Manufacturing I-123-labelled radiopharmaceuticals. Pitfalls and solutions

A Mild Method for Regioselective Labeling of Aromatics with Radioactive Iodine

“…in MeCN/TFA (7:3), and under these conditions, the conversion of 5, 6, and 7 into the iodo products was 1, 5, and 20 %, respectively. In complete absence of Tl(OCOCF 3 ) 3 , no conversion of the starting material took place, and this underlines that protodesilylation does not occur under the conditions.…”

“…In continuation of the work by McKillop et al, a regioselective variant of the iodination method was published by Bell et al [18] They discovered that trimethylsilyl (TMS)-substituted aryls, such as 3-trimethylsilyltoluene, undergo ipso substitution when treated with Tl(OCOCF 3 ) 3 , whereas none of the other regioisomers are formed above trace levels. Furthermore, the introduction of the TMS group increases the reactivity of the aromatic system, whereby less activated aryls can be thallated and iodinated.…”

“…Iodinated drug candidates are used for screening antibodies in radioimmunoassays (RIAs) [1] and in preclinical ADME (absorption, distribution, metabolism, and excretion) studies. [2] Owing to emission of gamma radiation, iodinated radiopharmaceuticals are also used in scintigraphic imaging for disease diagnostics, [3] for example, in the localization of tumors by use of meta-iodobenzylguanidine (MIBG) labeled with 123 I. [4] The iodination of aromatics can be achieved by different methods, [5] and the choice of labeling method depends very much on the substrate.…”

“…[13] As the activities of the three iodinated isomers of 2 (i.e., 8-10, see Scheme 1) in a phenotypic whole-cell assay for multipolarity [11] are markedly different (data not shown), we found it crucial to apply a method that would afford a single regioisomer and thus enable us to access the ortho-(i.e., 8), meta-(i.e., 9), and paraiodo (i.e., 10) isomers. McKillop et al [14] have introduced a method for the iodination of small aryl-containing organic molecules by the use of Tl(OCOCF 3 ) 3 and iodide. Mechanistically, the thallated aromatics are formed by direct electrophilic metalation of the aryl ring with Tl(OCOCF 3 ) 3 , after which ligand exchange with iodide followed by ipso substitution creates the aryl-iodine bond.…”

“…[16] However, addition of a cosolvent also lowers the reactivity, which means that deactivated aromatics can be challenging to label. When we exposed griseofulvin analogue 2 to the reaction conditions [Tl(OCOCF 3 ) 3 in neat TFA], hydrolysis to form griseofulvic acid (3, Figure 1) took place within minutes, but when milder conditions [Tl(OCOCF 3 ) 3 in MeCN/TFA, 7:3] were used, no conversion of 2 was observed.…”