RADIOPHARMACEUTICALS

František Melichar

UK 3. LF Praha

RadiopharmaceuticalsScope of Presentation

• Basic information

• Diagnostic radiopharmaceuticals

– SPECT,

– PET

• Therapeutic radiopharmaceuticals

– palliative radiopharmaceuitcals

– Immunotherapeutic radiopharmaceuticals

– radiation synovectomy

František MelicharFrantišek Melichar

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

ZX (n,) A+1 ZX

98Mo (n,) 99Mo 99mTc

Particle accelerators68Zn (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 radionuclides99Mo/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

© J.Lepej, ONM BB Slovakia

153SmSamárium

- 103 keV46,7 h

186ReRénium

- 137 keV3,78 d

131 IJód

- 158 keV8,02 d

Ac

HB FC N O Ne

Na Mg Al ClSi P S ArGa BrGe As Se KrK Ca

Rb Sr In ISn Sb Te XeTl AtPb Bi Po RnCs Ba

Fr Ra

He

Cu ZnCo NiMn FeV CrSc TiAg CdRh PdTc RuNb MoY ZrAu HgIr PtRe OsTa WLa Hf

MtBh HsDb SgRf

Dy HoGd TbSm EuNd PmCe Pr Yb LuEr Tm

Cf EsCm BkPu AmU NpTh Pa No LrFm Md

Li BePřirozené radioaktivní prvky ( )

Radionuclide suitable for application in nuclear medicine

99mTcTechnécium - 140 keV

6,0 h

18FFluór+

110 min

111InIndium

- 171, 245 keV2,8 d

67GaGálium

- 93, 184 keV3,26 d

201TlTálium

- 167, 135 keV3,04 d

DiagnostikaTerapie

Pozitronovézářiče

Diagnostic radiopharmaceuticals for SPET

99mTc dominant radionuclide in the NMRadiofarmaceuticals precurzor

source is radionuclide generator

99Mo (-,T1/2=66,2 h) / 99mTc (IT,T1/2=6,02 h)

Other radionuclides for labeling radiopharmaceuticals

201 Tl (EC, T1/2= 72 h) , 67 Ga (EC, T1/2 =77,9 h),111 In (EC, T1/2 =2,8 d), 123 I (EC, T1/2 = 13,2 h),

125 I (EC, T1/2 =60,1 d),

81Rb (EC, +, T1/2 = 4,57h, /81mKr(IT, T1/2 = 13 s)

Radionuclide generator99Mo (-,T1/2=66,2 h) / 99mTc (IT,T1/2=6,02 hod)

99Mo

99Ru

99mTc T1/2 = 6,02 hodin

T1/2 = 66,2 hodin

= 140 keV

-

14%

-

86%

99Tc T1/2 = 2.1 x 105 let

-

100%

99mTc-HMPAO

99mTc-ECD

Na99mTcO4

99mTc-HIDA

99mTc-SESTAMIBI

99mTc-L,L-EC

99mTc-PEG liposomy

99mTc-Q12

99mTc-SCN

99mTc-IODIDA

99mTc-MAG3

99mTc-(V)-DMSA

99mTc-(III)-DMSA

99mTc-anti-SSEA-1

99mTc-GH

99mTc-MIBI99mTc-DTPA

99mTc-MDP

99mTc-EHDP

99mTc-citrát

99mTc-DPD

99mTc-PYP

99mTc-DMPE

99mTc-EDTMP

Další…

Sorption generator

Diagnostic radiopharmaceuticals

for PETEmission + , anihililation gama kvant 511 keV

Cyclotron radionuclide preparation Cyclotron radionuclide preparation

Biogen nuclide, short T/2, Biogen nuclide, short T/2,

preparation( syntetisationpreparation( syntetisation automat), aseptic preparation , automat), aseptic preparation ,

generator nuclidegenerator nuclide

124124I, I, 86 86 YY

intravenose aplicationintravenose aplication

Positron (+) radiation - annihilation

p n + + +

18F

= 511 keV

= 511 keV

OF 188

189

1. a proton inside the 18F nucleus turns to a neutron while a positron (+) and a neutrino are emitted

2. positron gradually loses kinetic energy during interaction with surrounding atoms

3. positron combines with an surrounding electron

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

Application of Positron Emission Tomography

Cerebral oxygen extraction and metabolism: [15O]-O2

Cerebral blood volume: [15O]-CO2

Myocardial blood volume: [15O]-CO2,

Cerebral blood flow: [15O]-H2O, [11C]-n-bulanol

Myocardial blood flow: [15O]-H2O, [ 13N]-ammonia , [82Rb]-Rb+

Cerebral glucose metabolism: [ 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

18F - Physical properties

8O

9F

+ 96.73%EC 3.27%

T1/2 = 109.8 minutes

E+max = 635 keV

E = 511 keV

Methods of preparation:

18O ( p , n ) 18F 16O ( , 2n ) 18F

16O ( 3He , n ) 18Ne 18F 20Ne ( d , ) 18F

16O ( 3He , p ) 18F 20Ne ( 3He , p ) 18F

16O ( , pn ) 18F 20Ne ( 3He , n ) 18Ne 18F

18

18

Cyclotron production of 18F

Cyclotron U-120Mtarget

Filling equipment with a reservoir of 18O enriched target water H2

18O

Target equipment

The metabolic „fate“ of glucose (GLU) and FDG

The metabolic pathways of FDG are blocked after formation of FDG-6-phosphate (FDG-6-Phos) FDG remains in tissue.

FDG

Glucose is used as a source of energy

Oncology

before therapy after therapy

A patient with a lymphoma

Chemotherapy efect evaluation

Process of 2-[18 F]FDG syntesis

Alu

min

a c

ou

mn

C-1

8 c

olu

mn

Ta

rge

t w

ate

r re

cov

ery

co

lum

n

Ma

nn

ose

tri

fla

te

Labelling vesselC-18 column for hydrolysis

18F-FDG synthesis assembly

Radiochemical purity - HPLC method

• The area of each peak is proporcional to radioactivity of 18F in selected form

• radiochemical purity is given by

Ai = area of 18F-FDG peak

i=total peak area

[%]100 Ai

Ai

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

ECAT EXACT2D, TAC = 68Ge/GaEm = 5,6‘Tx = 2,4‘

Biograph duo LSO3D, TAC = CTEm = 3,0‘Tx = ?‘‘

UT ~ UT ~

C

S T PET+CT

Nucleoside overview1. 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 radionuclideRadionuclide 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 synovectomycompounds 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)32P 2.2 7.990Y 2.8 10.8

153Sm 0.7 3.1165Dy 1.3 5.6166Ho 2.1 8.7186Re 1.0 4.5188Re 2.1 10.1198Au 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

DTPADiethylentetraaminpentaacetyl

acid

DOTA1,4,7,10 –tetraazacyklododekan-N,N,,N,,,

N,,,, tetraacetyl acid

H4do3a-PBnNH2

10-[4-aminobenzyl(hydroxy)fosfonylmethyl]-

1,4,7,10-tetraazacyklo-1,4,7-triacetyl acid

166Ho - Basic Information

166Ho Physical Properties Overview

- Radiation

• Maximum Energy: 1.85 MeV1.77

MeV Gamma Radiation

• Energy: 81 keV

1379 keV

Half life time: 26.8 hours Daughter isotope:Eu-166 (stable)

• Therapeutic effect: 2.1 mm

• Max. soft tissue penetration: 8.5 mm

Production of 166Ho

Nuclear reactor: 165Ho (n, ) 166Ho activation

Neutron Flux: 1013 - 1014 neutr.cm-2.s-1

• Gamma Camera detection of 166Ho after injection

166Ho-Macroaggregates

Rheumatoid Arthritis Treatment

The Principle of Therapy

Inflamed synovial membrane destruction

The Method of Treatment

Radiation synovectomy

Suspension of 166Ho-Macroaggregates 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,19782. The Polysaccharides v.3 Edited by G.O.Aspinall, Academic Press, Inc. 19853. Šístková N.V., Franta P., Melichar F. : Report NPI, NRI 1998