Investigation of a vitamin B₁₂ conjugate as a PET imaging probe

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 (B ₁₂-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.