[124 I]Iodine-β-CIT• INTRODUCTION• RADIOIODINE PRODUCTION• LABELLING REACTION• USES and APPLICATIONS• CONCLUSIONSPaola Panichelli, Vancouver 08/09/2008
INTRODUCTION:[ 124 I]Iodine-β-CIT is a radiopharmaceutical injectable solution. [ 124 I]β-CITbelongs to a group of compounds derived from cocaine that bind to dopaminetransporters (TDA). The replacement of the ester link between tropane andphenyl fraction in cocaine with a stable C-C gives rise to a higher metabolicstabilization and enhance the affinity of union with the TDA.( 124 I) is a radioactive isotope of iodine which is produced by the following nuclear reaction:124Te(p,n) 124Ifrom 124TeO with an isotopic purity higher than 99.5%.124I has a half-life of 4.176 days(100.22 hours). 124 I decays in stableTellurium [ 124 Te] ( 100%) by anemission of β+ (23%) with amaximum energy of 0.603 MeV andby an electronic capture (>98%)according the decay scheme:
Irradiation:IBA CyclotronCOSTIS Solid TargetRADIOIODINE PRODUCTION:124I is produced on an 18MeV IBA cyclotron using aCOSTIS (Compact SolidTarget Irradiation System)solid target holder. COSTISis designed for irradiationof solid materials.COSTIS Solid TargetPeculiarities of Compact Solid Target System(COSTIS) Solid target:-Allows the use any solid form (oxides, plated andpressed powder compounds )-Allows degrading of energy, for optimizingradioisotope yield and minimizing impurities.-Allows helium cooling for irradiation of lowconductivity materials.-Allows the repeated use of target disks (in the caseof 124 I up to ten times).- 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 theincident energy of protons and limit the production of 123I.124Te(p,n)124I Cross Section124Te(p,n)123I Cross SectionIn this range of energy the time to limit 123I percentage to less than 5% isabout 84h; so we decided to set the time of application (TOA) of the mixture at96h from the end of synthesis (EOS)
124I Recovery:-The separation of radioiodine ( 124 I) from the irradiated target occurs bya thermo-distillation process.-TERIMO is an automated module for thermo-chromatographicseparation of radionuclides :• GMP compliant module• Small footprint – fits into mini-hotcells• Autonomous, PLC controlled• Ethernet based PLC/SCADAcommunicationThe apparatus for thermo-distillation separation of radioiodine ( 124 I) from theirradiated 124 TeO2 possesses an holder in quartz for positioning of the disk, afast electric heater, a thermocouple for temperature measurements, an aluminatrap for adsorbing tellurium oxide vapours, and a quartz bulb containing thetrapping solution.The irradiated target is placed inside the quartz furnace of the synthesismodule TERIMO. It is heated up 780° C until it melts, and the radioiodine isreleased as ( 124 I2) 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 forimaging and dosimetry of radioiodine treatmentsThe most interesting molecules in nuclear medicine labeled with124I are:( 124 I)Iodoßcit( 124 I)IodoDopa( 124 I)-PIBCH 3NCOOCH 3[ 124 I]COOHHOSI 124HNH 2NHCH 3I 124HONOH( 124 I)-Curcumina
RADIOLABELLING REACTION:The synthesis of [ 124 I]-β-CIT consists of the following procedure:H 3 CHN3 CNCO 2 MeCO 2 Me1)Na 124 I/CH 3 CO 3 HSn(CH 3 ) 32)C 18 Sep Pack Lignt124 I[2β-carbomethoxy-3β-(4-trimethylstannylphenyl)tropane][124I]Iodine-β-CIT ( 2β-carbomethoxy-3β-(4-iodiophenyl)-tropaneThe first step of the synthesis is the iodination of the stannylatedprecursor.Ortophosforic acid is used to make a mixture acid. Peracetic acid is usedto 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 iswashed with water and eluted withan ethanolic solution at 95 %.
Product’s Specifications :Specifications for radiopharmaceuticals should include:•Appearance•Radioactive concentration•Radionuclidic Identity•Radionuclidic purity•Radiochemical identity•Radiochemical purity•Chemical purity•Specific radioactivityEMEA/CHMP/QWP/306970/2007: Guideline onRadiopharmaceuticalsEuropean Pharmacopoeia 5.0 01/2005:0125:Radiopharmaceuticals Preparation•Bacterial Endotoxins-Pyrogens•pH•Osmolality•Sterility
Appearance: Clear colourless, free of particles solutionRadioactive concentration: the radioactivity of a radionuclide per unit volumeRadioconcentration 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, itshalf-life and the energy of its nuclear emission.Characteristic peak of 124 I decay schemeCharacteristic peaks of beta+ emittersHalf life of 124 IRadionuclidic purity: The ratio, expressed as a percentage, of the radioactivityof the radionuclide concerned to the total radioactivity of the radiopharmaceuticalpreparation.It is aimed at excluding those isotopes having characteristics similar to 124 I, that,if present in the product, would interfere with the emission spectrum and hencewith diagnostic imaging.
Radiochemical identityRadiochemical purity: the ratio expressed as a percentage of the radioactivity ofthe radionuclide concerned which is present in the radiopharmaceuticalpreparation in the stated chemical form, to the total radioactivity of thatradionuclide present in the radiopharmaceutical preparation.Chemical purity: on radiopharmaceutical preparations chemical purity iscontrolled by specifying limits on chemical impurities.Radiochemical purity and Chemical purity and used to evaluate the presenceand the quantity of impurities..Specific Radioactivity: the radioactivity of a radionuclide per unit mass of theelements or of the chemical form concerned.pH, Osmolality, Bacterial Endotoxins-Pyrogens, Sterility must be tested for allproducts intended for parenteral use.
SPECIFICATIONS TEST LIMITSAppearance Visual Inspection Clear; colorless solution free of particulatesRadioactive concentration( at calibration time and date)Ionization chamber 13MBq/mL ± 10%Radionuclidic identification Gamma Spectroscopy Energy of γ-ray Peak at 511 Kev andRadionuclidic identification Gamma Spectroscopy Peak at 602.72 Kev / 1691.02 Kev/ 722.79KevHalf-life Gamma Spectroscopy 4.18 days ±5%Radionuclidic purity Gamma Spectroscopy ≥ 95 %Radiochemical PurityHPLC (test A)[ 124 I]-β-CITTLC (test B)[ 124 I]-β-CITChemical PurityHPLC (test A)[ 124 I]-β-CITSPECTROPHOTOMETRY UV/VIS (Test B)TelluriumHPLCTLCHPLCSpectrophotometerUV/VIS≥ 95 %≥ 95 %≤ ,2 µg/ml≤ 1 µg/mlSpecific Radioactivity HPLC >107.3GBq/mlpH potentiometric 5≤pH≤6Residual SolventsEthanolGC≤5 mg/mlosmolality osmometer 260-320 mosm/kgBacterial Endotoxin LAL Ph.Eur ≤17.5 EU/mLSterility Ph.Eur sterile
SPC for AIC REGISTRATION [124I]-β-CIT is a new radiopharmaceutical compound forneurodegenerative disorder diagnosis with PET imaging.[ 124 I]-β-CIT CocaineIt is an anologue of cocaine and binds to dopamine and serotonintransporters.Neurodegenerative disorders, such as Parkinson’s disease, arecharacterized by degeneration of dopaminergic neurons in thesubstantia nigra, with loss of their nerve terminals in the basalganglia structure, especially in the striatum.
CLINICAL PROTOCOL:Phase III clinical trial, open label, non-randomized, single dosePatientsThirty Parkinson patients “de novo”Radiopharmaceutical124I Beta CITDoseMaximum injectable dose 18 MBqClinical Sites for patients recruitment- Firenze- Grosseto- Pisa
124I Beta CIT Dosimetry:Lung123 I-β-CIT(mGy/MBq)124 I-β-CIT(mGy/MBq)Polmone 0,1 0,8360656Liver 0,09 0,7791045Colon Descendig 0,05 0,4484536Colon Ascending 0,05 0,425Urinary bladder 0,03 0,26Bowel 0,02 0,1670588Surrenal 0,02 0,2057143Pancreas 0,02 0,1605263Bone 0,02 0,1308642Ovarium 0,02 0,1612245Kidney 0,01 0,0909091Stomach 0,01 0,0826087Marrow 0,01 0,062766Speen 0,01 0,0828571Breast 0,01 0,0928571Thyroid 0,01 0,0980392Testes 0,01 0,1072464
[ 124 I]-β-CIT vs [ 123 I]-β-CITWith respect to [ 123 I]-β-CIT, the most used radiotracer for SPECT (SinglePhoton Emission Tomography) diagnosis of Parkinson disease, thecompund labeled with iodine-124 has several advantages in the diagnosticapplications:1. the possibility of a reliable quantitative analysis of tracer kinetics, instead ofthe semi-quantitative approach with iodine-123 in SPECT;2. the possibility to follow over time tracer kinetics, thanks to the longer half lifeof 124 I (t1/2 :4.18 d) than 123 I (t1/2:13,27 h).3. the better resolution of PET in comparison to SPECT.
USES and APPLICATIONS:EXAMPLE OF PET IMAGING WITH [124I]-Β-CIT
CONCLUSIONS:Nowadays dopamine transporters 124 I-tracersseem to be the best markers for identifyingParkinson’s disease patients with highsensitivity and specificity .Dopamine transporter (DAT) imaging with[ 124 I]-β-CIT represents a new promisingdiagnostical technique to evaluate dopamineneuron loss, which is responsible for most ofthe symptoms in Parkinson’s Disease patients.