MCR Scaffolds Get Hotter with 18F-Labeling

Abstract

Imaging techniques, such as positron emission tomography (PET), represent great progress in the clinical development of drugs and diagnostics. However, the efficient and timely synthesis of appropriately labeled compounds is a largely unsolved problem. Numerous small drug-like molecules with high structural diversity can be synthesized via convergent multicomponent reactions (MCRs). The combination of PET labeling with MCR synthesis of biologically active compounds can greatly simplify radioanalytical and imaging-based analysis. In a proof-of-concept study, we optimized robust on-site radiolabeling conditions that were subsequently applied to several structurally different drug-like MCR scaffolds (e.g., arenes, β-lactam, tetrazole, and oxazole). These labeled scaffolds were synthesized via pinacol-derived aryl boronic esters (arylBPin) by copper-mediated oxidative 18F-fluorination with radiochemical conversions (RCCs) from 15% to 76%.

Automated synthesis of 18F radiolabelled indole containing Oncrasin-like molecules; a comparison of iodonium salts and boronic ester chemistry

“…Recent work by Zarganes-Tzitzikas et al (Zarganes-Tzitzikas et al 2019 ) suggest that increasing the quantities of precursor approximately 4 fold could improve radiolabelling yields, however protodeborylation side products which were observed were difficult to separate and would likely be increased with the increase in precursor. This would potentially impact on the purity and molar activity of the tracer.…”

“…In addition to the iodonium salt precursor class, a new boronic acid pinacol ester precursor has become of significant interest for aryl radio fluorination, with the functional group being known for good long-term stability and chemical resilience (Preshlock et al 2016 ; Mossine et al 2015 ; Tredwell et al 2014 ; Zarganes-Tzitzikas et al 2019 ). The synthetic routes for these compounds are also well characterized due to their prevalence in synthetic chemistry, and the conditions for radiolabelling are not as harsh as those for iodonium salts.…”

Nucleophilic Synthesis of 6-l-[18F]FDOPA. Is Copper-Mediated Radiofluorination the Answer?

“…Therefore, recent research in the field has been focused on the late-stage radiofluorination of non-activated (electron-rich) aromatic structures. In the past few years, several innovative 18 F-labeling approaches have been introduced using, for example, iodonium salts, spirocyclic hypervalent iodine (III) complexes, organoborons and stannanes (for the reviews see [ 37 , 52 , 53 , 54 , 55 , 56 , 57 ]).…”

Automated synthesis of 18F radiolabelled indole containing Oncrasin-like molecules; a comparison of iodonium salts and boronic ester chemistry.

“…Recent work by Zarganes-Tzitzikas et. al (16) suggest that increasing the quantities of precursor approximately 4 fold could improve radiolabelling yields, however protodeborylation side products which were observed were di cult to separate and would likely be increased with the increase in precursor. This would potentially impact on the purity and molar activity of the tracer.…”

“…In addition to the iodonium salt precursor class, a new boronic acid pinacol ester precursor has become of signi cant interest for aryl radio uorination, with the functional group being known for good long-term stability and chemical resilience (9,10,15,16). The synthetic routes for these compounds are also well characterized due to their prevalence in synthetic chemistry, and the conditions for radiolabelling are not as harsh as those for iodonium salts.…”