New radiolabeled derivatives of vitamin B12 with abolished transcobalamin II binding reveal selective targeting of tumors

237 Objectives: The cellular supply of vitamin B12 (Cbl) via transport vectors (e.g. Transcobalamin-II, TC-II) and cell membrane receptors (e.g. Megalin) is attractive for the delivery of radionuclides into hyperfroliferative tumor cells because of their increased demand on vitamins. Radiolabeled Cbl-derivatives (Co-57, Tc-99m, In-111) have been reported in the literature. The results showed good tumor uptake. However, high and specific accumulation of the radiotracers was observed in normal tissues and organs (kidneys, liver) because of TC-II binding and cellular absorption of the TC-II-Cbl complexes via Megalin and other receptors in these organs. The aim of our work was the development of novel radiolabeled Cbl derivatives featuring a vector-less uptake into cancer cells (abolished TC-II binding) for diagnosis and therapy. Methods: Two, new Cbl derivatives carrying a tridentate metal chelating moiety and different spacers (butyl 1 and hexyl 2) at b-position of the corrin ring were synthesized. The compounds were radiolabeled with 99mTc-tricarbonyl. Biodistribution studies were performed in xenografted mice. SPECT/CT studies were performed with a small animal scanner. Results: Derivatives 1 and 2 accumulated specifically in syngeneic melanoma tumors (1: 9.03 ± 2.78 % ID/g; 2: 7.29 ± 3.89 % ID/g, 24 h p.i.). However, the TC-II binder 2 (determined in vitro), showed high uptake and retention in blood, kidney and liver (tu/bl: 3; tu/ki: 0.5; tu/li: 1.5) as expected. On the other hand, compound 1 with abolished TC-II binding capacity displayed significantly improved ratios (tu/bl: 153; tu/ki: 3; tu/li: 6). SPECT/CT studies confirmed these findings. Melanoma, bladder, pancreas, small cell lung and renal carcinoma showed tumor uptake, whereas colon and prostate carcinoma were negative. Conclusions: By abolishing TC-II binding the undesired uptake of Cbl-derivatives in normal organs and tissues can be essentially suppressed whereas high tumor uptake is retained. This potentially allows a therapeutic indication of radiolabeled Cbl-derivatives. A diagnostic, clinical study with derivative 1 is initiated.