Iodine CIT

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                 •    INTRODUCTION


          •     LABELLING REACTION

      •       USES and APPLICATIONS

                  •   CONCLUSIONS

              Paola Panichelli, Vancouver 08/09/2008
[124I]Iodine-β-CIT is a radiopharmaceutical injectable solution. [124I]β-CIT
belongs to a group of compounds derived from cocaine that bind to dopamine
transporters (TDA). The replacement of the ester link between tropane and
phenyl fraction in cocaine with a stable C-C gives rise to a higher metabolic
stabilization and enhance the affinity of union with the TDA.

(124I) is a radioactive isotope of iodine which is produced by the following nuclear reaction:
                                      124Te(p,n) 124I
 from 124TeO with an isotopic purity higher than 99.5%.

  124I has a half-life of 4.176 days
  (100.22 hours). 124I decays in stable
  Tellurium [124Te] ( 100%) by an
  emission of β+ (23%) with a
  maximum energy of 0.603 MeV and
  by an electronic capture (>98%)
  according the decay scheme:
                      124I is produced on an 18
                      MeV IBA cyclotron using a
                      COSTIS (Compact Solid
                      Target Irradiation System)
                      solid target holder. COSTIS
                      is designed for irradiation
                      of solid materials.
    IBA Cyclotron                                     COSTIS Solid Target
                      Peculiarities of Compact Solid Target System
                      (COSTIS) Solid target:
                      -Allows the use any solid form (oxides, plated and
                      pressed powder compounds )
                      -Allows degrading of energy, for optimizing
                      radioisotope yield and minimizing impurities.
                      -Allows helium cooling for irradiation of           low
                      conductivity materials.
                      -Allows the repeated use of target disks (in the case
                      of 124 I up to ten times).
COSTIS Solid Target   - Allows remote handling of irradiated target disk.
                   RADIOIODINE PRODUCTION:
Evaluation of the nuclear reaction best value of irradiation energy:

Beam energy has a cross section of 15.4 Mev maximum in order to reduce the
incident energy of protons and limit the production of 123I.

        124Te(p,n)124I Cross Section          124Te(p,n)123I Cross Section
In this range of energy the time to limit 123I percentage to less than 5% is
about 84h; so we decided to set the time of application (TOA) of the mixture at
96h from the end of synthesis (EOS)
 124I   Recovery:
 -The separation of radioiodine (124I) from the irradiated target occurs by
 a thermo-distillation process.
 -TERIMO is an automated module for thermo-chromatographic
 separation of radionuclides :
   •     GMP compliant module
   •     Small footprint – fits into mini-hot
   •     Autonomous, PLC controlled
   •     Ethernet     based       PLC/SCADA
The apparatus for thermo-distillation separation of radioiodine (124I) from the
irradiated 124TeO2 possesses an holder in quartz for positioning of the disk, a
fast electric heater, a thermocouple for temperature measurements, an alumina
trap for adsorbing tellurium oxide vapours, and a quartz bulb containing the
trapping solution.
The irradiated target is placed inside the quartz furnace of the synthesis
module TERIMO. It is heated up 780° C until it melts, and the radioiodine is
released as (124I2) gas and trapped in an absorption solution of NaOH 0.02M.
                         USES and APPLICATIONS:
  Iodine-124(124 I) labeled compounds can be used with PET for
imaging and dosimetry of radioiodine treatments

The most interesting molecules in nuclear medicine labeled with
124I are:

(124 I)Iodoßcit                  (124I)IodoDopa             (124I)-PIB
CH3                               [124I]
N                                                                        I124
      COOCH3                                    COOH           S

                                           H   NH2                              NHCH3

                            HO                                 N


                          RADIOLABELLING REACTION:
The synthesis of [124I]-β-CIT consists of the following procedure:
 H3C                                                                            H3C
        N                                                                             N
                 CO2Me                                                                          CO2Me

                                                   1)Na124I/CH3 CO3H

                                   Sn(CH3)3                                                                    124
                                                   2)C18 Sep Pack Lignt

[2β-carbomethoxy-3β-(4-trimethylstannylphenyl)tropane]         [124I]Iodine-β-CIT ( 2β-carbomethoxy-3β-(4-iodiophenyl)-tropane

          The first step of the synthesis is the iodination of the stannylated
precursor.Ortophosforic acid is used to make a mixture acid. Peracetic acid is used
      to transforms the Iodide (I-) in Iodine (I2) for the electrophylic reaction.
             Subsequently Iodine attacks the tin group of the precursor.
                       Sodium Bisolphite traps the iodine excess.
    After Iodination, the compound is purified through a C-18 cartridge which is
                          washed with water and eluted with
                             an ethanolic solution at 95 %.
                      Product’s Specifications :
Specifications for radiopharmaceuticals should include:

•Radioactive concentration

•Radionuclidic Identity

•Radionuclidic purity

•Radiochemical identity
                                     EMEA/CHMP/QWP/306970/2007: Guideline on
•Radiochemical purity                Radiopharmaceuticals
•Chemical purity                     European Pharmacopoeia 5.0 01/2005:0125:
                                     Radiopharmaceuticals Preparation
•Specific radioactivity

•Bacterial Endotoxins-Pyrogens



Appearance: Clear colourless, free of particles solution

Radioactive concentration: the radioactivity of a radionuclide per unit volume

    Radioconcentration is a specific typical control for a radiopharmaceutical,
    to determine stability of strength, as well as uniformity of dosage units.

Radionuclidic Identity: a radionuclide can be identify by its mode of decay, its
half-life and the energy of its nuclear emission.

   Characteristic peak of 124I decay scheme
   Characteristic peaks of beta+ emitters
   Half life of 124I

Radionuclidic purity: The ratio, expressed as a percentage, of the radioactivity
of the radionuclide concerned to the total radioactivity of the radiopharmaceutical

It is aimed at excluding those isotopes having characteristics similar to 124I, that,
if present in the product, would interfere with the emission spectrum and hence
with diagnostic imaging.
Radiochemical identity

Radiochemical purity: the ratio expressed as a percentage of the radioactivity of
the radionuclide concerned which is present in the radiopharmaceutical
preparation in the stated chemical form, to the total radioactivity of that
radionuclide present in the radiopharmaceutical preparation.

Chemical purity: on radiopharmaceutical preparations chemical purity is
controlled by specifying limits on chemical impurities.

 Radiochemical purity and Chemical purity and used to evaluate the presence
                       and the quantity of impurities..

Specific Radioactivity: the radioactivity of a radionuclide per unit mass of the
elements or of the chemical form concerned.

pH, Osmolality, Bacterial Endotoxins-Pyrogens, Sterility must be tested for all
products intended for parenteral use.
SPECIFICATIONS                      TEST                 LIMITS
Appearance                          Visual Inspection    Clear; colorless solution free of particulates
Radioactive concentration           Ionization chamber   13MBq/mL ± 10%
( at calibration time and date)
Radionuclidic identification        Gamma Spectroscopy   Energy of γ-ray Peak at 511 Kev and
Radionuclidic identification        Gamma Spectroscopy   Peak at 602.72 Kev / 1691.02 Kev/ 722.79Kev

Half-life                           Gamma Spectroscopy   4.18 days ±5%

Radionuclidic purity                Gamma Spectroscopy   ≥ 95 %

Radiochemical Purity
HPLC (test A)                       HPLC
[124I]-β-CIT                                             ≥ 95 %
TLC (test B)                        TLC
[124I]-β-CIT                                             ≥ 95 %
Chemical Purity
HPLC (test A)
[124I]-β-CIT                        HPLC                 ≤ ,2 µg/ml

SPECTROPHOTOMETRY UV/VIS (Test B)   Spectrophotometer
Tellurium                                                ≤ 1 µg/ml
Specific Radioactivity              HPLC                 >107.3GBq/ml
pH                                  potentiometric       5≤pH≤6
Residual Solvents                   GC
Ethanol                                                  ≤5 mg/ml
osmolality                          osmometer            260-320 mosm/kg
Bacterial Endotoxin                 LAL Ph.Eur           ≤17.5 EU/mL
Sterility                           Ph.Eur               sterile
                  SPC for AIC REGISTRATION
   [124I]-β-CIT is a new radiopharmaceutical compound for
 neurodegenerative disorder diagnosis with PET imaging.

   [124I]-β-CIT                                   Cocaine

It is an anologue of cocaine and binds to dopamine and serotonin
Neurodegenerative disorders, such as Parkinson’s disease, are
characterized by degeneration of dopaminergic neurons in the
substantia nigra, with loss of their nerve terminals in the basal
ganglia structure, especially in the striatum.

Phase III clinical trial, open label, non-randomized, single dose

Thirty Parkinson patients “de novo”

124I Beta CIT

Maximum injectable dose 18 MBq

Clinical Sites for patients recruitment
- Firenze
- Grosseto
- Pisa
  124I Beta CIT Dosimetry:
                  123          124
                    I-β-CIT      I-β-CIT
                  (mGy/MBq)    (mGy/MBq)
   Polmone              0,1    0,8360656
     Liver              0,09   0,7791045
Colon Descendig         0,05   0,4484536
Colon Ascending         0,05         0,425
Urinary bladder         0,03         0,26
    Bowel               0,02   0,1670588
   Surrenal             0,02   0,2057143
   Pancreas             0,02   0,1605263
     Bone               0,02   0,1308642
   Ovarium              0,02   0,1612245
    Kidney              0,01   0,0909091
   Stomach              0,01   0,0826087
    Marrow              0,01   0,062766
    Speen               0,01   0,0828571
    Breast              0,01   0,0928571
    Thyroid             0,01   0,0980392
    Testes              0,01   0,1072464
           [124I]-β-CIT                   vs            [123I]-β-CIT

With respect to [123I]-β-CIT, the most used radiotracer for SPECT (Single
   Photon Emission Tomography) diagnosis of Parkinson disease, the
   compund labeled with iodine-124 has several advantages in the diagnostic

1. the possibility of a reliable quantitative analysis of tracer kinetics, instead of
    the semi-quantitative approach with iodine-123 in SPECT;

2. the possibility to follow over time tracer kinetics, thanks to the longer half life
    of 124I (t1/2 :4.18 d) than 123 I (t1/2:13,27 h).

3. the better resolution of PET in comparison to SPECT.
Nowadays dopamine transporters 124 I-tracers
seem to be the best markers for identifying
Parkinson’s disease patients with high
sensitivity and specificity .

Dopamine transporter (DAT) imaging with
[124I]-β-CIT represents a new promising
diagnostical technique to evaluate dopamine
neuron loss, which is responsible for most of
the symptoms in Parkinson’s Disease patients.

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