A protocol for controlled reactivity shift in the 2,2-difluorovinyl motif used for selective S-18F and C-18F bond formation.

Positron emission tomography (PET) is a powerful imaging technique for biomedical research, drug development and medical diagnosis. The power of PET lies in biochemically selective radiotracers, labelled with positron emitters like fluorine-18 image chemical processes in vivo. A rapid and remarkably efficient, unprecedented protocol to select between S-F and C-F bond formation based on activation of 1,1-difluoroethylene groups followed by selective oxidation or reduction is described. While transition metal mediated conditions can be employed, the reaction proceeds in high yield using unobjectionable chemical reagents amenable to routine radiotracer production. The latter bodes well for facile clinical translation of the method. The new technique affords radiotracers and the labelling reagent 2,2-difluoro-2-(fluoro-18F)ethyl 4-methylbenzenesulfonate ([18F]1b) in excellent yield. Following oxygenation of the reaction mixture with medical oxygen or air, sulfonyl fluorides are obtained as the primary product. The new protocol was employed in a proof of principle to develop a radiometric assay for quantitation of sulfonylation yield with sulfonyl fluoride reagents. With operational ease and mild conditions, the method bodes a high potential for radiolabelling of biomolecules, known enzyme inhibitors and other temperature-sensitive compounds.

Transition metal free, late-stage, regiospecific, aromatic fluorination on a preparative scale using a KF/crypt-222 complex.

We herein report the development of a convenient, regioselective, aromatic fluorination method of hypervalent iodonium ylides for synthesising fluoro-arenes on a preparative scale. This transition metal free, nucleophilic methodology provides good yields for sterically hindered substrates, irrespective of activation. The methodology simplifies reference synthesis for PET imaging.

Organocatalyst-assisted Ar-18F bond formation: a universal procedure for direct aromatic radiofluorination.

A metal free, phosphane-catalysed protocol for C-F bond formation based on ipso-elimination of iodanes is described. The reaction proceeds in significantly higher yield and with markedly reduced variability of yields (yield range) than previously described procedures. Rapid and efficient radiofluorination is achieved using unobjectionable chemical reagents with precedence in routine radiotracer production. With operational ease and mild conditions, the method promises a high potential for radiolabelling of biomolecules.

A triazacyclononane-based bifunctional phosphinate ligand for the preparation of multimeric 68Ga tracers for positron emission tomography.

For application in positron emission tomography (PET), PrP9, a N,N',N''-trisubstituted triazacyclononane with methyl(2-carboxyethyl)phosphinic acid pendant arms, was developed as (68)Ga(3+) complexing agent. The synthesis is short and inexpensive. Ga(III) and Fe(III) complexes of PrP9 were characterized by single-crystal X-ray diffraction. Stepwise protonation constants and thermodynamic stabilities of metal complexes were determined by potentiometry. The Ga(III) complex possesses a high thermodynamic stability (log K([GaL])=26.24) and a high degree of kinetic inertness. (68)Ga labeling of PrP9 is possible at ambient temperature and in a wide pH range, also at pH values as low as 1. This means that for the first time, the neat eluate of a TiO(2)-based (68)Ge/(68)Ga generator (typically consisting of 0.1 M HCl) can be directly used for labeling purposes. The rate of (68)Ga activity incorporation at pH 3.3 and 20 degrees C is higher than for the established chelators DOTA and NOTA. Tris-amides of PrP9 with amino acid esters were synthesized to act as models for multimeric peptide conjugates. These conjugates exhibit radiolabeling properties similar to those of unsubstituted PrP9.

Synthesis and monoamine uptake inhibition of conformationally constrained 2beta-carbomethoxy-3beta-phenyl tropanes.

A series of 2beta-carbomethoxy-3beta-phenyl tropanes with conformationally constrained nitrogen substituents were synthesized as potential selective dopamine transporter ligands. These novel compounds were examined for their monoamine uptake inhibition potency at the human dopamine transporter (hDAT), the human serotonin transporter (hSERT) and the human noradrenalin transporter (hNET), stably expressed in human embryonic kidney cells (HEK). A SAR-study was conducted to determine the contribution of extended, 4-fluorinated, conformationally constrained C4 chains at the tropane nitrogen to human monoamine transporter affinity and selectivity.

A convenient chemo-enzymatic synthesis and 18F-labelling of both enantiomers of trans-1-toluenesulfonyloxymethyl-2-fluoromethyl-cyclopropane.

The present report is concerned with a stereoselective, reliable route to trans-1,2-disubstituted cyclopropanes and in particular to (S,S)-1-tosyloxymethyl-2-fluoromethyl-cyclopropane (1) and (R,R)-1-tosyloxymethyl-2-fluoromethyl-cyclopropane (ent-1) as conformationally restricted, terminally fluorinated C4-building blocks for medicinal chemistry. The enzymatic kinetic resolution based synthesis of 1 and ent-1 utilises inexpensive, commercially available starting materials. It is based on enantiomeric resolution of rac-cyclopropane carboxylic esters using esterase from Streptomyces diastatochromogenes. Both enantiomers of 1 were prepared selectively in high overall yield over nine steps, starting from ethyl acrylate. The successful radiosynthesis of [18F]-1 and [18F]-ent-1 is also reported.