Discovery of new mutually orthogonal bioorthogonal cycloaddition pairs through computational screening.

Density functional theory (DFT) calculations and experiments in tandem led to discoveries of new reactivities and selectivities involving bioorthogonal sydnone cycloadditions. Dibenzocyclooctyne derivatives (DIBAC and BARAC) were identified to be especially reactive dipolarophiles, which undergo the (3+2) cycloadditions with N-phenyl sydnone with the rate constant of up to 1.46 M-1 s-1. Most signifcantly, the sydnone-dibenzocyclooctyne and norbornene-tetrazine cycloadditions were predicted to be mutually orthogonal. This was validated experimentally and used for highly selective fluorescence labeling of two proteins simultaneously

Discovery of new mutually orthogonal bioorthogonal cycloaddition pairs through computational screening.

Density functional theory (DFT) calculations and experiments in tandem led to discoveries of new reactivities and selectivities involving bioorthogonal sydnone cycloadditions. Dibenzocyclooctyne derivatives (DIBAC and BARAC) were identified to be especially reactive dipolarophiles, which undergo the (3 + 2) cycloadditions with N-phenyl sydnone with the rate constant of up to 1.46 M-1 s-1. Most significantly, the sydnone-dibenzocyclooctyne and norbornene-tetrazine cycloadditions were predicted to be mutually orthogonal. This was validated experimentally and used for highly selective fluorescence labeling of two proteins simultaneously

18 F-Labeled brain-penetrant EGFR tyrosine kinase inhibitors for PET imaging of glioblastoma

Significant evidence suggests that the failure of clinically tested epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (e.g. erlotinib, lapatinib, gefitinib) in glioblastoma (GBM) patients is primarily attributed to insufficient brain penetration, resulting in inadequate exposure to the targeted cells. Molecular imaging tools can facilitate GBM drug development by visualizing drug biodistribution and confirming target expression and localization. To assess brain exposure via PET molecular imaging, we synthesized fluorine-18 isotopologues of two brain-penetrant EGFR tyrosine kinase inhibitors developed specifically for GBM. Adapting our recently reported radiofluorination of N-arylsydnones, we constructed an ortho-disubstituted [18F]fluoroarene as the key intermediate. The radiotracers were produced on an automated synthesis module in 7-8% activity yield with high molar activity. In vivo PET imaging revealed rapid brain uptake in rodents and tumor accumulation in an EGFR-driven orthotopic GBM xenograft model

Synthesis of [18 F]Fluoroarenes by Nucleophilic Radiofluorination of N-Arylsydnones.

A practical method for radiofluorination of anilines with [18 F]fluoride via N-arylsydnone intermediates is described. These precursors are stable, easy to handle and facilitate direct and regioselective 18 F-labeling to prepare [18 F]fluoroarenes. The value of this methodology is further highlighted by successful application to prepare an 18 F-labeled neuropeptide

Automated concentration of [18F]fluoride into microliter volumes

Concentration of [18F]fluoride has been mentioned in literature, however, reports have lacked details about system designs, operation, and performance. Here, we describe in detail a compact, fast, fully-automated concentration system based on a micro-sized strong anion exchange cartridge. The concentration of radionuclides enables scaled-up microfluidic synthesis. Our system can also be used to provide highly concentrated [18F]fluoride with minimal water content. We demonstrate how the concentrator can produce varying concentrations of [18F]fluoride for the macroscale synthesis of N-boc-5-[18F]fluoroindole without an azeotropic drying process, while enabling high starting radioactivity. By appropriate choice of solid-phase resin, flow conditions, and eluent solution, we believe this approach can be extended beyond [18F]fluoride to other radionuclides

A Transmetalation Reaction Enables the Synthesis of [¹⁸F]5-Fluorouracil from [¹⁸F]Fluoride for Human PET Imaging

Translation of new ¹⁸F-fluorination reactions to produce radiotracers for human positron emission tomography (PET) imaging is rare because the chemistry must have useful scope and the process for ¹⁸F-labeled tracer production must be robust and simple to execute. The application of transition metal mediators has enabled impactful ¹⁸F-fluorination methods, but to date none of these reactions have been applied to produce a human-injectable PET tracer. In this article we present chemistry and process innovations that culminate in the first production from [¹⁸F]­fluoride of human doses of [¹⁸F]­5-fluorouracil, a PET tracer for cancer imaging in humans. The first preparation of nickel σ-aryl complexes by transmetalation from arylboronic acids or esters was developed and enabled the synthesis of the [¹⁸F]­5-fluorouracil precursor. Routine production of >10 mCi doses of [¹⁸F]­5-fluorouracil was accomplished with a new instrument for azeotrope-free [¹⁸F]­fluoride concentration in a process that leverages the tolerance of water in nickel-mediated ¹⁸F-fluorination

A Transmetalation Reaction Enables the Synthesis of [18F]5-Fluorouracil from [18F]Fluoride for Human PET Imaging

Translation of new 18F-fluorination reactions to produce radiotracers for human positron emission tomography (PET) imaging is rare because the chemistry must have useful scope and the process for 18F-labeled tracer production must be robust and simple to execute. The application of transition metal mediators has enabled impactful 18F-fluorination methods, but to date none of these reactions have been applied to produce a human-injectable PET tracer. In this article we present chemistry and process innovations that culminate in the first production from [18F]fluoride of human doses of [18F]5-fluorouracil, a PET tracer for cancer imaging in humans. The first preparation of nickel σ-aryl complexes by transmetalation from arylboronic acids or esters was developed and enabled the synthesis of the [18F]5-fluorouracil precursor. Routine production of >10 mCi doses of [18F]5-fluorouracil was accomplished with a new instrument for azeotrope-free [18F]fluoride concentration in a process that leverages the tolerance of water in nickel-mediated 18F-fluorination