• INTRODUCTION

• RADIOIODINE PRODUCTION

• LABELLING REACTION

• USES and APPLICATIONS

• CONCLUSIONS

Paola Panichelli, Vancouver 08/09/2008

[[124124I]IodineI]Iodine--ββ--CITCIT

[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.

INTRODUCTION:

124Te(p,n) 124I

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 a radioactive isotope of iodine which is produced by the following nuclear reaction:

from 124TeO with an isotopic purity higher than 99.5%.

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

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).- Allows remote handling of irradiated target disk.

Irradiation: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)

RADIOIODINE PRODUCTION:

-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 :

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.

124I Recovery:

• GMP compliant module• Small footprint – fits into mini-hot

cells• Autonomous, PLC controlled• Ethernet based PLC/SCADA

communication

USES and APPLICATIONS:

Iodine-124(124 I) labeled compounds can be used with PET forimaging and dosimetry of radioiodine treatments

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

(124 I)IodoßcitCH3N

I124

COOCH3

(124I)IodoDopa

(124I)-Curcumina

(124I)-PIB

N

S

NHCH3

HOI124[124I]

HO

OH

COOH

NH2H

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

NH3C

CO2Me

Sn(CH3)3

NH3C

CO2Me

124I

1)Na124I/CH3CO3H

2)C18 Sep Pack Lignt

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 withan ethanolic solution at 95 %.

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

•Appearance

•Radioactive concentration

•Radionuclidic Identity

•Radionuclidic purity

•Radiochemical identity

•Radiochemical purity

•Chemical purity

•Specific radioactivity

•Bacterial Endotoxins-Pyrogens

•pH

•Osmolality

•Sterility

Product’s Specifications :Specifications for radiopharmaceuticals should include:

EMEA/CHMP/QWP/306970/2007: Guideline on Radiopharmaceuticals

European Pharmacopoeia 5.0 01/2005:0125: Radiopharmaceuticals Preparation

Appearance: Clear colourless, free of particles solution

Radioactive concentration: the radioactivity of a radionuclide per unit volume

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+ emittersHalf life of 124I

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

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 hencewith diagnostic imaging.

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

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.

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.

pH, Osmolality, Bacterial Endotoxins-Pyrogens, Sterility must be tested for all products intended for parenteral use.

SPECIFICATIONS TEST LIMITSAppearance Visual Inspection Clear; colorless solution free of particulates

Radioactive concentration( at calibration time and date)

Ionization chamber 13MBq/mL ± 10%

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 PurityHPLC (test A)[124I]-β-CITTLC (test B)[124I]-β-CIT

HPLC

TLC≥ 95 %

≥ 95 %

Chemical Purity HPLC (test A)[124I]-β-CIT

SPECTROPHOTOMETRY UV/VIS (Test B)

Tellurium

HPLC

Spectrophotometer UV/VIS

≤ ,2 µg/ml

≤ 1 µg/ml

Specific Radioactivity HPLC >107.3GBq/ml

pH potentiometric 5≤pH≤6

Residual SolventsEthanol

GC≤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.

It is an anologue of cocaine and binds to dopamine and serotonintransporters.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.

[124I]-β-CIT Cocaine

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

PatientsThirty Parkinson patients “de novo”

Radiopharmaceutical124I Beta CIT

DoseMaximum injectable dose 18 MBq

Clinical Sites for patients recruitment- Firenze- Grosseto- Pisa

CLINICAL PROTOCOL:

124I Beta CIT Dosimetry:

Lung123I-β-CIT(mGy/MBq)

124I-β-CIT(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

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 applications:

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.

[124I]-β-CIT vs [123I]-β-CIT

USES and APPLICATIONS:

EXAMPLE OF PET IMAGING WITH [124I]-Β-CIT

CONCLUSIONS: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.