Pyrimidine analogs: Different roles in PET imaging

PET uses positron labeled molecules that are specifically targeted to different biochemical pathways and allows one to perform quantitative biological assays repeatedly and non-invasively. In recent years, PET has been used for the initial diagnosis, assessing disease extension, prognosis, planning and monitoring treatment and finally detecting recurrent disease in oncology. With the use of molecular biologic approaches to medicine, there is a growing need to target specific cellular pathways that would accurately mirror the developments in the clinic. The strategies can range from imaging tumor proliferation by targeting DNA synthesis to monitoring gene therapy with reporter gene imaging. I have investigated several pyrimidine analogs including FBAU 1-(2'-deoxy-2'-fluoro-1-beta-D-arabinofuranosyl)-5-bromouracil), FBAU-DB (1-(2'-deoxy-2'-fluoro-3',5'-O-dibenzoyl-beta-D-arabinofuranosyl)-5-bromouracil), FIAU (1-(2'-deoxy-2'-fluoro-beta-D-arabinofuranosyl)-5-iodouracil), and FAU-phosphoramidate as an ongoing effort to develop new imaging agents. Our preliminary data demonstrates that FBAU is resistant to metabolism and readily incorporated into DNA in proliferative tissues and tumors. These findings indicate use of FBAU as an agent to measure DNA synthesis with PET. Our studies with FBAU-DB, a lipophilic prodrug of FBAU, demonstrated a tracer that may readily cross the blood brain barrier. This may allow FBAU-DB to more readily image leaky brain tumors. FIAU, is preferentially phosphorylated by the herpes simplex TK (HSV-TK) compared to cellular TK1. FIAU shows specific accumulation in HSV-tk expressing tumors and may play a significant role in monitoring gene therapy with HSV-tk as a reporter gene. FAU, a neoplastic agent developed to treat tumors over expressing thymidylate synthase (TS), is limited in its tumor uptake due to poor phosphorylation by TK1. The proposed FAU-phosphoramidate prodrug produced superior growth inhibition rates than FAU. Our findings indicate that FAU-phosphoramidate may deliver FAU-monophosphate intracellularly and improve its antineoplastic properties. Attempts to activate FAU intracellularly using other nucleoside kinases such as deoxyribonucleoside kinase of Drosophila melanogaster (Dm-dNK) were met with limited success. In summary, all of the above mentioned pyrimidine analogs have specific properties that may allow them to be used for different imaging and therapeutic purposes.