John D. Fissekis

Synthesis of a novel bifunctional chelator AmBaSar based on sarcophagine for peptide conjugation and 64Cu radiolabelling

Copper-64 shows promise as both a suitable PET imaging and therapeutic radionuclide due to its nuclear characteristics. Stable attachment of radioactive (64)Cu(2+) to targeted imaging probes requires the use of a bifunctional chelator. Sarcophagine (Sar) ligands coordinate the metal ion (64)Cu(2+) within the multiple macrocyclic rings comprising the cage structure, yielding extraordinarily stable complexes that are inert to dissociation of the metal ion in vivo. Several (64)Cu labelled RGD derivatives have been applied in imaging of the alpha(nu)beta(3) integrin receptor expression during tumour angiogenesis. In order to design and develop novel molecular imaging probes containing RGD and Sar ligands, we designed a novel versatile Sar cage-like bifunctional chelator named AmBaSar, synthesized using a conventional synthetic strategy. Conjugation with the cyclic peptide RGD, and subsequent labelling with (64)Cu, provided a new PET probe (64)Cu-AmBaSar-RGD for imaging the alpha(nu)beta(3) integrin receptor.

Stereospecific fluorination of 1,3,5-tri-O-benzoyl-α-d-ribofuranose-2-sulfonate esters: preparation of a versatile intermediate for synthesis of 2′-[18F]-fluoro-arabinonucleosides

Abstract A detailed investigation on fluorination of 1,3,5-tri-O-benzoyl-α- d -ribofuranose-2-sulphonate esters is reported. Various combinations of sulfonate esters, fluorinating agents and solvents were evaluated in this study. Organic ammonium fluoride, in particular n-Bu4NF, was found to be better fluorinating agent than inorganic fluoride, and 1,3,5-tri-O-benzoyl-α- d -ribofuranose-2-trifluoromethylsulphonate ester appeared to be the best substrate. The developed method is suitable for stereospecific (arabino) incorporation of radiofluorine ( 18 F ) into the sugar moiety.

SYNTHESIS OF 2′-DEOXY-2′-FLUORO- 1-β-d-ARABINOFURANOSYL URACIL DERIVATIVES: A METHOD SUITABLE FOR PREPARATION OF [18F]-LABELED NUCLEOSIDES

ABSTRACT N-glycosylation of 2,4-bis-O-(trimethylsilyl)-pyrimidine bases with 2-deoxy-2-fluoro-3,5-di-O-benzoyl-1-(Br, OBz)-α-d-arabinose derivatives are reported. 1-Bromo-arabinose provides high yield and a favorable anomeric ratio (β/α) of pyrimidine nucleoside in either MeCN or CH2Cl‒CH2Cl. This method should be suitable for the synthesis of 2′-deoxy-2′-[18F]fluoro-1-β-d-arabinofuranosyluracil derivatives.

α-Alkylation of amino acid derivatives: Synthesis and chiral resolution of [11C]β-aminoisobutyric acid

Abstract A synthesis of 11 C-labeled β-aminoisobutyric acid ([ 11 C]β-AIB) and its enantiomeric resolution by high performance liquid chromatography (HPLC) are reported. β-Alanine ethyl ester 2 was converted to benzaldimine-β-alanine ethyl ester 3 in 87% yield. Treatment of the imine derivative 3 with lithium diisopropylamide (1.1 eq) in tetrahydrofuran at −78 °C, followed by addition of cold iodomethane (1.1 eq) produced the α-methylated benzaldimine-β-alanine ethyl ester 4 in 73% chemical yield. Deprotection of the amino group by acidic hydrolysis followed by basic hydrolysis of the ester group produced the desired product 1 in 37% chemical yield. Labeling was accomplished using [ 11 C]methyl iodide. The radiola-beled product was purified by HPLC using a semipreparative reversed-phase C-18 column and 2 mM phosphate buffer (pH 5.9) as the mobile phase. The synthesis time was 35–40 min including HPLC purification, with 20–60% radiochemical yield (decay corrected). Radiochemical purity was >99%, with average specific activity being 450 mCi/μmol. Enantiomers of β-AIB were well separated by analytical HPLC using a chiral column and aqueous perchloric acid as the mobile phase. (S)-β-AIB was eluted at 17.4 min and the (R)-enantiomer was eluted at 20.0 min when the jacketed column was maintained at low temperature by circulation of ice-cold water, and the pH of the mobile phase was 1.05.