Investigation of a Vitamin B12 Conjugate as a PET Imaging Probe

• Published in: ChemMedChem 2014-06, Vol.9 (6), p.1244-1251
• Main Authors: Ikotun, Oluwatayo F., Marquez, Bernadette V., Fazen, Christopher H., Kahkoska, Anna R., Doyle, Robert P., Lapi, Suzanne E.
• Format: Article
• Language: English
• Subjects: Animals; CD320; Cell Line, Tumor; cobalamin; Coordination Complexes - chemistry; Coordination Complexes - pharmacokinetics; Copper Radioisotopes - chemistry; HCT116 Cells; Heterocyclic Compounds - chemistry; Humans; Melanoma, Experimental - diagnosis; Melanoma, Experimental - diagnostic imaging; Mice; Mice, Nude; Positron-Emission Tomography; radiochemistry; Radiopharmaceuticals - chemistry; Radiopharmaceuticals - pharmacokinetics; Tissue Distribution; Tomography, X-Ray Computed; Transplantation, Heterologous; Transplantation, Homologous; Vitamin B 12 - chemistry; vitamins
• ISSN: 1860-7179; 1860-7187
• DOI: 10.1002/cmdc.201400048

Nutrient demand is a fundamental characteristic of rapidly proliferating cells. Vitamin B12 is vital for cell proliferation; thus neoplastic cells have an increased demand for this essential nutrient. In this study we exploited the vitamin B12 uptake pathway to probe the nutritional demand of proliferating cells with a radiolabeled B12 derivative in various preclinical tumor models. We describe the synthesis and biological evaluations of copper‐64‐labeled B12–ethylenediamine–benzyl‐1,4,7‐triazacyclononane‐N,N′,N′′‐triacetic acid (B12‐en‐Bn‐NOTA‐64Cu), the first example of a B12 derivative for positron emission tomography (PET) imaging. Small‐animal imaging and pharmacological evaluation show high tumor uptake ranging from 2.20 to 4.84 % ID g−1 at 6 h post‐administration. Competition studies with excess native B12 resulted in a 95 % decrease in tumor accumulation, indicating the specificity of this radiopharmaceutical for B12 endocytotic transport proteins. These results show that a vitamin B12 PET radiopharmaceutical has potential utility for non‐invasive imaging of enhanced nutrient demand in proliferating cells. Co‐opting cobalamin: Vitamin B12 is an essential nutrient for all proliferating cells. Rapid proliferation is a common hallmark of cancer; consequently, neoplastic cells have an increased demand for vitamin B12. We exploited the vitamin B12 uptake pathway to non‐invasively probe the nutrient demand of cancer cells. The synthesis, characterization, and tumor‐homing properties of a vitamin B12 PET radiotracer are described.