An acylation‐Finkelstein approach to radioiodination of bioactives: The role of amide group anchimeric assistance

Abstract

Herein, we report a straightforward sequential acylation-Finkelstein approach to achieve iodination of amine containing bioactives. The utility was demonstrated by successful radiolabelling with 123 I in high radiochemical yield. Moreover, microwave-assisted Finkelstein reaction can be employed to enhance conversion and reaction rates to obtain the desired iodides. The method is of interest for radioiodination of amine-containing bioactives. The mechanistic details of the iodination process were studied by kinetics and density functional theory calculations, which revealed the mechanistic complexity of the reaction involving amide group anchimeric assistance. We disclose a number of fundamental aspects of amide group anchimeric assistance in substitution reactions.

First in vivo evaluation of a potential SPECT brain radiotracer for the gonadotropin releasing hormone receptor

“…The key intermediate 1a and Compound- 1 were prepared according to literature procedures [ 4 , 11 ]. In brief, non carrier added Na 123 I was prepared in a concentration step over 4 h evaporating the solvent.…”

“…Our aim was to target the GnRH-R in the CNS by SPECT imaging since quantifying GnRH-R expression will give valuable information for diagnosis, treatment and pathophysiology. We have previously disclosed the radiolabelling of Compound- 1 using an acylation-Finkelstein approach in 80% analytical RCY and 17% isolated yield [ 4 ]. This gave us a straightforward access to the radioiodinated compound which is in compliance with requirements for radiolabelling [ 16 ].…”

“…However, evaluation of the Compound- 1 distribution at shorter time points (1–5 min) post-injection could have been tested avoiding deiodination at early time points. In addition, further studies for similar compounds with longer chain lengths and fluorine or fluorine-18 for future PET are planned and our chemical kinetics experiments indicate far more robust compounds in this series [ 4 ].…”

“…We have previously disclosed the discovery of GnRH-R antagonists and a thorough mechanistic analysis of halogen exchange by the use of anchimeric assistance by amide groups [ 4 ]. In addition, Compound- 1 has been radiolabeled in high radiochemical yield [ 5 ].…”

Evaluation by metabolic profiling and in vitro autoradiography of two promising GnRH‐receptor ligands for brain SPECT imaging

“…We have recently revealed the discovery of GnRH‐R antagonist candidates based on a benzimidazole‐piperazine molecular scaffold suitable for SPECT imaging, compounds 1 and 2 , Figure . Further diversification from the initial study led to the discovery of two highly promising 123 I‐labelled triazole‐benzimidazole GnRH‐R antagonists, compounds 3 and 4 , Figure…”