Organic compounds bearing radioisotopes of iodine play a major role in nuclear medicine and molecular imaging. (1−3) As there are a number of radioactive iodine isotopes, a single biologically or medicinally active iodinated compound can be labeled with different radioisotopes for a particular application. For example, compounds bearing iodine-123 or iodine-124 can be used for the diagnostic imaging of disease via single photon emission computed tomography (SPECT) or positron emission tomography (PET) techniques, respectively. (4−6) Radiopharmaceuticals bearing iodine-131 are used for radiotherapy, while iodine-125 labeled compounds are commonly used in preclinical, biological, and medicinal chemistry applications.
γ: gamma ray emission, β+: positron emission, β–: electron emission.
The importance of radioiodinated probes and agents in nuclear medicine and imaging has required the development of efficient synthetic methods for the preparation of these compounds. (4−6) In a similar manner to conventional synthetic chemistry, the aim of these methods is to produce radioiodinated compounds as efficiently as possible. In radiochemistry, this is measured using RadioChemical Yield (RCY, the amount of activity in the isolated product expressed as a percentage of starting activity) or RadioChemical Conversion (RCC, the amount of activity in the nonisolated product, usually obtained from a radio-HPLC and expressed as a percentage of starting activity) and RadioChemical Purity (RCP, the percentage of activity of the radionuclide with respect to the total activity of all radionuclides in the sample). (7) The other important property of radioiodinated compounds is Molar Activity (A m, the measured radioactivity per mole of compound, typically expressed as becquerels per micromole). For imaging applications, radiolabeled compounds with high molar activity are important to generate actual tracer conditions, where the biological target is mainly bound with radioactive compounds and not nonradioactive species. The level of molar activity required for imaging is highly dependent on the context and biological target. However, in developing radioiodination methods, final compounds with molar activities in the GBq.μmol–1 range of magnitude are considered suitable. Unlike the radioisotopes commonly used in PET imaging (e.g., 11 C, 18 F), the radioisotopes of iodine have relatively long half-lives and for this reason, synthetic methods for radioiodination are more varied. (4−6,8−11) As radioiodine isotopes are produced in iodide form, (12) early reported methods have involved nucleophilic substitution reactions, such as the use of high temperature and solid state halogen exchange reactions. (13) Alternatively, radioactive iodide can be oxidized to iodine or iodine monochloride and used in electrophilic substitution reactions, such as the iododestannylation of aryltin compounds. (14)
Although these methods allow the iodination of various compounds with high RCY and RCP, the harsh reaction conditions, challenging purifications (such as the removal of organotin residues) and the need for more varied and sometimes complex targets have required the development of new radioiodination reactions. To meet this demand, a variety of new transformations for the incorporation of radioiodine into organic compounds have been developed in recent years. This synopsis describes these key synthetic advances and in particular, the main transformations used for the preparation of radioiodine bonds with C sp, C sp2, and C sp3 centers.
Direct replacement of stable iodine isotopes on organic molecules by a radioiodine isotope, also called isotopic exchange, is a well-known procedure. The reaction is usually performed neat, with the radioiodide ion, at very high temperature and most often in the presence of sulfate salts and oxidants such as dioxygen from the air. (13) Isotopic exchange can also be realized in water at high temperature, but in this case, addition of copper sulfate as a reagent has been evidenced to both promote the radioiodination and shorten reaction times. (13,15,16) However, due to the impossible separation of nonradioactive and radioactive iodinated products, this method is not suitable to access radioiodinated molecules in the GBq·μmol–1 range of magnitude.
In order to restore optimal molar activities, bromine–iodine exchanges can be performed using the same conditions as isotopic exchanges. Thus, in 2014, Brownell et al. described the radioiodination of [123 I]IPEB, a metabotropic glutamate receptor subtype 5 radioligand, through bromine–iodine exchange at high temperature in the presence of copper and tin sulfate. (17) Solid-state synthesis can also be used. For example, the radiosynthesis of a Matrix MetalloProteinase-12 (MMP-12) iodinated probe was described by Mukai in 2018. (18) Overall, bromine–iodine exchange appears to give comparable RCYs as isotopic exchange along with higher molar activities but in all cases at the cost of very harsh reaction conditions.
In 2017, Sutherland et al. described an efficient methodology to radioiodinate aryl amines via stable diazonium salts. (19) This methodology is based on the use of widely available starting materials and a polymer supported nitrite reagent, which allowed both the formation of diazonium salts and the subsequent Sandmeyer reaction to take place under mild conditions. The incorporation of the radioiodine atom was done thereafter using sodium iodide. This one-pot methodology was used on eight example substrates, demonstrating its functional tolerance, as well as generating several SPECT tracers, including [125 I]iomazenil, [125 I]CNS1261, and [125 I]IBOX with RCYs between 47 and 75%. Triazene derivatives can also be used in S N Ar reactions; however, even if these precursors are stable and can be isolated, they are usually less reactive than the corresponding diazonium salts. (20,21)
In 2016, Gestin et al. published a systematic study aimed at comparing the reactivity of aryliodonium salts in radiolabeling using either sodium iodide or astatide. (22) Their investigations showed that the use of acetonitrile as solvent, at 90 °C, with iodonium sulfonate were the optimal conditions to perform efficient radioiodination from iodonium salts. The regioselectivity of the nucleophilic substitution of unsymmetrical iodoniums salts was found to be controlled by electronic and steric effects. The same authors have used this methodology to radiolabel activated esters acting as prosthetic groups able to bind biomolecules. Thus, N-[125 I]succinimidyl-3-iodobenzoate ([125 I]SIB) was obtained in 36–87% RCY, depending on the nature of the electron-rich arene moiety. (23) In 2019, this methodology was applied to the radiolabeling of two other prosthetic groups, for attachment to biomolecules by either click chemistry or inverse-electron-demand Diels–Alder reactions. (11)
Electrophilic aromatic substitution is a very popular strategy to perform radioiodination, which can be applied either directly with the compound of interest or using a prefunctionalized precursor. Nevertheless, this procedure requires the generation of an electrophilic iodine species, which is typically prepared from sodium iodide and a strong oxidant such as hydrogen peroxide, peracids, N-halosuccinimides, or N-chloroamides.
Direct electrophilic aromatic substitution is a typical process to perform radioiodination of aromatic molecules. (24) Generally, this strategy exhibits low regioselectivity unless there has been careful choice of starting compound. In these cases, the reaction can lead to the radioiodinated compound with good RCY and high molar activity. For example, this approach has been used for the direct and regioselective radioiodination of the 4-aminobenzoic core found in numerous 5-HT 4 receptor ligands.
In 2016, a silver-catalyzed radioiodination was reported, which used the mild Lewis acid nature of a silver triflimide salt, avoiding the poly iodination of activated aromatic rings. (25) The completely regioselective radioiodination of electron-rich substrates (as observed by nonradioactive reactions) facilitated by this method has enlarged the panel of substrates accessible to direct S E Ar reactions. Nevertheless, to overcome the regioselectivity issues of other S E Ar strategies, the preparation of stannylated, silylated, or boronated precursors is generally required to perform ipso S E Ar.
Iododestannylation is the most used methodology to perform radioiodination in research facilities. (1−5) Starting from a stannane precursor, using an in situ generated iodinated reagent from NaI and an oxidant, the transformation proceeds smoothly and selectively to afford, via an ipso S E Ar reaction, the radiolabeled derivatives. Despite issues concerning their stability and toxicity, aryltrialkylstannanes are generally prepared from the corresponding halogenated precursor through metalation or palladium-mediated reactions. The major drawback of this reliable method, often hampering its use in clinics, is the contamination of the obtained radiotracer with organotin residues. Nevertheless, radioiododestannylation is currently the main method of choice to perform radioiodination and many small molecules used as radiotracers, such as [125 I]AGI-5198, have been prepared accordingly. (26)
Several approaches have been described recently to specifically address the purification issues inherent to iododestannylation. In 2006, the Valliant group employed fluorine-rich organostannane to perform radioiododestannylation in order to discard organotin residues through fluorous solid-phase extraction. Thus, labeling with [125 I]NaI in the presence of the oxidant, iodogen allowed the quick formation of the radiolabeled derivatives with RCYs up to 85% and RCPs up to 98%. (27) This method was used by the same group to produce [125 I]iodoxuridine and [125 I]FIAU, with RCYs of 94 and 88%, respectively, while allowing the efficient removal of organotin precursors through a simple filtration technique as evidenced by a UV-HPLC technique. (28)
A similar approach was proposed by the Gestin group in 2016, using an ionic liquid supported stannylated precursor for radiolabeling. (29) This strategy significantly facilitated the formation and purification of the product, using a simple SiO 2 filtration to separate radio-iodinated product and organotin precursor, allowing the isolation of [125 I]SIB with 67% RCY and 100% RCP.
In the challenging field of biomolecules radiolabeling, taking into account synthetic efficacy, half-lives and/or safety issues, the introduction of the radionuclide is preferred at the last step of the radio-synthesis. This late stage diversification is generally achieved using a prosthetic group strategy in order to reach selectivity toward the radio-labeling site. Several prosthetic groups have been radioiodinated using an iododestannylation approach. For example, [125 I]1,2,4,5-tetrazines (30,31) and a [125 I]benzamide moiety (32) have been efficiently prepared using iododestannylation and then attached to the target biomolecules using inverse electron demand Diels–Alder and copper-catalyzed condensation reactions, respectively.
Silanes can be used as precursors for the labeling of molecules of interest. However, compared to iododestannylation, the obtained RCYs are generally lower due to the higher stability of the carbon–silicon bond. This methodology has nevertheless been used to label specific substrates with success, generally in acidic media, starting from an activated precursor and an electrophilic source of iodine. For example, in 1993, [131 I]MIBG was labeled in 85–90% RCY by Zalutsky, (33) starting from the corresponding aryltrimethylsilane in TFA, using trifluoroperacetic acid to generate [131 I]I 2 in situ.
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