TY - JOUR T1 - Utilization of <sup>18</sup>F-Fluorodeoxyglucose–Positron Emission Tomography To Understand the Mechanism of Nicotinamide Phosphoribosyltransferase Inhibitors In Vivo JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther SP - 583 LP - 589 DO - 10.1124/jpet.119.259135 VL - 371 IS - 3 AU - Sarah R. Mudd AU - Martin J. Voorbach AU - Dong Cheng AU - Min Cheng AU - Jun Guo AU - Wenqing Gao AU - Fritz G. Buchanan AU - Chris Tse AU - Julie Wilsbacher Y1 - 2019/12/01 UR - http://jpet.aspetjournals.org/content/371/3/583.abstract N2 - Cancer cells are highly dependent on NAD+/NADH produced via the nicotinamide salvage pathway. The rate-limiting enzyme in this pathway is the nicotinamide phosphoribosyltransferase (NAMPT), which we have targeted with novel NAMPT inhibitors. NAMPT inhibition elicits depletion of total cellular NAD+ levels and ultimately cytotoxicity via depletion of cellular ATP levels. 18F-fluorodeoxyglucose– positron emission tomography (FDG-PET) is a translational imaging tool to assess glucose utilization in tumors and normal tissue. We used FDG-PET to understand the timing of ATP depletion in vivo and better understand the pharmacology of NAMPT inhibitors. Because of the intimate relationship between cellular ATP levels and cell viability, we developed an in-depth understanding of our NAMPT inhibitor pharmacology and the relationship with changes in tumor FDG uptake. Taken together, we show that FDG-PET could be used as a biomarker in clinical studies to understand dose and provide proof of mechanism for NAMPT inhibitors.SIGNIFICANCE STATEMENT Our imaging data suggest that tumor 18F-fluorodeoxyglucose uptake can provide insight into the ATP status inside the tumor after nicotinamide phosphoribosyltransferase (NAMPT) therapy, with a novel NAMPT inhibitor. Such an approach could be used clinically as a pharmacodynamic biomarker to help understand the implications of dose, schedule, rescue strategy, or other clinical biomarkers. ER -