Iodine and its isotopes

Iodine is an important trace element necessary for proper function and development of human body. As the iodide, it forms an essential component of thyroid hormones which are responsible for regulation of various metabolic processes in the body. Iodine (atomic number 53) has approximately 37 isotopes that can be produced in a nuclear reactor or cyclotron. Those isotopes that are used in the diagnosis and therapy of medical disorders will be illustrated here with reference to 124I, the isotope of review.

The thyroid has the ability to trap iodine via integral membrane proteins called sodium-iodide symporters (NIS) residing in the epithelial basolateral membrane of thyroid follicular cells. The trapped iodine is integral to thyroid hormone synthesis. Functional characteristics of the thyroid in health and disease may thus be assessed by imaging and measuring radioiodine thyroid uptake. Such measures, in addition to providing pathophysiologic information, optimize treatment with 131I. Iodine is absorbed as the iodide through ingestion, inhalation, puncture, wound and skin contamination. It is concentrated in the salivary glands, thyroid and gastric mucosa, and the choroid plexus in the brain. The critical organ in humans is the thyroid and the predominant route of iodide excretion is through the urine, with variable fecal excretion. The long biological half-life of iodide is 120–138 days primarily due to incorporation into thyroid hormone and precursor proteins. Iodide is not retained intracellularly, and thus clears rapidly from non-target tissues.

Iodine-123 and -131, with half-lives (T1/2) of 13.3 h and 8.02 days respectively, have been increasingly used for measuring radioiodine uptake, and imaging its in vivo distribution at multiple times after ingestion. Iodine-123 is widely used in delineation of thyroid functional status and assessment of thyroid nodules. Its principal photon emission of 159 keV is ideally suited to successful single photon imaging on modern gamma cameras optimized for imaging the 140 keV photon of technetium-99 m (99mTc), the most widely used single photon radionuclide.

Iodine-131 is widely used in the diagnosis and therapy of thyroid disorders. Widely available and relatively inexpensive, with abundant principal photon emission of 364 keV and long physical T1/2 of 8.02 days, it may be used to image bio-distribution and dosimetry for several days after ingestion. These images enable decisions regarding therapy with 131I; the nuclide emits beta rays (average β-minus 606 keV), enabling successful therapy in hyperthyroidism as well as thyroid cancer. It may be sometimes necessary to calculate 131I absorbed doses for vital organs like bone marrow, particularly before treatment with large amounts of 131I in thyroid cancer.

Iodine-125 in its unsealed form is mainly used for in vitro assays. Its long half-life of 60 days and low energy gamma photon emission (27, 35 keV) makes it unsuitable for patient imaging (though suitable as a sealed source for high dose brachytherapy).

Iodine-124, with a T1/2 of 4.2 days, is a positron emitting isotope of iodine. It may be used for PET imaging in humans as the iodide, as well as attached to a broad range of molecules of varying size. PET permits in vivo quantification of bio-distribution and dosimetry. PET with 124I has thus found several oncologic and non-oncologic applications. This clinically oriented review will include a brief description of its physicochemical properties including reference to its use as a radiolabel, followed by a discussion of its current applications in clinical and research molecular imaging.

A thorough literature search was carried out in two phases. In the first phase, literature search of Medline and Google Scholar databases yielded approximately 950 studies using the keywords Iodine124, 124I with Boolean operator OR. In the second phase, the potential relevance was examined and the number was reduced by excluding the studies not associated directly with properties and role of 124I in imaging and quantitation.

Physico-chemical properties of 124I

Physical characteristics

Iodine-124 decays, by dual energy positron emission (1532 keV (11 %) and 2135 keV (11 %)) and electron capture with gamma emissions of 511 keV (46 %), 603 keV (61 %) and 1691 keV (11 %) [1]. About a quarter of all decay events thus result in positron emission, unlike 18F, where positron emission occurs in >96 % of decay events. The high positron energy makes it travel a longer distance (than 18F) before it annihilates with an electron, which can give result in a falsely identified line of response (LOR) [2]. The single photon emissions also negatively impact the resolution, and signal to noise ratio of images. While initial PET imaging could be satisfactorily conducted with septal collimation, current 3D PET/CT devices implement suitable reconstruction algorithms [2, 3]. Spatial resolution, count rate performance, sensitivity and scatter fraction, and other measures have now been found to be quite satisfactory for 3D reconstruction methods [4]. Radiation dose to human subjects is comparable to 131I, though higher than 18F [4].

Production

Tellurium, in its natural state, is composed of many isotopes and can give rise to multiple radioiodine daughters. Iodine-124 is produced by bombardment of an enriched tellurium-124 (124Te) solid target in a cyclotron. 124Te enrichment is expensive, and this is invariably reflected in the cost of 124I. The method initially used for production of 124I involved enriched 124Te in a 124Te(d,2n)124I reaction. However, this has largely been replaced by the 124Te(p,n)124I, which has the advantages of being produced by proton bombardment with incident beam energy of 11 or 14 MeV (based on the target composition), a feasible and indeed preferred method in most 16-18 MeV medical cyclotrons [5]. This results in a good target yield with high radionuclidic purity and low quantity of impurities like 123I and 125I [6].

Multiple factors like target composition, thermal stability of the irradiated sample and selection of target support can influence the production of 124I. The target material is usually tellurium oxide (TeO2) with 5 % by mass aluminium hydroxide (Al2O3) added to improve heat exchange and prevent vaporization of 124I [7, 8]. Adequate thermal control is crucial to high current target irradiations, and is achieved by cooling the back of the target support plate with water, and the front with helium [5].

Recently, a robotic, fully automated system for large scale production of 124I has been developed in Japan, which uses a capsulated target and gives good yield. The capsule consists of three pieces of gold (99.99 %), which have shown best chemical resistance against TeO2 under high temperatures. Enriched TeO2 with alumina is used as target material and the calculated proton energy on the target surface is 11.6 MeV for the 124Te(p,n)124I reaction. The capsulated target can be reused repeatedly and requires no special processing, adding to the economic efficiency of the procedure [9]. Other target materials have also been investigated for production, particularly antimony (Sb), in a 123Sb(α,3n)124I reaction, yielding sufficient amount of 124I with relatively low level of 125I and 126I impurities [10, 11]. However, the reaction requires an alpha particle beam in a cyclotron of intermediate energy.

The 124I is extracted from the oxide target by dry distillation in a quartz capillary tube with gas flow to remove traces of TeO2, trap radioiodine and retain the target material on the target plate. To increase trapping efficiency, the tubes are usually primed with sodium hydroxide (NaOH). 124I settled on the walls of the tube can be recovered by washing with a weak buffer solution while recovery of target material ensures its reuse and economic sustainability [5, 6].

Attachment of 124I to molecules of interest

124I, like all iodine isotopes, is a volatile halide, and care must be taken to avoid contamination including particularly inhalation. Since it is a large atom, it can modify the in vitro and in vivo pharmacological properties of a molecule after attachment. To circumvent the latter issue, the iodine atom is introduced in a position as far as possible from the pharmacophore. There are both direct and indirect methods of radioiodination, accomplished by either electrophilic or nucleophilic substitution reactions [5].

Direct iodination with iodide as the nucleophile in an oxidation state of -1 can be carried out in a simple nucleophilic substitution reaction. This can be used in the radioiodination of both aliphatic and aromatic compounds; however, it proceeds slowly with aromatic compounds. To accelerate the process, metal-assisted reactions can be useful, like copper (I) and copper (II) assisted radio-iodination [12].

Iodine can be easily oxidized by a variety of oxidants. Chloramine-T (used in some mouthwash) is efficient, and its fairly strong oxidizing properties may be mitigated by immobilization onto polystyrene beads (Iodobeads). Iodogen, peracetic acid, hydrogen peroxides and other mild oxidizing agents, and enzymes like lactoperoxidase, are preferred for sensitive substrates [13]. Oxidation reactions help form a reactive electrophilic species with an oxidation state of +1. This species can conveniently substitute an activated proton from the aromatic ring of tyrosine in the ortho position to a phenol group, useful in labelling aromatic compounds. A disadvantage to this method is the lack of regioselectivity, i.e., formation of the chemical bond with preference for a particular direction of bond making or breaking over all other possible directions, with simultaneous production of numerous isomers that are difficult to separate. However, due to its intrinsic simplicity, electrophilic substitution remains the most commonly employed method for radio-iodination [14]. Metal cations and strong acids can be harsh to organic materials, while N-halosuccinimides such as N-bromosuccinimide, are rarely used due to the possibility of chlorination, oxidation side reactions and need for aggressive solvent systems [15].

The carbon-iodine bond in aliphatic compounds is not very stable and may result in deiodination in vivo, leading to accumulation in salivary glands, thyroid and stomach (consequently, clinical use of radioiodine for other than thyroid disorders includes administration of a large amount of stable iodide to block these normal uptake sites.) This has led to the exploration of more stable methods of attachment.

Indirect methods of electrophilic radio-iodination include demetallation using organometallic compounds, which have the advantages of using very little precursor, and regioselective labeling of non-carrier added radiopharmaceuticals with a high yield under relatively mild conditions. Compounds like organo-boranes, silicon, germanium, tin, organo-mercury and organo-thallium have been used. Destannylation appears to be the most preferred reaction due to highly selective cleavage of the weak sp2 tin-carbon bond. However, tin compounds are toxic and the organo-tin reagents used in synthesis need to be removed via time-consuming purification methods, reducing radiochemical yield. To circumvent this problem, Hunter et al. developed an insoluble polystyrene resin with a reactive dialkyl tin moiety that can be functionalized to a variety of polymer-supported arylstannanes [16]. This approach, commercialized as Ultratrace™ Resin, avoids toxic impurities observed in solution by tethering the reactive arylstannane to the solid support.

Indirect protein radioiodination has been carried out with a range of prosthetic groups. They differ vastly with respect to overall synthesis time, radiochemical yield, efficiency of conjugation to the biomolecule, chemoselectivity of conjugation step and influence of the group on ligand pharmacokinetics. 124I-SHPP (N-succinimidyl 3-(4-hydroxy-5-iodophenyl) propionate) or Bolton-Hunter reagent has been used to indirectly label the VEGF antibody for imaging tumor angiogenesis, and an anti-HER2 antigen-binding protein for PET imaging of HER2-expressing tumors (Glaser et al., Chacko et al.). 124I-SHPP has a tendency to undergo enzymatic de-iodination in vivo and in order to achieve radiolabel stability, a variety of radioiodinated carboxylic acid esters have been developed for conjugation to proteins [17]. Other prosthetic groups, notably N-succinimidyl-3 or 4-124I-iodobenzoate (3- or 4-[124I] SIB) have been successfully conjugated to proteins.

Applications

124I in thyroid disease

In the characterization of benign thyroid disorders, 124I may prove beneficial over planar scintigraphy/SPECT imaging using 99mTc-pertechnetate or 123I. It has the advantage of higher resolution images, computed tomography and superior delineation of nodules. In a study conducted by Darr et al., low activity 124I-PET/low dose CT detected significantly more hot and cold nodules than 99mTc planar/SPECT imaging [18]. More patients with retrosternal thyroid tissue were identified, demonstrating the potential of 124I PET to provide superior imaging of benign thyroid disease. The implications of better detection of discernible nodules on management is yet to be analyzed.

124I-PET has proven useful in staging of recurrent and residual disease in thyroid malignancy [19–21]. Phan et al. showed in their study that 124I scans pre-therapy detected more lesions than 131I imaging, with results comparable to the post-131I therapy scan. Only 3 of 11 patients with positive 124I scans had positive pre-therapy 131I scans, with 2 of 5 patients with negative 131I scans showing positive lesions on 124I PET [22]. A comparison between 124I and 18F-Fludeoxyglucose (18F-FDG) PET in 21 patients with differentiated thyroid cancer (DTC) reported sensitivities of 80 % and 70 %, respectively [23]. Capoccetti et al. [24] reported matching 124I PET and 131I WBS results in 58 of 67 patients with additional findings in 10. Similar results were seen in other studies as well.

The utilization of 131I-therapy for benign and malignant thyroid disease is already well established. 131I has a principal gamma emission of 364 keV that is considerably higher than the ideal for imaging with gamma cameras. Several groups have demonstrated that 124I image acquisition in 3D mode is feasible even in the presence of large amounts of 131I on a standard clinical PET scanner [25]. Even with low amounts of 124I (~74 MBq), a time of flight PET/CT scanner showed comparable lesion detectability as 131I WBS for small spheres less than equal to 10 mm as reported by Beijst et al. using NEMA phantoms [26].

Dosimetry: Simultaneous administration of 124I enables in vivo determination of bio-distribution and dosimetry of 131I. It helps to measure (average) absorbed doses of 131I to organs of interest, enabling quantitative dose–response studies, dose planning before therapy, dose evaluation during therapy and further investigations of the “stunning” phenomenon [27–31]. On the basis of a theoretical dosimetry based model using 124I, Jentzen et al., showed that the lowest effective therapy activity required for thyroid remnant ablation in low risk differentiated thyroid cancer appears to be approximately 2.2 GBq [32]. In a study by Hartung-Knemeyer et al. [33], 198 patients with DTC had undergone a pre-therapeutic blood dosimetry using 124I and values were compared with blood dose administered post 131I therapy. There was a clear correlation between cytopenia and predicted blood doses for both white cells and platelets. Ho et al. used 124I for dosimetry before administering radioiodine-131 therapy in patients treated with selumetenib (MEK1 and MEK2 inhibitor). Selumetenib increased the uptake of 124I in 12 of 20 patients, and effectiveness was found to be greater in patients with RAS-mutant disease [34]. The utility of pre-therapeutic 124I PET/CT dosimetry as a prognostic tool and in assessment of dose–response relationship was recently illustrated by Wierts et al. [35]. All lesions were accurately identified and the threshold absorbed dose value calculated for remnants and metastases to predict the achievement of complete response was calculated to be 90 Gy and 40 Gy respectively. In contrast, a multicenter diagnostic cohort study (THYROPET) by Kist et al. [36], showed a high false negative rate of 124I PET/CT in patients with biochemical evidence of recurrent thyroid cancer and negative ultrasound. However, the number of patients included in the study were small (n = 17) as it was terminated preliminarily, after three patients had a negative 124I PET/CT and a positive post therapy 131I. Another retrospective study by Khorjekar et al. [37] showed a low predictive value of a negative 124I PET scan in patients with elevated serum Tg levels and negative diagnostic 131I scan. Further validation studies with higher sample size may be needed to determine the value of pretherapeutic 124I PET scans.

124I labelled biomacromolecules

There is increasing interest in radiolabelling large biomolecules (oligonucleotides, oligosaccharides, peptides and proteins) and macromolecules especially monoclonal antibodies for applications in diagnosis and treatment of diseases.

Girentuximab (cG250) is a chimeric antibody that binds to carbonic anhydrase IX, expressed on more than 95 % of clear cell renal cell cancer (ccRCC). 124I-girentuximab PET/CT was demonstrated to be useful in identifying the ccRCC phenotype with high accuracy, in an initial single center verification trial with 25 patients, validated subsequently in a multi-center study with 226 patients [38, 39]. It represents the first molecular imaging modality that identifies an immunohistologically specific prognostic marker for a human solid tumor.

Pryma et al. further demonstrated a linear relationship between in vivo estimates of antibody uptake measured by 124I PET/CT with ex vivo biopsy measurements of radioactivity, confirming the ability of PET/CT with 124I to provide quantitative estimates of radioactivity in normal organs and tumors [40].

124 I-huA33—Antibody huA33 recognizes the A33 antigen, present in more than 95 % of colorectal cancers and in normal bowel. 124I-huA33 PET/CT has been utilized at Memorial Sloan-Kettering Cancer Center to demonstrate targeting of the antibody to colorectal metastases, confirming previous work done by the group to establish the utility of this antibody for radioimmunotargeting [41, 42].

Schwartz et al. demonstrated that red marrow radiation absorbed dose could be identified in both the above instances, with the potential to estimate the optimal therapeutic dose for radioimmunotherapy [43].

Several other antibodies have been studied in murine models, including 124I-VEGF MAB HUMV833,which was evaluated in a human tumor xenograft model [44], and another antibody targeting neo-vasculature, which employed a murine model with murine VEGFr-positive cells [45].

124I labelled mIBG

Meta-iodobenzylguanidine is a structural analogue of guanethidine. It shows energy dependent uptake mediated by nor-epinephrine transporter in cells rich in sympathetic neurons. It is used both as a diagnostic and therapeutic tool in neuroendocrine tumors and neuroblastoma [46–48].

Patients undergo 123I-mIBG or low dose 131I-mIBG single photon imaging to identify sites of disease (and suitability for 131I-mIBG therapy) predict the organ and whole body dose, which can guide in deciding on a safe therapeutic dose for each patient. Moreover, quantification of single photons in vivo can be fraught. 123I-mIBG has been found to be inferior to 18F-FDG in depicting lesions in stage I and II neuroblastoma [49]. Images are obtained the day after injection; later imaging is difficult given the 13-hour half-life of 123I.

124I-mIBG permits better identification of disease as well as more accurate quantification of radiation dose to normal and pathological organs, with the potential for more precise I131-mIBG therapy. Improvement in sensitivity, lesion detection, increased precision to count individual lesions and better characterization of skull lesions are incremental benefits. Accurate determination of semi-quantitative TMRR (Total 123I-MIBG retention ratio), MIBG/Curie score and SIOPEN (International Society of Pediatric Oncology Europe Neuroblastoma Group) score during scan interpretation improves extent of disease evaluation and may help in deciding the appropriate next step in management i.e., choosing between medical and surgical treatment [50–53]. The scoring, typically done using 123I-mIBG, will likely be improved with 124I-mIBG PET; the longer half-life of 124I also enables delayed images up to a week after administration.

Preliminary experience in two pediatric patients with an IV dose of 50 MBq and image acquisition done at 24 and 48 h showed promise [53]. Improved characteristics of current PET/CT scanners allow decreasing administered amount of radioactivity while maintaining adequate image quality [54], though it must be noted that radiation exposure is a secondary concern in these children with life-threatening disease and considerable mutagenic therapy. Further investigational studies are warranted to validate and standardize the use of 124I-mIBG in patients with neuroblastoma.

Patient specific dosimetry for 131I-mIBG using pretherapy 124I-mIBG and Monte Carlo dosimetry has recently been used for better treatment planning. This method estimated dose to normal organs and tumors with more realistic simulation geometry [55]. Organ-absorbed doses for the salivary glands, heart wall and liver were determined to be 98.0 Gy, 36.5 Gy, and 34.3 Gy, respectively, whereas tumor-absorbed dose range was 143.9–1641.3 Gy.

Hypoxia imaging

Tumor hypoxia is associated with aggressive tumor phenotypes, and increased resistance to chemotherapy/radiotherapy; it is an independent prognostic factor of clinical outcome. New therapies like hypoxia-activated prodrugs, and hypoxia triggered gene therapy are being developed and the need to assess tumor hypoxia is necessary to select patients who will benefit with this therapy [56]. Many members of the 2-nitroimidazole family have been investigated, including 124I- iodoazomycinarabinofuranoside (IAZA) and 124I-IAZGP. None has been shown to be superior to 18F-labeled compounds [57, 58]. Reischl et al. performed a study to compare 124I-IAZA, 18F-FAZA and 18F-MISO in visualization of tumor hypoxia in a mouse model of human cancer using microPET and showed that 18F-FAZA has superior biokinetics compared to the others; imaging at later time points was of no advantage for 124I-IAZA as the absolute whole body radioactivity was then very low [59].

Nanoparticles

Nanoparticles coated with appropriate ligands can be targeted to specific cells. Incorporating 124I to the structure of nanoparticles retains their bio-functionality and enables PET imaging [60]. Animal studies using 124I-labelled nanopolymers targeted to specific endothelial determinants aid in optimization of targeted drug delivery, and nanophosphors tagged with radiolabelled (124I) RGD for tumor imaging, have shown promising results [61, 62].

Other compounds of interest

124 I-Beta-CIT (124I-2beta-carboxymethoxy-3beta-(4-iodophenyl)tropane) is a cocaine analog that binds to dopamine transporter and has been used to image the sub-thalamic nuclei in drug abuse and Parkinson’s disease. In a normal brain, there is high tracer accumulation in striatum and much lower in the thalamus, neocortex and cerebellum. 124I potentially provides quantification, with its long half-life also permitting delayed imaging [12]. 124I-Epidepride for extended imaging of dopamine D2/3 receptors may have applications in imaging of receptors in brain and pancreatic islet cells [63]. 124-I labelled to a small molecule, MIP-1095, that targets prostate specific membrane antigen was used for dosimetry as a guide to therapy with the 131-I labelled molecule [64].

The suitable half-life, quantifiable and relatively abundant positron emission, and well characterized chemistry, have led to a plethora of 124I labeled compounds being developed; most have currently not gone beyond rodent imaging studies. 124I-labeled CDK4/6 inhibitors [65], 1-(2-deoxy-beta-d-ribofuranosyl)-2,4-difluoro-5-iodobenzene (124I-dRFIB) [66] and 124I-deoxyuridine (124I-IUdR) have been developed for use in imaging cell proliferation. 124I-IUdR) has been used to measure cell proliferation in vivo in non small cell lung cancer [67] and glioma [68]. 124I-labeled-hypericin for imaging protein-kinase C, 2′-fluoro-2′-deoxy-1β-d-arabinofuranosyl-5-[124I]iodouracil (124I-FIAU) for imaging herpes virus thymidine kinase [69], (E)-But-2-enedioic acid [4-(3-[(124)I]iodoanilino)-quinazolin-6-yl]-amide-(3-morpholin-4-yl-propyl)-amide (124I-morpholino-IPQA) for imaging EGFR kinase activity [70], 124I-labeled-6-anilino-quianilino-quinazoline for imaging EGFR Inhibitor, 124I-labeled Annexin V and MBP Annexin V for imaging of apoptosis [71, 72], 124I-anti-PSCA (prostate stem cell antigen) A11 minibody for imaging of prostate cancer bone metastases [73] and 124I-labeled purpurinimide derivative for tumor imaging [74], have been studied in a few subjects in each instance, 124I-iodometomidate (124I-IMTO) appears to be an attractive PET tracer for imaging adrenals [75].

Summary of clinical studies

Iodine-124 has now become established as a PET nuclide of considerable potential. Radioactive iodine itself has been a mainstay of Nuclear Medicine, and 124I now brings the quantitative potential and superior contrast of PET to a wide variety of applications that have utilized other isotopes of iodine in the past. In particular, it has been found to be extremely useful in assessment of those patients in whom imaging is unsatisfactory with other radioisotopes. Figure 1 is an example of a patient with thyroid carcinoma (papillary at initial presentation) who had a negative 131I scan; the pulmonary and cervical iodine-avid disease is clearly visualized in the 124I PET scan, and serial imaging enabled calculation of tumor radiation dose from 131I therapy.

Fig. 1
figure 1

3D Maximum intensity projection of a 124I PET obtained 3 days after administration to a patient with papillary thyroid carcinoma (at presentation) who had a negative 131I scan

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Rapid clearance of radioiodine from the body is feasible with administration of stable iodide, and conjugating radioactive iodine to molecules of interest can thus be carried out with the secure knowledge that any radioactivity that becomes unbound will be rapidly eliminated, and with the knowledge that there is no non-specific accumulation in major organs like liver or bone marrow—an often vexing problem with radiometals. The relatively long half-life of 124I lends itself to conjugation particularly with macromolecules that require imaging to be carried out days after administration of the radionuclide (a list of clinical trials utilizing 124I PET is provided in the Table 1). Figure 2 is an example of a positive scan obtained a week after intravenous 124I-girentuximab; the enhanced contrast is clearly evident. PET quantification has been found to be closely correlated with ex vivo measures of radioactivity concentration. Figure 3 is a digital autoradiograph from the resected clear cell renal carcinoma visualized in Fig. 2—the concordance between antigen expression (brown stain, right) with the distribution of radioactivity (dark, left) demonstrating the specificity of immunoPET.

Table 1 Ongoing clinical trials: a list of current clinical trials that utilize 124I-based PET/CT was obtained from the clinicaltrials.gov website. They include
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Fig. 2
figure 2

Fusion coronal image of a PET/CT obtained a week after 124I-girentuximab administration to a patient with clear cell renal cell carcinoma (ccRCC)

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Fig. 3
figure 3

Digital autoradiography (left) and immunohistochemistry (right) of the ccRCC obtained from patient in Fig. 2

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Production and distribution of 124I is certainly feasible with far fewer production sites than are necessary for shorter-lived nuclides; the relatively high (compared to 18F) whole body dose from 124I remains a major drawback to its increasing use. So does its cost—this latter may however be considerably decreased if there is greater utilization (and thus demand) for 124I. It is of course to be remembered that intracellular dehalogenation of radioiodine-conjugate molecules can occur, particularly when these are internalized through clathrin-coated pits. However, newer methods of conjugation may minimize/obviate this concern.

Exploration of the potential of PET using 124I continues apace. Newer therapies in thyroid cancer are being explored with 124I PET to assess and measure the feasibility of 131I therapy. Conjugation of 124I to a variety of molecules of varying sizes has enabled better assessment of disease, in particular the cancer phenotype. More accurate quantification also aids decision-making, be it for therapy with 131I or for evaluation of therapeutic promise (a “predictive” biomarker) or efficacy (a “pharmacodynamic” biomarker). Crucial to the growth of 124I PET will be a reduction in cost of production, potentially possible as more groups begin to produce this promising radionuclide.

Conclusion

This review summarizes the current and ongoing applications of 124I as a PET radionuclide for molecular imaging. The positron emitting ability and 4.2 day half-life is particularly attractive for in vivo detection and quantification of slower biological and physiological processes.

Iodine-124 permits quantitative PET/CT of a wide variety of compounds, in addition to its use as the iodide in thyroid disorders. It is available throughout the world, although it currently is not inexpensive to produce. Its radiation dosimetry is similar to that of 131I. Its half-life permits delayed images as well as autoradiography. Quantification of its distribution over time provides information regarding the biologic behavior of the agent to which it is attached, as well as enables estimates of radiation dose delivery (of therapeutic 131I) that can be obtained with an accuracy comparable to ex vivo measurement. Pre-administration of stable iodide limits accumulation of radioiodine in normal tissue, reducing normal tissue toxicity.