Synthesis and preclinical evaluation of [11C]PAQ as a PET imaging tracer for VEGFR-2

Abstract

(R,S)-N-(4-Bromo-2-fluorophenyl)-6-methoxy-7-((1-methyl-3-piperidinyl)methoxy)-4-quinazolinamine (PAQ) is a tyrosine kinase inhibitor with high affinity for the vascular endothelial growth factor receptor 2 (VEGFR-2), which plays an important role in tumour angiogenesis. The aim of this work was to develop and evaluate in mice the ¹¹C-labelled analogue as an in vivo tracer for VEGFR-2 expression in solid tumours. [¹¹C]PAQ was synthesized by an N-methylation of desmethyl-PAQ using [¹¹C]methyl iodide. The tracer’s pharmacokinetic properties and its distribution in both subcutaneous and intraperitoneal tumour models were evaluated with positron emission tomography (PET). [¹⁸F]FDG was used as a reference tracer for tumour growth. PET results were corroborated by ex vivo and in vitro phosphor imaging and immunohistochemical analyses. In vitro assays and PET in healthy animals revealed low tracer metabolism, limited excretion over 60 min and a saturable and irreversible binding. Radiotracer uptake in subcutaneous tumour masses was low, while focal areas of high uptake (up to 8% ID/g) were observed in regions connecting the tumour to the host. Uptake was similarly high but more distributed in tumours growing within the peritoneum. The pattern of radiotracer uptake was generally different from that of the metabolic tracer [¹⁸F]FDG and correlated well with variations in VEGFR-2 expression determined ex vivo by immunohistochemical analysis. These results suggest that [¹¹C]PAQ has potential as a noninvasive PET tracer for in vivo imaging of VEGFR-2 expression in angiogenic “hot spots”.