Review Article Iodine: A Longer-Life Positron Emitter Isotope New … · 2019. 7. 31. · 131 Iodine (131 I), 123 Iodine (123 I), and 125 Iodine (125 I), have limitations[ ]. Due

Review Article124Iodine A Longer-Life Positron Emitter IsotopemdashNewOpportunities in Molecular Imaging

Giuseppe Lucio Cascini1 Artor Niccoli Asabella2 Antonio Notaristefano2

Antonino Restuccia1 Cristina Ferrari2 Domenico Rubini2 Corinna Altini2

and Giuseppe Rubini2

1 Nuclear Medicine University of Catanzaro ldquoMagna Graeciardquo Viale Europa Localita Germaneto 88100 Catanzaro Italy2 Nuclear Medicine University of Bari ldquoAldo Morordquo Piazza Giulio Cesare No 11 70124 Bari Italy

Correspondence should be addressed to Artor Niccoli Asabella artorniccoliasabellaunibait

Received 28 December 2013 Accepted 18 April 2014 Published 8 May 2014

Academic Editor Gianluca Valentini

Copyright copy 2014 Giuseppe Lucio Cascini et alThis is an open access article distributed under the Creative Commons AttributionLicense which permits unrestricted use distribution and reproduction in any medium provided the original work is properlycited

124Iodine (124I) with its 42 d half-life is particularly attractive for in vivo detection and quantification of longer-term biological andphysiological processes the long half-life of 124I is especially suited for prolonged time in vivo studies of high molecular weightcompounds uptake Numerous small molecules and larger compounds like proteins and antibodies have been successfully labeledwith 124I Advances in radionuclide production allow the effective availability of sufficient quantities of 124I on small biomedicalcyclotrons for molecular imaging purposes Radioiodination chemistry with 124I relies on well-established radioiodine labelingmethods which consists mainly in nucleophilic and electrophilic substitution reactions The physical characteristics of 124I permittaking advantages of the higher PET image qualityThe availability of newmolecules thatmay be targeted with 124I represents one ofthe more interesting reasons for the attention in nuclear medicine We aim to discuss all iodine radioisotopes application focusingon 124I which seems to be the most promising for its half-life radiation emissions and stability allowing several applications inoncological and nononcological fields

1 Introduction

The use of radiopharmaceuticals for molecular imagingof biochemical and physiological processes in vivo hasevolved into an important diagnostic tool in modern nuclearmedicine and medical research Positron emission tomogra-phy (PET) is currently the most advancedmolecular imagingmethodology mainly due to its unrivalled high sensitivitywhich allows in vivo studying of molecular biochemistryThemost frequently used radionuclides for PET have relativelyshort half-lives (eg 11C 204min 18F 1098min) whichmaylimit both the synthesis procedures of different radiopharma-ceuticals and the time frame of longer biometabolic processesof in vivo studies Radionuclides of iodine are widely used innuclear medicine to label monoclonal antibodies receptorsand other pharmaceuticals in diagnostic and therapeuticapplications where quantitative imaging over a period ofseveral days is necessary [1]

Unfortunately the nuclides most commonly used131Iodine (131I) 123Iodine (123I) and 125Iodine (125I) havelimitations [2]

Due to its beta emission (606 keV 90) 131I is oftenused for therapy It also emits some gamma photons thatcan be used for SPECT imaging Their main emission energypeak is about 364 keV and requires the use of a high energyall purpose (HEAP) collimator However its spectrum ofemission is complex and some emission peaks above 364 keVcause high-energy contamination and degrade dosimetry123I is more suitable for imaging The energy of its

main gamma emission peak is 159 keV which is close tothe 140 keV from Tc-99m for which gamma-camera designhas traditionally been optimized 123I can be imaged in aSPECT system with a low energy high resolution (LEHR)collimator optimized for the Tc-99m (140 keV) or witha medium energy (ME) collimator optimized for energies

Hindawi Publishing CorporationBioMed Research InternationalVolume 2014 Article ID 672094 7 pageshttpdxdoiorg1011552014672094

2 BioMed Research International

up to 300 keV However this radionuclide also emits peaksof a higher energy which again can be responsible forhigh-energy contamination [3] Another limit of 123I-labeledradiopharmaceuticals is their short physical half-lives whichpermits only the rapid compounds synthesis and the study ofshort metabolic processes125I has mainly X-ray energy emission at 27 keV with low

gamma emission at 355 keV It has a photon energy too lowfor optimal imaging especially quantitative imaging and itshalf-life is undesirably long (42 days) For these reasons it hasnot found clinical applications to date [4]124Iodine (124I) is an alternative long-lived PET radionu-

clide attracting increasing interest for long-term clinical andPET studies 124I a positron-emitting nuclide with a half-life of 42 days could permit PET quantitative imaging overseveral days Only about 23 of disintegrations result inpositron emission and these are of relatively high energy [5]In fact 124I has appropriate physical characteristics in certainPET radiopharmaceuticals which can be utilized at low dosealso the spatial resolution of images for this radionuclideis comparable to that obtained with the more conventionalPET ones and the half-life of 42 days is appropriate forslow physiological processes also thanks to the clearance ofnonspecific radioactivity [6]

PET systems are using an electronic collimation basedon interaction time The emission spectrum of 124I isalso very complex In 50 of the cases the emissionof a positron is followed by the emission of a gammaof 602 keV which is likely to create a false coincidence(similar to scattered coincidences) However it offers thebest image quality due to its electronic collimation whichgives a better efficiency of detection and resolution Theshort coincidence window also limits the influence of high-energy peaks For these reasons 124I seems to be the mostpromising iodine isotope for an individual pretherapeuticdosimetry [7]

2 Physical Data of 124I

124I has dual energy emission beta radiation emissions of1532 keV (11) and 2135 keV (11) and gamma emissionsof 511 keV (46) 603 keV (61) and 1691 keV (11) Thegamma constant is 205E-4mSvhr perMBq 10 meterThephysical half-time (T12) is of 418 days the biological half-time is of 120ndash138 days and the effective half-time is of 4daysThe critical organ is the thyroid glandThe radiotoxicitydiffers if the 124I is ingested (282E-7 SvBq) or inhaled (169E-7 SvBq) The intake routes for 124Iodine may be ingestioninhalation puncture wound and skin contamination [8]

According to these physical properties 124I is the onlylong-life positron emitter isotope of iodine that may be usedfor both imaging and therapy aswell as for 131I dosimetryThetherapeutic effect of 124I relies on the Auger electron emissionresponsible for the local action within a few nanometersthe full cell killing becomes evident when a 124I moleculedecays within the DNA molecule mainly if placed betweenthe strands

However if the 124Iodine physical properties are favorablefor clinical practice two major features of the radioactivedecay should to be accounted for One is the image resolu-tion due to the high energy of emitted positron with longrange the other is a high fraction of nonpositron decaysaccompanied by single photon emission in the same energywindow These factors negatively affect resolution and thesignal to noise ratio as well as the fact that they may limitthe quantitative evaluation of PET imagesMore recently newalgorithms of reconstruction and more specific set-up forisotopes different from 18F have been implemented to reducethe image degradation

3 Isotope Production

One of the first schemes for 124I production has been based on124Te(d2n)124I nuclear reactionMore recently however withthe increase in the number of low-energy proton cyclotronsthe 124Te(pn)124I reaction has been reaching popularitybecause it offers the chance of obtaining the highest levelsof purity [9] The two main contaminants affecting iodinepreparation are related to the presence of Tellurium isotopes(due to the target physical properties) and to a mixture of125I and 123I isotopes for competitive reaction [10] Accordingto their different half-life the 125I reduces 124I purity duringtime Because the development of competing reactions mayincrease with the irradiation energy it is common to select anoptimal irradiation energy window to maximize the produc-tion minimizing impurities Other alternative schemes for124I production include the use of enriched Tellurium (125Te(p2n) 124I and 126Te(p3n)124I) characterized by higher124I production with a high level of long-life radioactivecontaminants or reactions with nontellurium-based targettypically with antimony [11ndash13] Factors influencing the124I production are the thermal performance of target thetarget composition and the iodine separation The targettemperature is a critical aspect during production becausehigh yields require high currents of irradiation limited bythermal performance of the target material that may becompensated by an efficient cooling system Therefore theirradiation is effective if target temperature is appropriatefor thermal performance of target material avoiding volatileisotopes production Moreover the thermal stability andperformance are related to the chemical form of the targetCommonly targets for iodine production are composed ofTellurium as TeO

2that warrants a good thermal efficiency

More recently Al2O has been added to TeO

2providing a

better target uniformity and new promising targets withAl2Te3have been proposed [14] Finally 124I is separated with

the dry distillation method by using a vapor pressure in aquartz tube that removes radioactive iodine from the target[15]

4 Radiochemistry of 124I

The iodination procedure with 124I has to consider thephysical half-life of the radionuclide and the small-scaleconcentrations and may be performed by using two main

BioMed Research International 3

Table 1 Principal radiopharmaceutical labeled with 124I

Radiopharmaceutical Chemical reaction Function124I-MIBG Nucleophilic exchange Adrenergic activity124I-IAZA Nucleophilic exchange Hypoxia agent124I-IAZG Nucleophilic exchange Hypoxia agent124I-dRFIB Nucleophilic exchange Cell proliferation124I-IUdR Direct electrophilic substitution on activated aromatic systems Cell proliferation124I-labeled-hypericin Direct electrophilic substitution on activated aromatic systems Protein-kinase C124I-FIAU Direct electrophilic substitution on activated aromatic systems Herpes virus thymidine kinasem-124I-IPPM Electrophilic radioiododestannylation reactions Opioid receptors124I-IPQA Electrophilic radioiododestannylation reactions EGFR kinase activity124I-labeled-6-anilino-quinazoline deriv Electrophilic radioiododestannylation reactions EGFR inhibitors124I-labelpurpurinimide derivatives Electrophilic radioiododestannylation reactions Tumor imaging124I-labelCDK46 inhibitors Electrophilic radioiododestannylation reactions Cell proliferation

types of chemical reactions electrophilic and nucleophilicsubstitution (Table 1)

The direct electrophilic substitution approaches wereinitially developed for protein labeling and later broadened toaromatic compounds As observed in thyroid hormones syn-thesis the tyrosine present in peptides or proteins is the pre-ferred site for radiolabeling In this chemical reaction iodidein oxidation state minus1 is oxidized by common reagents suchas chloramine-T or Iodogen to form a reactive electrophilicspecies in the oxidation state +1 which simply substitutes anactivated proton from the aromatic ring of tyrosine in theortho position to the phenol group The method is simpleand usually high yields are obtained The main disadvantageis the low selectivity if more than one tyrosine moiety ispresent with also low stability in vivo Moreover electrophilicradioiodinations can be also performed by means of variousdemetallation techniques Demetallation reactions requireorganometallic compounds as precursors An importantdifference from the direct electrophilic substitution is thatnonactivated aromatic compounds can be labeled with goodor excellent yields In addition due to the lack of activatinggroups the labeled compounds usually show a much highermetabolic stability when compared to the activated aromaticcompounds

The nucleophilic substitution represents the more simplemethod for direct iodination using iodide as nucleophilein the oxidation state minus1 This exchange reaction can occurin aliphatic and aromatic compounds but proceeds slowlyon aromatic ones An example of this is the exchange ofstable iodine bound to the precursor by radioactive iodine(isotope exchange) This can be achieved by simply heatingthe components in a suitable solvent such as acetone orwater The consequence however is a product of low specificactivity and therefore used only in very selected cases forexample with 124I-MIBG

Finally other methods have been developed includingthe direct labeling of proteins through radioiodination oftyrosine residues with electropositive radioiodine Chlo-ramine T and various oxidative enzymes are useful oxidizingagents for the in situ oxidation of radioiodine for directprotein labeling Another approach for iodination employs

the prosthetic groups Prosthetic groups are bifunctionalreagents one allows for high yield radiohalogenation and theother allows for conjugation to the biomoleculeThis strategybecame known as the ldquoBolton-Hunter methodrdquo [16]

5 Clinical Applications of 124I

The increased use of imaging with PET is accompanied bya demand for versatile radiopharmaceuticals and positronemitters with relatively long half-life suitable for the PETprocedure and able to highlight the tumor cell characteristics(alteration of enzymology increased rate of glycolysis pro-tein and lipid synthesis rate and DNA syntheses)

Among the radioactive iodine radionuclides using nucle-ophilic substitution reaction there are 124I-MIBG 124I-IAZA124I-IAZG and 124I-dRFIBM-Iodobenzylguanidine (MIBG)is used in diagnosis (labeled with 123I or 124I) and therapy(labeled with 131I) of neuroblastoma and pheochromocytoma[17 18] The mean effective dose from 124I-MIBG to the adultmale human extrapolated from animal data was estimated tobe 025mSvMBq The highest mean equivalent dose was inthe thyroid at 2343mSvMBq [19] Clinical trials regardingmeasurements of organ and tumor dosimetry using 124I-MIBG PETCT in patients with refractory or relapsed neu-roblastoma and the assessment of the accuracy of tumorimaging using 124I-MIBG PETCT versus 123I-MIBG scanwith 3-dimensional imaging by SPECT or SPECTCT bynumber intensity of uptake and localization of sites of tumorare in progress [20] Moroz et al described the use of 124I-labeledMIBG for imaging norepinephrine transporter (NET)function [21]124I-IAZA and 124I-IAZG are hypoxia imaging agents

and were used in a comparative study with two other 2-nitroimidazole derivatives (18F-FMISO and 18F-FAZA) forthe visualization of tumor hypoxia in A431 bearing mice bymeans of PET [22]

While 124I-dRFIB was synthetized by Stahlschmidt et al[23] to image cell proliferation no data on the radiopharma-cological evaluation of [124I]dRFIB are reported in practice todate


All the other radioactive iodine radionuclides use elec-trophilic substitution reaction One of the first moleculesintroduced for radiotherapy and labeled with 124I was theiododeoxyuridine (IUdR) Radiosynthesis of 5-[124I]iodo-21015840-deoxyuridine ([124I]IUdR) for functional imaging of cellproliferation by means of PET was investigated by Guentheret al A rapid radioiodination in vivo resulting in highaccumulation of activity in the thyroid was demonstratedTwenty-four hours after [124I]IUdR injection brain tumorimaging was feasible [24]

Sang et al described the synthesis of 123I- and 124I-labeledhypericin derivatives Hypericin a natural polycyclic aro-matic anthraquinone was used in the treatment of depressionand showed antiretroviral activity against several virusesincluding human immunodeficiency virus (HIV) Addition-ally an elevated activity against protein kinase C (PK-C)was found in malignant gliomas Sang et al investigated thepossibility of using iodine labeled hypericin derivatives forimaging malignant gliomas with PET and SPECT [25]

Also 124I would be of important value for detecting theexpression of successful gene transduction in target tissueor specific organs Radioiodinated 21015840-fluoro-21015840-deoxy-1-120573-D-arabinofuranosyl-5-iodouracil (FIAU) has been used toobtain quantitative in vivo PET images of herpes virus thymi-dine kinase (HSVl-tk) gene expression with superior sensi-tivity and resolution over that of SPECT 131I-radiolabeledFIAU images and also to monitor clinical gene therapy[26 27]

Studies on central cannabinoid CB1 receptors inschizophrenic patients led to the development of 124I-labeledimaging probe n-(morpholin-4-yl)-1-(24-dichlorophenyl)-5-(4-[124I]iodophenyl)-4-methyl-1hpyrazole-3-carboxamide([124I]AM281) Two 124I-labeled cyclin-dependent kinase 46inhibitors were developed to study the role of Cdk 46 duringcell proliferation in tumor cells 80 of human tumorsshow a deregulation of the cell cycle relevant Cdk4-cyclinD1retinoblastoma (pRb)E2F signal cascade resulting inuncontrolled tumor growth Radiolabeled Cdk4 inhibitorshave been suggested as promising molecular probes forimaging tumor cell proliferation [28]124I is also important in the study of the expression

of multidrug resistance Colchicine a potent inhibitor ofcellular mitosis is a member of the multidrug resistancefamily of drugs As a potential indicator of resistance theC-10 methoxy group of n-colchicine has been labeled using11C- and 13C-iodomethane [29] However the restrictionsimposed by the short half-life of the carbon-11 compoundprompted the investigation into the syntheses of colchicineanalogues labeled with radiohalogens

Iozzo et al [30] prepared 124I-labeled human insulin bydirect electrophilic iodination at the A14-tyrosine residue Itretains receptor binding properties and biological activity asthe native hormone

The long physical half-life of 124I is particularly well suitedfor labeling large molecules like antibodies The relativelylong half-life allows PET imaging at late time points (gt 24 h)ensuring sufficient accumulation of the radiolabeled antibody

in the target tissue (eg tumor) Various 124I-labeled anti-bodies have been used for molecular imaging and therapyof differentiated thyroid cancer breast cancer colorectalcancer clear-cell renal cell carcinoma ovarian cancer andneuroblastoma

51The 124I Experience inThyroid Cancer 124I appears as oneof the more interesting imaging probes between new agentsintroduced for PETCT It emerged in clinical scenario ofthyroid cancer patients because of the high spatial resolutionof PET images and better sensitivity than 131I [31] In thissetting 124I combines the well-known diagnostic efficacy ofiodide family together with the individual dosimetry before131I treatment avoiding cellular stunning124I in PET is being usedmainly in the staging of recurrent

or residual thyroid malignancy and for pretherapy individu-alized dosimetry Moreover a combined use of 124I and 18F-FDG PETCT improves restaging in recurrent differentiatedthyroid cancer (DTC) This combination of PET agents isclaimed to better predict the outcome of high-dose 131I ther-apy and can be used clinically to decide further management[32] Moreover in the presence of biochemical recurrencewith an increased thyroglobulin (Tg) a negative 124I PETcan avoid high-dose 131I therapy which implies the needfor further additional imaging to estimate iodine nonavidmetastatic disease Phan et al [33] showed in their studythat 124I PET detected more abnormalities in comparison tothe diagnostic whole body 131I scan but showed comparablefindings with the posttreatment scanThey reported that only3 of 11 patients with positive 124I PET scanning had visibleabnormalities in pretherapy scans Furthermore PET alsoproved incremental value by showing lesions in 2 of the 5patientswith undetectable Tgwhereas thewhole body iodinescans were negative in all 5 patients In a comparison between124I and 18F-FDG PET in 21 DTC patients at staging or witharising Tg level or with Tg antibodies without cervical lymphnodes at standard imaging the reported sensitivities were80 and 70 for 124I and 18F-FDG respectively [32] Theauthors reported an incremental diagnostic value for 124Iwhen coregistered with diagnostic CT scan However near30 of the lesions were concordantly positive on both PETscans while positive with only one of these modalities inthe others Authors concluded that the combination of 124Iand 18F-FDG PETCT improves restaging in recurrent DTCAlthough diagnostic role for 124I PET should be proven ina large comparable series of patients affected by DTC thelesion-based dosimetry appears as well defined issue thatmay be addressed with wide consensus In fact by usingthe lesion-based dosimetry tumor stunning may be avoidedand replacing the fixed iodine dose the therapeutic effectsare now maximized reducing collateral ones Maxon using124I has shown that when the radiation dose was greaterthan 80Gy 98 of metastases responded to treatment onthe contrary only 20 of metastases responded to treatmentwhen the prescribed dose was lower [34] Furthermorenone of the lesions receiving less than 35Gy responded totreatment In a study reported by Dorn et al in DTC patients


Figure 1 124I-beta-CIT in severe PD Note a bilateral symmetric involvement of putamen and extrastriatal uptake at 48 h images

over 15 years they reported in 187 pretherapy 124I PETdosimetric evaluations that the delivered 131I dosewas safe forcritical organs (red marrow or lungs) and complete responsein metastases was achieved with absorbed doses of gt 100Gy[35]

52 124I-Beta-Cit Radiolabeled beta-CIT is often used forbrain imaging labeled with 123I but FP-CIT is more suit-able for imaging of dopamine transporter because of itshigher selectivity and faster kinetics In particular beta-CITis affected in clinical practice by higher affinity for sero-toninergic receptors than 123I-FP-CIT producing functionalimages of both neurotransmissions Moreover the dopaminebinding potential with beta-CIT is obtained after 18 hoursfrom injection far from an optimal acquisition time for123I-agents However beta-CIT has been demonstrated tovisualize the dopamine reuptake in different cortical areasas well as in mesolimbic or mesocortical regions that are notdetected by FP-CIT For these kinetic differences beta-CITis considered a very interesting dopamine tracer affected inpractice by physical properties of 123I More recently we havetested in patients affected by Parkinsonrsquos disease (PD) a novelradiopharmaceutical in which beta-CIT is labeled with 124I[36] It has been obtained by the addition in the followingorder 5mCi of Na124I in a solution of 500 120583L of NaOH005N 50120583g of trialkylstanyl precursor ([2b-carbomethoxy-3b-(4-tributylstannylphenyl)tropane] dissolved sonicatingfor 3 minutes in 150120583L of ethanol 50 120583L of H

3PO405N

50120583L of CH3CO3H 002M prepared at the moment of

use by 100 120583L 32 of peracetic acid dissolved in 24mL ofwater After 30 minutes at ambient temperature in an inertatmosphere we add 100120583L NaHSO

3in a solution prepared

by dissolving 10mg in 1mL In our unpublished study wehave administered 37MBq of 124I-beta-CIT intravenouslyin patients affected by PD and essential tremors then PETimages were obtained at 4 24 and 48 hours from injection Inall patients we have reported a precise and reproducible eval-uation of striatum morphology also in patients with severePD (Figure 1) as well as of mesolimbic and mesocorticalstructures probably due to serotoninergic uptake

6 Conclusions

Theiodine isotopeswith particular regard to 131I and 123I haverepresented the cornerstone of nuclear medicine in thyroiddiseases especially Nowadays this family has been enrichedby 124I the longer positron emitter of iodine which for thephysical properties has gained a role in the clinical practiceof molecular imaging

In fact 124I joins a suitable radioactive emission toa favorable simple and well-documented radiochemistryas well as standardized production and target processingAll these aspects together with the high quality of PETtechnology warrant an actual role in thyroid cancer imagingas well as promising applications in neurology and oncology

The future advances in probe development will lead tothe production of novel innovative radiopharmaceuticals forspecific molecular targeting for both imaging and therapywhere the emission of Auger electrons is associated with highresolution quantitative images

Conflict of Interests

The authors have no potential conflict of interests to discloseAll authors have no financial or nonfinancial relationships todisclose

References

[1] P B Zanzonico R E Bigler G Sgouros and A Strauss ldquoQuan-titative SPECT in radiation dosimetryrdquo Seminars in NuclearMedicine vol 19 no 1 pp 47ndash61 1989

[2] S R Thomas H R Maxon and J G Kereiakes ldquoTechniquesfor quantitation of in vivo radioactivityrdquo in Effective Use ofComputers in NuclearMedicine M J Gelfand and S RThomasEds pp 468ndash484 McGraw-Hill New York NY USA 1988

[3] L P Clarke F Qadir W Al Sheikh G Sfakianakis and A NSerafini ldquoComparison of the physical characteristics of I-131 andI-123 with respect to differentiating the relative activity in thekidneysrdquo Journal of Nuclear Medicine vol 24 no 8 pp 683ndash688 1983

[4] P Scalliet and A Wambersie ldquoWhich RBE for iodine 125 inclinical applicationsrdquo Radiotherapy and Oncology vol 9 no 3pp 221ndash230 1987


[5] KAKurdziel G Ravizzini B YCroft J L Tatum P L Choykeand H Kobayashi ldquoThe evolving role of nuclear molecularimaging in cancerrdquo Expert Opinion on Medical Diagnostics vol2 no 7 pp 829ndash842 2008

[6] R K Grewal M Lubberink K S Pentlow and S M LarsonldquoThe role of Iodine-124-positron emission tomography imagingin themanagement of patients with thyroid cancerrdquoPETClinicsvol 2 no 3 pp 313ndash320 2007

[7] S M Eschmann G Reischl K Bilger et al ldquoEvaluation ofdosimetry of radioiodine therapy in benign and malignantthyroid disorders by means of iodine-124 and PETrdquo EuropeanJournal of Nuclear Medicine vol 29 no 6 pp 760ndash767 2002

[8] K S Pentlow M C Graham R M Lambrecht et al ldquoQuan-titative imaging of iodine-124 with PETrdquo Journal of NuclearMedicine vol 37 no 9 pp 1557ndash1562 1996

[9] R M Lambrecht M Sajjad M A Qureshi and S J Al-Yanbawi ldquoProduction of iodine-124rdquo Journal of Radioanalyticaland Nuclear Chemistry vol 127 no 2 pp 143ndash150 1988

[10] J Schmitz ldquoThe production of [124I]iodine and [86Y]yttriumrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 38 no 1 supplement pp S4ndashS9 2011

[11] B Scholten S Takacs Z Kovacs F Tarkanyi and S M QaimldquoExcitation functions of deuteron induced reactions on 123Terelevance to the production of 123I and 124I at low and mediumsized cyclotronsrdquo Applied Radiation and Isotopes vol 48 no 2pp 267ndash271 1997

[12] K F Hassan S M Qaim Z A Saleh and H H CoenenldquoAlpha-particle induced reactions on natsb and 121sb with par-ticular reference to the production of the medically interestingradionuclide 124irdquo Applied Radiation and Isotopes vol 64 no 1pp 101ndash109 2006

[13] J A Nye M A Avila-Rodriguez and R J Nickles ldquoAnew binary compound for the production of 124I via the124Te(pn)124I reactionrdquo Applied Radiation and Isotopes vol 65no 4 pp 407ndash412 2007

[14] S M Qaim A Hohn T Bastian et al ldquoSome optimisationstudies relevant to the production of high-purity 124I and 120119892Iat a small-sized cyclotronrdquo Applied Radiation and Isotopes vol58 no 1 pp 69ndash78 2003

[15] R Van den Bosch J J M De Goeij and J A Van der Heide ldquoAnew approach to target chemistry for the iodine 123 productionvia the 124Te(p2n) reactionrdquo International Journal of AppliedRadiation and Isotopes vol 28 no 3 pp 255ndash261 1977

[16] S Guhlke A M Verbruggen and S Vallabhajosula ldquoRadio-chemistry and radiopharmacyrdquo inClinical NuclearMedicine HJ Biersack and L M Freeman Eds pp 34ndash76 Springer BerlinGermany 2007

[17] U Ficola N Quartuccio R Paratore G Treglia A Piccardoand A Cistaro ldquoUtility of 124I-MIBG PETCT in the follow-up of patients with advanced neuroblastoma first report of theAIMN PET-Pediatric Study InterGrouprdquo European Journal ofNuclear Medicine and Molecular Imaging vol 40 pp S204ndashS205 2013

[18] V Hartung-Knemeyer S Rosenbaum-Krumme C Buch-bender et al ldquoMalignant pheochromocytoma imaging with[124I]mIBGPETMRrdquoThe Journal of Clinical Endocrinology andMetabolism vol 97 no 11 pp 3833ndash3834 2012

[19] C-L Lee H Wahnishe G A Sayre et al ldquoRadiationdose estimation using preclinical imaging with 124I-metaiodobenzylguanidine (MIBG) PETrdquo Medical Physicsvol 37 no 9 pp 4861ndash4867 2010

[20] ldquo124I-Metaiodobenzylguanidine (MIBG) PETCT DiagnosticImaging and Dosimetry for Patients With Neuroblastoma APilot Studyrdquo httpwwwclinicaltrialsgov

[21] M A Moroz I Serganova P Zanzonico et al ldquoImaging hNETreporter gene expression with 124I-MIBGrdquo Journal of NuclearMedicine vol 48 no 5 pp 827ndash836 2007

[22] G Reischl D S Dorow C Cullinane et al ldquoImaging of tumorhypoxia with [124I]IAZA in comparison with [18F]FMISOand [18F]FAZAmdashfirst small animal PET resultsrdquo Journal ofPharmacy amp Pharmaceutical Sciences vol 10 no 2 pp 203ndash2112007

[23] A Stahlschmidt H-J Machulla G Reischl E E Knaus and LI Wiebe ldquoRadioiodination of 1-(2-deoxy-120573-d-ribofuranosyl)-24-difluoro-5-iodobenzene (dRFIB) a putative thymidinemimic nucleoside for cell proliferation studiesrdquo Applied Radi-ation and Isotopes vol 66 no 9 pp 1221ndash1228 2008

[24] I Guenther L Wyer E J Knust R D Finn J Koziorowskiand R Weinreich ldquoRadiosynthesis and quality assurance of 5-[124I]Iodo-21015840-deoxyuridine for functional PET imaging of cellproliferationrdquo Nuclear Medicine and Biology vol 25 no 4 pp359ndash365 1998

[25] W K Sang H P Jeong D Y Seung G H Min W C Changand H Y Kook ldquoSynthesis and in vitrovivo evaluation ofiodine-123124 labelled hypericin derivativesrdquo Bulletin of theKorean Chemical Society vol 29 no 10 pp 2023ndash2025 2008

[26] R G Blasberg and J G Tjuvajev ldquoHerpes simplex virusthymidine kinase as a markerreporter gene for PET imagingof gene therapyrdquo Quarterly Journal of Nuclear Medicine vol 43no 2 pp 163ndash169 1999

[27] J G Tjuvajev R Finn KWatanabe et al ldquoNoninvasive imagingof herpes virus thymidine kinase gene transfer and expression apotential method for monitoring clinical gene therapyrdquo CancerResearch vol 56 no 18 pp 4087ndash4095 1996

[28] L Koehler F Graf R Bergmann J Steinbach J Pietzsch andFWuest ldquoRadiosynthesis and radiopharmacological evaluationof cyclin-dependent kinase 4 (Cdk4) inhibitorsrdquo EuropeanJournal of Medicinal Chemistry vol 45 no 2 pp 727ndash737 2010

[29] P J Kothari R D Finn and S M Larson ldquoSyntheses ofcolchicine and isocolchicine labelled with carbon-11 or carbon-13rdquo Journal of Labelled Compounds and Radiopharmaceuticalsvol 36 no 6 pp 521ndash528 1995

[30] P Iozzo S Osman M Glaser et al ldquoIn vivo imaging ofinsulin receptors by PET preclinical evaluation of iodine-125and iodine-124 labelled human insulinrdquo Nuclear Medicine andBiology vol 29 no 1 pp 73ndash82 2002

[31] R M Lambrecht N Woodhouse R Phillips et al ldquoInvestiga-tional study of iodine-124 with a positron camarardquo AmericanJournal of Physiologic Imaging vol 3 no 4 pp 197ndash200 1988

[32] L S Freudenberg G Antoch W Jentzen et al ldquoValue of124I-PETCT in staging of patients with differentiated thyroidcancerrdquoEuropeanRadiology vol 14 no 11 pp 2092ndash2098 2004

[33] H T T Phan P L Jager A M J Paans et al ldquoThe diagnosticvalue of 124I-PET in patients with differentiated thyroid cancerrdquoEuropean Journal of Nuclear Medicine and Molecular Imagingvol 35 no 5 pp 958ndash965 2008

[34] H R Maxon ldquoQuantitative radioiodine therapy in the treat-ment of differentiated thyroid cancerrdquo Quarterly Journal ofNuclear Medicine vol 43 no 4 pp 313ndash323 1999

[35] R Dorn J Kopp H Vogt P Heidenreich R G Carroll andS A Gulec ldquoDosimetry-guided radioactive iodine treatmentin patients with metastatic differentiated thyroid cancer largest


safe dose using a risk-adapted approachrdquo Journal of NuclearMedicine vol 44 no 3 pp 451ndash456 2003

[36] G L Cascini A Ciarmiello A Labate S Tamburrini and AQuattrone ldquoUnexpected detection of melanoma brain metas-tasis by PET with iodine-124 120573CITrdquo Clinical Nuclear Medicinevol 34 no 10 pp 698ndash699 2009

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up to 300 keV However this radionuclide also emits peaksof a higher energy which again can be responsible forhigh-energy contamination [3] Another limit of 123I-labeledradiopharmaceuticals is their short physical half-lives whichpermits only the rapid compounds synthesis and the study ofshort metabolic processes125I has mainly X-ray energy emission at 27 keV with low

gamma emission at 355 keV It has a photon energy too lowfor optimal imaging especially quantitative imaging and itshalf-life is undesirably long (42 days) For these reasons it hasnot found clinical applications to date [4]124Iodine (124I) is an alternative long-lived PET radionu-

clide attracting increasing interest for long-term clinical andPET studies 124I a positron-emitting nuclide with a half-life of 42 days could permit PET quantitative imaging overseveral days Only about 23 of disintegrations result inpositron emission and these are of relatively high energy [5]In fact 124I has appropriate physical characteristics in certainPET radiopharmaceuticals which can be utilized at low dosealso the spatial resolution of images for this radionuclideis comparable to that obtained with the more conventionalPET ones and the half-life of 42 days is appropriate forslow physiological processes also thanks to the clearance ofnonspecific radioactivity [6]

PET systems are using an electronic collimation basedon interaction time The emission spectrum of 124I isalso very complex In 50 of the cases the emissionof a positron is followed by the emission of a gammaof 602 keV which is likely to create a false coincidence(similar to scattered coincidences) However it offers thebest image quality due to its electronic collimation whichgives a better efficiency of detection and resolution Theshort coincidence window also limits the influence of high-energy peaks For these reasons 124I seems to be the mostpromising iodine isotope for an individual pretherapeuticdosimetry [7]

2 Physical Data of 124I

124I has dual energy emission beta radiation emissions of1532 keV (11) and 2135 keV (11) and gamma emissionsof 511 keV (46) 603 keV (61) and 1691 keV (11) Thegamma constant is 205E-4mSvhr perMBq 10 meterThephysical half-time (T12) is of 418 days the biological half-time is of 120ndash138 days and the effective half-time is of 4daysThe critical organ is the thyroid glandThe radiotoxicitydiffers if the 124I is ingested (282E-7 SvBq) or inhaled (169E-7 SvBq) The intake routes for 124Iodine may be ingestioninhalation puncture wound and skin contamination [8]

According to these physical properties 124I is the onlylong-life positron emitter isotope of iodine that may be usedfor both imaging and therapy aswell as for 131I dosimetryThetherapeutic effect of 124I relies on the Auger electron emissionresponsible for the local action within a few nanometersthe full cell killing becomes evident when a 124I moleculedecays within the DNA molecule mainly if placed betweenthe strands

However if the 124Iodine physical properties are favorablefor clinical practice two major features of the radioactivedecay should to be accounted for One is the image resolu-tion due to the high energy of emitted positron with longrange the other is a high fraction of nonpositron decaysaccompanied by single photon emission in the same energywindow These factors negatively affect resolution and thesignal to noise ratio as well as the fact that they may limitthe quantitative evaluation of PET imagesMore recently newalgorithms of reconstruction and more specific set-up forisotopes different from 18F have been implemented to reducethe image degradation

3 Isotope Production

One of the first schemes for 124I production has been based on124Te(d2n)124I nuclear reactionMore recently however withthe increase in the number of low-energy proton cyclotronsthe 124Te(pn)124I reaction has been reaching popularitybecause it offers the chance of obtaining the highest levelsof purity [9] The two main contaminants affecting iodinepreparation are related to the presence of Tellurium isotopes(due to the target physical properties) and to a mixture of125I and 123I isotopes for competitive reaction [10] Accordingto their different half-life the 125I reduces 124I purity duringtime Because the development of competing reactions mayincrease with the irradiation energy it is common to select anoptimal irradiation energy window to maximize the produc-tion minimizing impurities Other alternative schemes for124I production include the use of enriched Tellurium (125Te(p2n) 124I and 126Te(p3n)124I) characterized by higher124I production with a high level of long-life radioactivecontaminants or reactions with nontellurium-based targettypically with antimony [11ndash13] Factors influencing the124I production are the thermal performance of target thetarget composition and the iodine separation The targettemperature is a critical aspect during production becausehigh yields require high currents of irradiation limited bythermal performance of the target material that may becompensated by an efficient cooling system Therefore theirradiation is effective if target temperature is appropriatefor thermal performance of target material avoiding volatileisotopes production Moreover the thermal stability andperformance are related to the chemical form of the targetCommonly targets for iodine production are composed ofTellurium as TeO

2that warrants a good thermal efficiency

More recently Al2O has been added to TeO

2providing a

better target uniformity and new promising targets withAl2Te3have been proposed [14] Finally 124I is separated with

the dry distillation method by using a vapor pressure in aquartz tube that removes radioactive iodine from the target[15]

4 Radiochemistry of 124I

The iodination procedure with 124I has to consider thephysical half-life of the radionuclide and the small-scaleconcentrations and may be performed by using two main





























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Documents

Review Article Iodine: A Longer-Life Positron Emitter Isotope New … · 2019. 7. 31. · 131 Iodine (131 I), 123 Iodine (123 I), and 125 Iodine (125 I), have limitations[ ]. Due