RESUMO
Induction of apoptosis is often necessary for successful cancer therapy, and the non-invasive monitoring of apoptosis post-therapy could assist in clinical decision making. Isatins are a class of compounds that target activated caspase-3 during apoptosis. Here we report the synthesis of the 5-iodo-1,2,3-triazole (FITI) analog of the PET tracer [18F]ICMT11 as a candidate tracer for imaging of apoptosis with SPECT, as well as PET. Labelling with radioiodine (123,125I) was achieved in 55 ± 12% radiochemical yield through a chelator-accelerated one-pot cycloaddition reaction mediated by copper(I) catalysis. The caspase-3 binding affinity and selectivity of FITI compares favourably to that of [18F]ICMT11 (Ki = 6.1 ± 0.9 nM and 12.4 ± 4.7 nM, respectively). In biodistribution studies, etoposide-induced cell death in a SW1222 xenograft model resulted in a 2-fold increase in tumour uptake of the tracer. However, the tumour uptake was too low to allow in vivo imaging of apoptosis with SPECT.
Assuntos
Apoptose/efeitos dos fármacos , Caspase 3/isolamento & purificação , Radioisótopos do Iodo/farmacologia , Neoplasias/diagnóstico por imagem , Animais , Apoptose/genética , Caspase 3/química , Caspase 3/genética , Linhagem Celular Tumoral , Cobre/química , Radioisótopos de Flúor/química , Radioisótopos de Flúor/farmacologia , Xenoenxertos , Humanos , Radioisótopos do Iodo/química , Isatina/síntese química , Isatina/farmacologia , Camundongos , Neoplasias/patologia , Neoplasias/terapia , Compostos Radiofarmacêuticos/síntese química , Compostos Radiofarmacêuticos/farmacologia , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Triazóis/síntese química , Triazóis/farmacologiaRESUMO
Herein, we report a novel intramolecular ring-closing reaction of biaryl thioethers that give access to highly functionalized dibenzothiophene sulfonium salts under mild conditions. The resulting precursors react regioselectively with [18F]fluoride to give [18F]fluoroarenes in predictable radiochemical yields. The strategy expands the available radiochemical space and provides superior labeling efficiency for clinically relevant PET tracers.
RESUMO
We report a concise approach to a multimodal imaging reagent for peptide labelling via disulfide bridging. The reagent is constructed using a one pot, three component, [3 + 2] cycloaddition of a fluorescent azide with a dithiomaleimide-alkyne, with concomitant incorporation of (125)I. The dithiomaleimide handle then enables site selective conjugation to a disulfide bond of a peptide whilst retaining the key structural bridging functionality, as exemplified on the therapeutic peptide octreotide.
