Synthesis and [18F] fluorine-radiolabelling of peptides for positron emission tomography imaging of cancer
Document TypePhD thesis
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© 2014 Dr. Mohammad Baqir Haskali
Positron Emission Tomography (PET) is a molecular imaging technique, requiring biologically active molecules that are radiolabelled with positron emitting radionuclides. [18F]Fluorine is considered an ideal radionuclide utilised for PET imaging. When high affinity peptides are labelled with [18F]fluorine, they form an excellent targeting molecule that can be utilised to characterise tumours using PET imaging. This project investigated an improved radiosynthesis route for the production of 4-nitrophenyl 2-[18F]fluoropropionate ([18F]NFP), a peptide [18F]fluorination synthon. [18F]NFP was produced in a single radiochemical step and the synthesis was fully automated on both TRACERLab FXFN and iPHASE FlexLab radiosynthesis modules. The automated radiosynthesis of [18F]NFP was accomplished in 45 min and in 29% decay corrected yield. The improved synthesis route of [18F]NFP, allowed the synthesis of the gold standard tracer for αvβ3 PET imaging [18F]FP-GalactoRGD in 7% n.d.c. yield and in less than half of the reported synthesis time.1 Furthermore, [18F]FPPRGD2 was prepared in 4% n.d.c. yield from free fluoride within 94–105 min . [18F]FP-GalactoRGD and [18F]FPPRGD2 were compared in-vivo under similar conditions. [18F]FPPRGD2 exhibited improved biological character in our model for αvβ3 expression. Moreover, novel RGD peptides were synthesised for the targeting of metastatic tumours. The biological properties of the novel RGD ligands were modified by site specific sulfonation of tyrosine. Sulfonation of tyrosine was accomplished utilising readily available chlorosulfonic acid and trifluoroacetic acid. The corresponding sulfonated peptides were generated in good chemical yields (60%). Sulfonated peptides were subsequently labelled with [18F]NFP and their biological properties were investigated. This methodology was employed to prepare [18F]FP-c(RGDy(SO3)K) and [18F]FP-E-c(RGDy(SO3)K)2. [18F]FP-c(RGDy(SO3)K) exhibited comprable biological properties to [18F]FP-GalactoRGD. However, [18F]FP-E-c(RGDy(SO3)K)2 demonstrated improved biological properties over all other peptides examined for the imaging of αvβ3 Integrins in our models. The project also exploited the radiolabelling of biomolecules targetting apoptotic cells. Annexin V was labelled by [18F]SFB, to generate the [18F]FB-Annexin V, an imaging agent for in-vivo apoptosis measurement. Furthermore, duramycin (an apoptosis targeting peptide) was initially labelled with [18F]SFB to generate [18F]FB-duramycin in 16% n.d.c. yield from [18F]SFB within 150–175 min. [18F]FB-duramycin exhibited high liver accumulation presumably as a result of its hydrophobic nature. The hydrophilicity of duramycin was modified by mono-glycosylation and latter labelling with [18F]NFP to form [18F]FP-galacto-duramycin in 45% n.d.c. from [18F]NFP within 90–100 min. [18F]FP-galacto-duramycin presented improved biological properties over [18F]FB-duramycin as demonstrated by small animal imaging. The biological properties of duramycin were further enhanced by di-glycosylation. The [18F]fluorinated di-glycosylated peptide, [18F]FP-digalacto-duramycin was prepared in 13% n.d.c. from [18F]NFP within 90–100 min. [18F]FP-digalacto-duramycin demonstrated further improvements in-vivo. [18F]FP-digalacto-duramycin also exhibited much lower LogD value as oppose to [18F]FB-duramycin.
Keywordsradiochemistry; PET imaging; radiolabelling; 18-fluorine; peptides
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