Preclinical development of small-molecular-weight folate-based radioconjugates: a pharmacological perspective.

The folate receptor (FR) has attracted attention as a target structure because of its frequent expression in cancer cells (FR-α) and activated macrophages (FR-β). The vitamin folic acid has served as a promising targeting ligand allowing selective delivery of attached radionuclides suitable for imaging of the diseased sites and for therapeutic application. A large number of folate radioconjugates with variable chemical structures have been developed over the last 25 years. Accumulation of radioactivity in healthy organs and tissues was always seen in the kidneys due to the expression of the FR in the proximal tubule cells. In some cases unspecific uptake of radiofolates was also seen in the liver and the intestinal tract. To address this situation and improve the target-to-off-target ratios of accumulated radioactivity several strategies were undertaken, including chemical modifications of the folate conjugates, selection of appropriate radionuclides and application of drug combinations. Depending on the radionuclide which was employed various chelators and linker entities were investigated and additional functionalities with albumin-binding properties were tested with the aim to increase the serum half-life of the radioconjugates. A number of diagnostic radionuclides ((99m)Tc, (111)In, (67)Ga, (155)Tb, (125)I) emitting γ-radiation were employed for single photon emission computed tomography (SPECT) and, β(+)-emitting radionuclides ((68)Ga, 44Sc, (152)Tb, (18)F) were used for positron emission tomography (PET). Moreover, therapeutic radionuclides emitting β(-)-particles ((177)Lu, (161)Tb, (47)Sc, (131)I) and α-particles ((149)Tb) were also used with folate conjugates. The present review focuses on the development of radiofolates and their in vivo properties and on strategies which were employed to modify their pharmacokinetic and pharmacodynamic properties.