I-Radioiodinated tyrosine-folate and tyrosine-click-folate

I-Radioiodinated tyrosine-folate ([I]-) and tyrosine-click-folate ([I]-) are two folic acid conjugates synthesized by Reber et al. for imaging tumors by targeting folate receptor (FR) (1). FR is a well-established target for molecular imaging and therapy. This receptor exhibits some favorable features as a target, such as high affinity for exogenous folate conjugates ( = ~100 pM), overexpression in a variety of human cancers, mediation of folate conjugates into cells, and self-recycling (2-4). In addition, conjugation of imaging labels the γ-carboxyl group of folate has no apparent effect on its binding affinity to FR. However, FR expresses at a relatively high density on tumor cell surface (1–3 million FR/cell), and the folate-FR binding can be saturated rapidly. FR also expresses on the luminal side of proximal tubule cells in kidneys and is accessible to filtered radiofolates (5, 6). For most radiofolates, high renal accumulation (tumor/kidney ratio = ~0.1) and the resulting damage to kidneys are constant concerns in radiotherapy (1, 7). Radioiodination of tyrosine residues is a common strategy for efficient radiolabeling of proteins and peptides (1, 4). The instability of radioiodinated tyrosine constructs as a consequence of deiodination is generally regarded as a disadvantage for radiopharmaceutical applications. However, studies have shown that the tumor/kidney ratios of radioiodinated conjugates are often higher than those of conjugates labeled with other radionuclides (8). The higher tumor/kidney ratios are considered to be due to partial deiodination of the radioiodinated conjugates. Reber et al. designed two radioiodinated folic acid conjugates, [I]- and [I]-, based on the hypothesis that radioiodinated folate conjugates would exhibit favorable properties, similar to those found with other radioiodinated conjugates (1) and the partial deiodination of the radioiodinated folate conjugates might result in a quick clearance of the released iodide kidneys and thus lead to improved tumor/kidney ratios. The findings obtained by Reber et al. confirm the hypothesis and indicate that the two radiofolates are potentially valuable for imaging applications (1). The radiofolate [I]- was also tested in combination with Pemetrexed (PMX), a multitargeted antifolate drug (7), for therapeutic purposes. This chapter summarizes the data obtained with [I]- and [I]-.