Fedor Zhuravlev

Homogeneous Nucleophilic Radiofluorination and Fluorination with Phosphazene Hydrofluorides

A series of phosphazenium hydrofluorides, P(1)(tBu)·[(18/19)F]HF, P(1)(tOct)·[(18/19)F]HF, P(2)(Et)·[(18/19)F]HF, and P(4)(tBu)·[(18/19)F]HF, was synthesized. The radioactive phosphazenium [(18)F]hydrofluorides were obtained by the one-step formation and trapping of gaseous [(18)F]HF with the respective phosphazene bases. The [(19)F] isotopomers were prepared from the corresponding phosphazene bases and Et(3)N·3HF. Under the design of experiment (DoE)-optimized conditions, P(2)(Et)·HF and P(4)(tBu)·HF fluorinated alkyl chlorides, bromides, and pseudohalides in 76-98% yield, but gave lower yields with iodides and electron-deficient arenes. DoE models showed that fluorination can be performed in glass vessels, and that the reactivity of P(2)(Et)·HF and P(4)(tBu)·HF is dominated by solvent polarity but is insensitive to water to at least 2 equiv. In contrast, P(1)(tBu)·HF and P(1)(tOct)·HF were unstable towards autofluorolysis. DFT calculations were performed to rationalize this finding in terms of diminished steric bulk, higher Parrs electrophilicity, and chemical hardness of P(1)(R)H(+). The corresponding radiofluorination reaction gave no valid DoE model but displayed similar substrate scope. High specific activity and excellent radiochemical yields with various pseudohalides (81-91%) suggest that the proposed radiofluorination methodology can complement the current [(18)F]KF/Kryptofix methods, particularly in the areas for which nonpolar reaction conditions are required.

Bringing Radiotracing to Titanium-Based Antineoplastics: Solid Phase Radiosynthesis, PET and ex Vivo Evaluation of Antitumor Agent [45Ti](salan)Ti(dipic)

We present a novel solid-phase based (45)Ti radiolabeling methodology and the implementation of (45)Ti-PET in titanium-based antineoplastics using the showcase compound [(45)Ti](salan)Ti(dipic). This development is intended to allow elucidation of the biodistribution and pharmacokinetics of promising new Ti-based therapeutics.

Automated Solid-Phase Radiofluorination Using Polymer-Supported Phosphazenes

The polymer supported phosphazene bases PS-P2tBu and the novel PS-P2PEG allowed for efficient extraction of [18F]F− from proton irradiated [18O]H2O and subsequent radiofluorination of a broad range of substrates directly on the resin. The highest radiochemical yields were obtained with aliphatic sulfonates (69%) and bromides (42%); the total radiosynthesis time was 35–45 min. The multivariate analysis showed that the radiochemical yields and purities were controlled by the resin load, reaction temperature, and column packing effects. The resins could be reused several times with the same or different substrates. The fully automated on-column radiofluorination methodology was applied to the radiosynthesis of the important PET radiotracers [18]FLT and [18F]FDG. The latter was produced with 40% yield on a 120 GBq scale and passed GMP-regulated quality control required for commercial production of [18F]FDG. The combination of compact form factor, simplicity of [18F]F− recovery and processing, and column reusability can make solid phase radiofluorination an attractive radiochemistry platform for the emerging dose-on-demand instruments for bedside production of PET radiotracers.

Towards automated solid phase radiofluorination for dose-on-demand PET: retention of activity by solid support

Abstract On-column [18F]fluoride trapping and radiofluorination of 2-(naphthalen-1-yl)ethyl-4-methylbenzenesulfonate (C10H7(CH2)2OTs), performed on polystyrene supported phosphazene base PS-P2tBu yielded [18F]1-(2-fluoroethyl)naphthalene ([18F]C10H7(CH2)2F) in 50% radiochemical yield but left up to 43% of activity unreacted on the resin. This activity could be eluted with Kryptofix/K2CO3 and then used for conventional radiofluorination of the same substrate, suggesting that the column-retained activity was present in the form of [18F]fluoride entrapped in polymer matrix. An approach to minimize the amount of entrapped [18F]fluoride by use of glass beads functionalized with alkylsilane-derivatized phosphazene residues was attempted but was stymied by fluorolysis/hydrolysis of the alkylsilane spacer. The results suggest that the key to high yield of on-column radiofluorination is to minimize the residual [18F]fluoride absorption in the matrix by the judicious choice of solid support.