Synthesis of a Novel γ-Folic Acid-Nτ-Histidine Conjugate Suitable for Labeling with 99mTc and 188Re

Radiolabeled folate derivatives have the potential to target folate receptor-positive tumor cells for noninvasive diagnosis and therapy. We report the synthesis of a novel gamma-folic acid-N-tau-histidine conjugate 1 wherein the N-tau-histidine is suitable for radiolabeling with isotopes Tc-99m (diagnosis) and Re-188 (therapy). A modular synthetic strategy was applied: N-alpha-Boc-alpha-carboxy-protected glutamic acid was amidically linked to N-tau-functionalized amino-alkyl)histidine via the gamma-carboxy group to form building block 8. Intermediate 8 was coupled to protected pteroic acid to give I in two steps in 47% yield. N-tau-(Functionalized aminoalkyl)histidine was synthesized by two different routes. The preferred route starting from Boc-His-OMe led in two steps to the N-tau-(functionalized aminoalkyl)histidine in 36% yield.