Radiolabeling and biological evaluation of novel quinazolone analogues for study of tyrosine kinases receptors

Quinazolone derivatives are used against cell prolieferation diseases such as psoriasis and cancer. As we all know that a cell may become cancerous by virtue of the transformation of a portion of its DNA into an oncogene i.e. a gene which, on activation, leads to the formation of malignant tumour cells. Several such oncogenes give rise to the production of peptides which are receptors for growth factors. The growth factor receptor complex subsequently leads to an increase in cell proliferation. It is known, for example, that certain growth factor receptors are tyrosine kinase enzymes.

Receptor tyrosine kinases are important in the transmission of biochemical signals which initiate cell replication. They are large enzymes which span the cell membrane and possess an extracellular binding domain for growth factors such as epidermal growth factor(EGF) and an intracellular portion which functions as a kinase to phosphorylate tyrosine amino acids in proteins and hence to influence cell proliferation. Various class of receptors as class1 receptor tyrosine kinases such as the EGF, TGF, NEU, HER and LET23 receptors, class2 receptors tyrosine kinases such as the insulin family of receptors such as IGFI and IRR. Class3 comprising the platelet-derived growth factor (PDGF) family of receptors and CSF are very common that are frequently present in common human cancers such as breast cancer.

Quinazolone analogues were synthesized by easily available material anthranilic acid with different acid derivatives in 4–6 steps having higher yield more then 85%. These novel compounds are labeled with Tc-99m by direct labeling method using stannous chloride as reducing agent. at optimized conditions of pH, stannous ion concentration and incubation time to achieve the maximum labeling efficiency (>96%). In vitro stability of the labeled complexes was checked and the complexes were found to be stable more than 30 h. The biodistribution study shows that novel compounds goes in all those tissues which overexpresses tyrosine kinase receptors.

The blood clearance kinetics was studied in New Zealand albino rabbits which confirms their nature as potent radiopharmaceuticals. The study signifies the potential of Quinazolone analogues as a tumor imaging agent. The approach can be further extended to other receptors such as CCK, EGFR etc.