Nickel‐Mediated Radioiodination of Aryl and Heteroaryl Bromides: Rapid Synthesis of Tracers for SPECT Imaging

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Radiopharmaceuticals that incorporate radioactive iodine in combination with single‐photon emission computed tomography imaging play a key role in nuclear medicine, with applications in drug development and disease diagnosis. Despite this importance, there are relatively few general methods for the incorporation of radioiodine into small molecules. This work reports a rapid air‐ and moisture‐stable ipso‐iododeboronation procedure that uses NIS in the non‐toxic, green solvent dimethyl carbonate. The fast reaction and mild conditions of the gold‐catalysed method led to the development of a highly efficient process for the radiolabelling of arenes, which constitutes the first example of an application of homogenous gold catalysis to selective radiosynthesis. This was exemplified by the efficient synthesis of radiolabelled meta‐[125I]iodobenzylguanidine, a radiopharmaceutical that is used for the imaging and therapy of human norepinephrine transporter‐expressing tumours.

Section: Discussionmentioning

confidence: 99%

Rapid Iododeboronation with and without Gold Catalysis: Application to Radiolabelling of Arenes

Webster

O’Rourke

Fletcher

et al. 2017

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“…However, these reactions are often associated with issues related to low radiochemical yields (RCYs), low specific activities, or concerns about the toxicity of the precursors and side products when considering human use. Consequently, the development of novel methodologies to improve the radiolabeling of arenes with heavy halogens remains an active area of research …”

Section: Introductionmentioning

confidence: 99%

Unexpected Behavior of the Heaviest Halogen Astatine in the Nucleophilic Substitution of Aryliodonium Salts

Guérard

Lee

Baidoo

et al. 2016

Aryliodonium salts have become precursors of choice for the synthesis of 18F-labelled tracers for nuclear imaging. However little is known on the reactivity of these precursors with heavy halogenides, i.e. radioiodide and astatide at the radiotracer scale. Herein, we report the first comparative study of radiohalogenation of aryliodonium salts with [125I]-iodide and [211At]-astatide. Initial experiments on a model compound highlight a higher reactivity of astatide compared to iodide that could not be anticipated from the trends previously observed within the halogen series. Kinetic studies indicate a significant difference in activation energy (Ea = 23.5 and 17.1 kcal/mol with 125I− and 211At−, respectively). Quantum chemical calculations support the hypothesis of a monomeric iodonium-astatide intermediate whereas radio-iodination occurs in a dimeric environment. The good to excellent regioselectivity of halogenation and high yields achieved with diversely substituted aryliodonium salts indicates that this class of compounds is a promising alternative to the stannane chemistry currently used for radiohalogen labeling of tracers in nuclear medicine.

“…Consequently, the development of novel methodologies to improve the radiolabeling of arenes with heavy halogens remains an active area of research. [17,18] Compared to iodine, the chemistry of astatine remains largely unexplored despite more than 70 years since the discovery of this element. [19] Its chemical behavior is not well understood and can differ significantly from the trends observed with the other halogens.…”

Section: Introductionmentioning

confidence: 99%

Unexpected Behavior of the Heaviest Halogen Astatine in the Nucleophilic Substitution of Aryliodonium Salts

Guérard

Lee

Baidoo

et al. 2016

What is the most significant result of this study?Astatine is definitely ah alogen apart and it was demonstrated again in this study.B ecause it is too rare to observe and analyze by conventional approaches, chemists have tried for decades to anticipate its reactivity by extrapolation from its closest neighbor, iodine, but experiments frequently proved these predictions wrong. In this study,w ei nitially anticipated the nucleophilic substitution of astatide on aryliodonium salts to occur similarly to iodide. However,w eobserved ar eactivity that was much higher.Quantum chemical calculations were then utilized to propose mechanisms for this reactivity since astatine is "invisible"; it is available only at the nanogram scale at best. These observations make diaryliodonium salts much more useful than expected to synthesize astatinated compounds, especially with the radioisotope