RADIOPHARMACEUTICALS
František Melichar
UK 3. LF Praha
František Melichar
Radiopharmaceuticals
Scope of Presentation
•
Basic information
•
Diagnostic radiopharmaceuticals
•
–
SPECT,
–
PET
Therapeutic radiopharmaceuticals
–
palliative radiopharmaceuitcals
–
Immunotherapeutic radiopharmaceuticals
–
radiation synovectomy
Radiopharmaceuticals
A radiopharmaceutical is
a radioactive compound used for the
diagnosis and therapeutic treatment
of human diseases
Radiofarmaceuticals
Has two components :
•radionuclide
•pharmaceutical
proteins, Mab, inorganic, organic
compounds
Radiopharmaceuticals designing
First chosen is on basis of its
preferential localization in given
organ
or
its participation in the physiologic
function of the organ
Radiopharmaceuticals
Difference
between
radiochemicals and
radiopharmaceuticals
Ideal radiopharmaceutical
•Easy availability
•Shorf effective Half-Life
•Particle Emission
•Decay by Electron Capture or Isomeric
Transition
•High Target-to Nontarget Activity Ratio
Radiopharmaceuticals
Radioactive element - 133Xe
Labeled compounds - 131I iodinated
proteins
99mTc labeled compounds
[18F]FDG
Radiopharmaceuticals
Radiopharmaceuticals usually have
no pharmacologic effect, because in
most cases they are used in trace
quantities
Differ from conventional drugs
but they should be sterile and pyrogen
free
Easy availability (1)
Nuclear reactor (n,p), (n,)
A X (n,) A+1 X
Z
Z
98Mo (n,) 99Mo 99mTc
Particle accelerators
68Zn (p,2n) 67Ga
203Tl (p,3n) 201Pb +or EC 201Tl
Easy availability (2)
Starting material and product have diferent
chemical identities
Enriched target
Secondary source
Generator of radionuclides
99Mo/99mTc, 113Sn/113mIn,
81Rb/81mKr,82Sr/82Rb, 90Sr/90Y,68Ge/68Ga
Short Effective Half-Life
Physical half-life TP , t1/2
p=0,693/Tp - decay constant
Biologic half-life Tb
b=0,693/Tb
Effective half-life Te
e= p+ b
1/Te=1/Tp +1/Tb
Particle Emission
Diagnostic purpose -undesirable
Therapeutic purpose - ,
Radiation damage of abnormal cells
High Target-to Nontarget Activity
Ratio
To provide maximum efficacy in
the diagnosis (therapy)
and minimum radiation dose to the
patient
Factors Influencing the Design of
New Radiopharmaceuticals (1)
Compatibility-incorporation radionuclide
into the molecule 111In-DTPA
Stechiometry- concentration 99mTc approx.
10-9 mol/l
Charge of the Molecule
Size of Molecule
Factors Influencing the Design of
New Radiopharmaceuticals (2)
Protein Binding
Solubility
Stability
Biodistribution
Type of radiopharmaceutical
for diagnostic and therapy
• Parenteral pharmaceuticals (solutions or
colloid suspenses),
• peroral pharmaceuticals
• inhalation pharmaceuticals
• topic pharmaceuticals
Radionuclide suitable for application in
nuclear medicine
H
Li
Na
K
Rb
Cs
Fr
Be
Přirozené radioaktivní prvky (   
Mg
Ca Sc Ti V Cr Mn Fe Co Ni Cu
Sr Y Zr Nb Mo Tc Ru Rh Pd Ag
Ba La Hf Ta W Re Os Ir Pt Au
Ra Ac Rf Db Sg Bh Hs Mt
B
)
Al
Zn Ga
Cd In
Hg Tl
C
Si
Ge
Sn
Pb
N
P
As
Sb
Bi
O F
S Cl
Se Br
Te I
Po At
He
Ne
Ar
Kr
Xe
Rn
Ce Pr Nd Pm Sm Eu Gd Tb Dy Ho Er Tm Yb Lu
Th Pa U Np Pu Am Cm Bk Cf Es Fm Md No Lr
18F
99mTc
111In
67Ga
201Tl
Technécium
Indium
Gálium
Tálium
Fluór
110 min
 - 140 keV
 - 171, 245 keV
 - 93, 184 keV
 - 167, 135 keV
6,0 h
2,8 d
3,26 d
3,04 d
131 I
153Sm
186Re
Jód
Samárium
Rénium

 - 158 keV
8,02 d

 - 103 keV
46,7 h

 - 137 keV
3,78 d
+
Pozitronové
zářiče
Diagnostika
Terapie
© J.Lepej, ONM BB Slovakia
Diagnostic radiopharmaceuticals
for SPET
99mTc
dominant radionuclide in the NM
Radiofarmaceuticals precurzor
source is radionuclide generator
99Mo (-,T =66,2 h) / 99mTc (IT,T =6,02 h)
1/2
1/2
Other radionuclides for labeling radiopharmaceuticals
201 Tl (EC, T = 72 h) , 67 Ga (EC, T
1/2
1/2 =77,9 h),
111 In (EC, T
123 I (EC, T
1/2 =2,8 d),
1/2 = 13,2 h),
125 I (EC, T
1/2 =60,1 d),
81Rb (EC, +, T = 4,57h, /81mKr(IT, T = 13 s)
1/2
1/2
Radionuclide generator
99Mo
(-,T1/2=66,2 h) / 99mTc (IT,T1/2=6,02 hod)
99mTc-HMPAO
99mTc-ECD
Na99mTcO4
99mTc-HIDA
99mTc-SESTAMIBI
99mTc-L,L-EC
99mTc-PEG
liposomy
99mTc-Q12
99mTc-SCN
99mTc-IODIDA
99mTc-MAG
3
99mTc-(V)-DMSA
99mTc-(III)-DMSA
99mTc-anti-SSEA-1
99mTc-GH
99mTc-DTPA
99mTc-DPD
99mTc-MDP
99mTc-PYP
99mTc-EHDP
99mTc-DMPE
99mTc-citrát
99mTc-EDTMP
99mTc-MIBI
Další…
Sorption generator
Diagnostic radiopharmaceuticals
for PET
Emission + , anihililation gama kvant 511 keV
Cyclotron radionuclide preparation
Biogen nuclide, short T/2,
preparation( syntetisation automat), aseptic preparation ,
generator nuclide
124I, 86 Y
intravenose aplication
Positron (+) radiation - annihilation
1. a proton inside the 18F nucleus
turns to a neutron while a
positron (+) and a neutrino are
emitted
n + + + 
p
18
9
F 188O
 = 511 keV
2. positron gradually loses kinetic
energy during interaction with
surrounding atoms
3. positron combines
surrounding electron
with
an
4. positron and electron are being
converted
to
the
gamma
photons which are emitted at
180° to each other, each with
energy 511 keV - annihilation
18F
 = 511 keV
Application of Positron Emission
Tomography
Cerebral oxygen extraction and metabolism:
Cerebral blood volume:
[15O]-CO2
[15O]-O2
Myocardial blood volume:
[15O]-CO2,
Cerebral blood flow:
[15O]-H2O, [11C]-n-bulanol
Myocardial blood flow:
[15O]-H2O, [ 13N]-ammonia , [82Rb]-Rb+
[ 11C]-glucose, [18F]-FDG
Myocardical metabolism:
[ 11C]-palmitate, [ 11C]-acetate
Myocardial glucose metabolism: [18F]-FDG
Tumour glucose metabolism:
[18F]-FDG
Dopamine receptor binding:
[18F]-spiperone, [ 11C]-N-methylspiperone
Estrogen receptor binding:
[18F]-16-fluoro-17-estradiol
Plasma volume:
[68Ga]-citrate
Cerebral glucose metabolism:
18F
- Physical properties
18
9F
T1/2
+ 96.73%
EC 3.27%
= 109.8 minutes
E+max = 635 keV
E
= 511 keV
8O
18
Methods of preparation:
18O
( p , n ) 18F
16O
( 3He , n ) 18Ne
16O
16O
16O
( , 2n ) 18F
20Ne
( d ,  ) 18F
( 3He , p ) 18F
20Ne
( 3He , p ) 18F
(  , pn ) 18F
20Ne
( 3He , n ) 18Ne
18F
18F
Cyclotron production of 18F
Cyclotron U-120M
target
Filling equipment with a
reservoir of 18O enriched
target water H218O
Target equipment
The metabolic „fate“ of glucose (GLU)
and FDG
Glucose is used as a source of energy
FDG
The metabolic pathways of FDG are blocked after formation of FDG6-phosphate (FDG-6-Phos)
FDG remains in tissue.
Oncology
Chemotherapy efect evaluation
before therapy
A patient with a lymphoma
after therapy
Process of
18
2-[ F]FDG
syntesis
Labelling vessel
18F-FDG
C-18 column for
hydrolysis
synthesis assembly
C-18 column
Alumina coumn
Mannose triflate
Target water recovery
column
Radiochemical purity - HPLC method
• The area of each
peak is proporcional
to radioactivity of 18F
in selected form
• radiochemical purity
is given by
Ai
100[%]
 Ai
Ai = area of 18F-FDG
peak
SAi=total peak area
Radiodetection using a NaI (Tl) scintilation detector
[18F]NaF, injection – syntetisation modul
[18F]NaF injekce- picture of rabbit
Laboratory rabits, M, m = 3,1 kg,
activity 130 MBq i.v., 60 min before investigation
UT ~
UT ~
ECAT EXACT
2D, TAC = 68Ge/Ga
Em = 5,6‘
Tx = 2,4‘
Biograph duo LSO
3D, TAC = CT
Em = 3,0‘
Tx = ?‘‘
PET+CT
C
S
T
Nucleoside overview
1. Contended in the deoxyribonucleid acid
(DNA)
2. Contended in the ribonucleid acid (RNA)
3´-FLT and biosynteze DNA
thymidin
3´-[18F]FLT
• vazebná skupina –OH nahrazena –F
• řetězec DNA ukončen – nelze fosfodiesterovou
vazbou navázat další nukleosid
A,T,G,C – dusíkaté báze, P – H3PO4,
- deoxyribóza
Therapeutic radionuclide
Radionuclide for teletherapy
60Co
, 137Cs
Radionuklidy for brachytherapy
192 Ir, 145 Sm ,103Pd , 125I
Palliative aplication
[89Sr]SrCl2, ,,[153Sm]SmEDTMP (etylendiaminN,N,Nˇ,Nˇ,tetrakismethylenfosfonová kyselina)
[186 Re] ReHEDP (hydroxyethylendifosfonová kyselina)
Radiation synovectomy
compounds 166Ho, 186Re, 90Y
Therapeutic radiofarmaka
Compounds 131I, 32
P, 188Re, 90Y, 166Ho , radiolanthanoides
Immunotherapeutics- requested no added carry (carry free
radionuclide 90Y, 188Re
Therapeutic and maximum
range of  radionuclides in
tissue
Radionuklid Terapeut.dosah (mm) Maximální dosah (mm)
32
P
2.2
7.9
90
Y
2.8
10.8
153
Sm
0.7
3.1
165
Dy
1.3
5.6
166
Ho
2.1
8.7
186
Re
1.0
4.5
188
Re
2.1
10.1
198
Au
0.9
3.9
5. L.S.Johnson, J.C. Yanch, S. Shortkoff, C.L. Barnes, A.I. Spitzer, C.B. Sledge: Eur. J. Nucl. Med. 22, 977(1995).
ÚJF AV ČR,Laboratoř PET radiofarmak,1998
Chelation compounds
DTPA
Diethylentetraaminpentaacetyl
acid
H4do3a-PBnNH2
DOTA
,,
1,4,7,10 –tetraazacyklododekan-N,N,,N ,
,,,
N , tetraacetyl acid
10-[4-aminobenzyl(hydroxy)fosfonylmethyl]1,4,7,10-tetraazacyklo-1,4,7-triacetyl acid
166Ho
- Basic Information
Production of 166Ho
(n,  ) 166Ho activation

Nuclear reactor:
165Ho

Neutron Flux:
1013 - 1014 neutr.cm-2.s-1
166Ho

Physical Properties Overview
 - Radiation
•


1.85 MeV
1.77 MeV
• Therapeutic effect:
mm
81 keV
1379 keV
• Max. soft tissue penetration: 8.5
mm
• Gamma Camera
detection of 166Ho after
injection
Gamma Radiation
•

Maximum Energy:
Energy:
Half life time:
Daughter isotope:
(stable)
26.8 hours
Eu-166
2.1
166Ho-Macroaggregates
Rheumatoid Arthritis Treatment
The Principle of Therapy

Inflamed synovial membrane
destruction
The Method of Treatment

Radiation synovectomy
 Suspension of 166HoMacroaggregates particles
injection into the diseased joint
 Particles are trapped by the
inflamed synovial membrane
 Destruction of the membrane
through radiation
Advantages of the Therapy


Does not require the
hospital stay and long
rehabilitation period
Minimise of the risks
associated with surgery
Disadvantages

non-biodegradable
particles
CHITOSAN CHARACTERISATION AND
MEDICAL APPLICATIONS [1-3]

organic matrix in skeletons of crabs,
 biodegradable, biocompatible, non-toxic pharmaceutical carriers,
 hemostatics and blood anticoagulants,
 aggregation of leukemia cells,
 enzyme immobilization,
 hypocholesterolemic activity -inhibition of micille formation,
adsorption of cholesterol, fatty acids and monoglycerides,
 metal ion chelation (amino groups of chitosan),
 gel-forming in neutral conditions, soluble and viscous in acidic
conditions.
1. Muzzarelli R.A.: Chitin, Pergamon Press, New York,1978
2. The Polysaccharides v.3 Edited by G.O.Aspinall, Academic Press, Inc. 1985
3. Šístková N.V., Franta P., Melichar F. : Report NPI, NRI 1998