Radioiodination of new EGFR inhibitors as potential SPECT agents for molecular imaging of breast cancer

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Abstract

In our search for the development of novel SPECT radioligands for EGFR positive tumours, new potentially irreversible tyrosine kinase (TK) inhibitors are being explored. The radioiodination of N-{4-[(3-chloro-4-fluorophenyl) amino]quinazoline-6-yl}-3-bromopropionamide, a novel EGFR-TK inhibitor synthesised in our laboratory, was accomplished via halogen exchange. Purification by RP-HPLC gave [125I]-N-{4-[(3-chloro-4-fluorophenyl)amino]quinazoline-6-yl}-3-iodopropionamide with a radiochemical purity higher than 95% and a high specific activity. In vitro studies indicate that both iodinated quinazoline and its bromo precursor inhibit A431 cell growth and also possess higher potency than the parent quinazoline to inhibit the EGFR autophosphorylation. In vivo stability studies suggest metabolization of the radioiodinated quinazoline indicating a short biological half-life. The in vitro results point out that these quinazoline derivatives could be promising candidates for SPECT imaging of EGFR positive tumours provided that they are selectively modified in order to achieve better in vivo radiochemical stability.

Graphical abstract

[125I]-N-{4-[(3-Chloro-4-fluorophenyl)amino]quinazoline-6-yl}-3-iodopropionamide ([125I]-7), a potential EGFR-TK inhibitor, was synthesised from 4-hydroxyquinazoline 1 and was in vitro evaluated for inhibitory activity of EGFR.

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Introduction

The epidermal growth factor receptor (EGFR) belongs to the ErbB family of receptor tyrosine kinases (TK) involved in the proliferation of normal and malignant cells. EGFR is often overexpressed in many tumour cells, namely in breast and prostate cancer and non-small cell lung carcinoma.1 Therefore, the EGFR has become an attractive target for the design and development of potential anticancer drugs. Several compounds that selectively bind the receptor and inhibit its tyrosine kinase activity have been reported. The most active tyrosine kinase inhibitors are quinazoline-based small molecules that compete with adenosine triphosphate (ATP) and prevent its binding to the intracellular tyrosine kinase region. Such compounds can serve for therapeutics and, when labelled, as targeted diagnostic agents. The two compounds that are at the most advanced stage of development are the 4-(phenylamino)quinazolines, Gefitinib2 and Erlotinib,3 both of which reversibly target EGFR. The Gefitinib (ZD1839, Iressa®)2 was approved by the FDA as a third-line treatment of chemotherapy-refractory non-small cell lung carcinomas. The Erlotinib (OSI-774, Tarceva©)3 is presently undergoing phase 3 clinical trials (Fig. 1).

A predictive marker that will help to select patients for treatment with EGFR inhibitors is needed to optimise the therapeutic potential of EGFR inhibition in cancer. Recently, there has been a growing interest in the use of EGFR-TK inhibitors, such as quinazoline derivatives, as radiotracers for molecular imaging. Several reversible and irreversible inhibitors, particularly from the 4-anilinoquinazoline class, were labelled with positron emitters such as fluorine-18, carbon-11 and iodine-124 and their potential as PET biomarkers was evaluated.4, 5, 6 In our search for the development of novel SPECT radioligands for early detection and staging of EGFR positive tumours, and having in mind that to date there are no promising SPECT imaging agents for targeting the EGFR, novel 125I probes based on quinazoline inhibitors of tyrosine kinase activity are being explored with the ultimate goal of labelling the molecules with 123I, the most adequate radioisotope of iodine for SPECT imaging.

In this work, we report the synthesis and characterization of the novel bioactive precursor, N-{4-[(3-chloro-4-fluorophenyl)amino]quinazoline-6-yl-3-bromopropionamide, as well as the synthesis of the corresponding iodinated and radioiodinated analogues. The in vitro biological behaviour of the halogenated quinazolines was studied. In vivo stability studies of the radioiodinated compound, [125I]-N-{4-[(3-chloro-4-fluorophenyl)amino]quinazoline-6-yl}-3-iodopropionamide, are also reported in this study.

Section snippets

Chemistry

N-{4-[(3-Chloro-4-fluorophenyl)amino]quinazoline-6-yl}-3-iodopropionamide 7 was prepared from 4-hydroxyquinazoline 1 as depicted in Scheme 1.

4-Hydroxy-6-nitroquinazoline 2, prepared by nitration of 4-hydroxyquinazoline 1, was used as the starting material for the preparation of 4-chloro-6-nitroquinazoline 3. Hence the synthesis of 3 was accomplished according to a slightly modified reported procedure by treatment of the 4-hydroxy-6-nitroquinazoline 2 with PCl5/POCl3 at 160 °C.7

Conclusions

In order to find a potential SPECT biomarker for molecular imaging of EGFR positive tumours the novel quinazoline derivative [125I]-N-{4-[(3-chloro-4-fluorophenyl)amino]quinazoline-6-yl}-3-iodopropionamide, [125I]-7, has been synthesised and characterized by comparing its chromatographic behaviour with that of its non-radioiodinated analogue 7 which has been fully characterized by multinuclear NMR spectroscopy, elemental analysis and HPLC.

The radiolabelled quinazoline [125I]-7 was obtained with

General

All commercial reagents and solvents were of analytical grade and used as supplied from Sigma–Aldrich, Merck or Lancaster. Carrier-free [125I]-NaI was obtained from Amersham Biosciences, UK.

Proton and carbon nuclear magnetic resonance spectra (1H and 13C) were performed on a Varian Unity 300 MHz spectrometer using DMSO or CD3OD as solvents. Infrared analyses were performed on a Bruker Tensor 27 spectrometer. Elemental analyses were performed on an EA-1110, CE Instruments Equipment. High

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