molecules:

• Peptides• Peptide mimics

• Nucleotides

• Small molecules

• Antibodies

Targets (unique features)

• Cell surface receptors

• Transport

mechanisms

• Proteins

• DNA/RNA



































Types of Radiopharmaceuticals

Small molecule Fast circulation Good specificity Less than 1,000 daltons Metal chelate considerable % of mass

Large molecule Slow circulation Excellent specificity

Usually contains a biologically active motif Antibodies or fragments, B-12

Metal chelate insignificant % of mass


























Peptide Labeling

Small peptides for specificreceptors

Easy to produce

Greater number of variations tooptimize the system

Faster circulation through thebody

Maintains specificity. Better clearance

Via kidneys rather than liver

Somatostatin






















Labeling Antibodies

High specificity to an

antigen or binding site

Large molecular weight

50,000 daltons

Labeling Direct non specific method

( 131I)

Bifunctional chelate

Mab fragments (F(ab’)2, Fab)

Similar immune response toMab

Mab

F(ab’)2 Fab































http://www.srinstitute.com/abworldsummit/



Documents

Radio Pharmacy