Synthesis and radiofluorination essays of hypervalent iodine (III) precursors for rapid generation of 18F-fluoroquine radiotracer

Author

Ramos Valle, Andrés

Abstract

Positron emission tomography (PET) is a highly valuable imaging technique capable of providing qualitative and quantitative information on biological processes in vivus. Among all of them, fluorine-18 (t 1/2 = 109.7 min) is one of the most widely used isotopes in radiopharmaceuticals for obtaining molecular images by PET. Despite the remarkable advances in 18F labeling of relevant aromatic nuclei via rSNA processes, there is an unmet need for efficient 18F fluorination methods in non-activated arenes. One of the most prominent solutions to this problem is the "hypervalent iodine" route, which consists of placing a high valence iodine group, usually iodine (III), at the target position. Thus, the replacement of this group by the 18F-fluoride anion (little reactive) occurs thanks to the exceptional reactivity of the carbon-iodine (III) bond, something ~ 106 times higher than that of the standard triflate group. Being very useful, the synthesis of such species must go through the oxidation of the iodine atom in its iodine (III) stage. This could be problematic for substrates not compatible with strong oxidants, including certain heterocycles, unsaturated carbon-carbon bonds, NH amines, and amides, that is, many of the groups found in bioactive nuclei. Therefore, the oxidation conditions must be adjusted for each type of bioactive skeleton. In this project, we focus on the synthesis of a series of hypervalent iodine precursors from the chloroquine molecule, which in addition to its antimalarial activity, has recently been shown to be endowed with a lysosomotropic effect that improves the endosomal escape of genetic material in some nanoformulations used for gene therapy.
To this end, a series of hypervalent iodine compounds have been successfully prepared, based on a simplified model (4-chloro-7-iodoquinoline) or with the complete iodoquinol backbone. Then, in collaboration with the CIC-Biomagune Radiochemistry group, all these iodane precursors were subjected to radiofluorination. From this study, spirocyclic iodonium ylide 39 has been shown to be endowed with the best radiofluorination profile and has been proposed as the ideal precursor to gain access to a chloroquine-based 18F radiotracer.

Director

Cuenca González, Ana Belén

Degree

IQS SE - Master’s Degree in Industrial Engineering

Date

2021-07-05