ci-1033 br Current limitations and future directions
Current limitations and future directions There are several limitations associated with PET imaging of aromatase using carbon-11 labeled aromatase inhibitors. Due to the very short half-life of carbon 11 (20min), PET studies with currently available, validated tracers can only be performed in medical or research centers in possession of a cyclotron, which represent only a small percentage of hospitals, most of which do possess PET scanners. This problem can only be overcome by the development and validation of aromatase tracers labeled with a longer-lived isotope such as Fluorine-18 (Erlandsson et al., 2008). A Fluorine-18 labeled aromatase tracer may also address the difficulty encountered in quantification of aromatase content in the majority of peripheral organs, which express aromatase at relatively low levels. [11C]vorozole binding to aromatase in vivo is slow, such that good signal-to-noise ratios are only obtained 50–90min after administration, at which point the absolute counts are quite low and low uptake tissues are hard to visualize. However, the low uptake in the majority of peripheral organs (all besides the liver) may actually be an advantage if the tracers are used to detect primary tumors overexpressing aromatase or their metastases in breast, lung, bone and most of the brain. It is also important to remember that PET with aromatase inhibitors is useful in detecting changes in aromatase availability but not in enzyme activity. While it is true that no estrogen is produced in the absence of aromatase, changes in enzyme activity can result in increases or decreases in tissue estrogen levels with no change in aromatase expression. In fact, such changes have been shown to occur relatively quickly and appear to account for at least some behaviors related to estrogen in the ci-1033 of animals (Cornil et al., 2013, Dickens et al., 2014). To gain a complete picture of normal and abnormal changes in regional estrogen synthesis capacity, it would be advantageous to develop radiotracers which are substrates rather than non-competitive inhibitors of the enzyme. The development of the synthetic L-DOPA decarboxylase substrate 6-[18F]-fluoro-3,4-dihydroxyphenyl-l-alanine ([18F]-DOPA) was an early success in this regard (Garnett et al., 1983, also see Holland et al., 2013 for a recent review). The ability to measure aromatase content non-invasively throughout the human body and in distinct brain regions offers an unprecedented opportunity to determine the involvement of this enzyme in multiple physiological and pathological conditions; since aromatase, along with specific estrogen receptors, has been implicated in cellular proliferation, reproduction, sexual differentiation, sexual behavior, aggression, cognition, memory and neuroprotection in various animal species (McEwen et al., 1977, Sierra et al., 2003, Trainor et al., 2006, Garcia-Segura, 2008; Roselli et al., 2009). In humans, postmortem studies have also shown that aromatase expression in the brain and aromatase genotype are linked to Alzheimer’s disease (Ishunina et al., 2005; Iivonen et al., 2004; Huang and Poduslo, 2006, Hiltunen et al., 2006) and autism (Sarachana et al., 2011, Sarachana and Hu, 2013). In addition, increases in aromatase expression are implicated in a wide range of peripheral human diseases, most prominently in breast cancer (Bulun and Simpson, 2008), but also other pathologies including endometriosis (Fedele et al., 2008) brain, lung and hepatic cancer (Wozniak et al., 1998, Márquez-Garbán et al., 2009, Miceli et al., 2009) and unexplained female infertility (Mitwally and Casper, 2003). Future studies with [11C]vorozole PET in these and additional disorders have the potential of identifying aromatase as a treatment target in disorders which are not currently treated with aromatase inhibitors, to improve early detection of aromatase-overexpressing tumors and help identify patients more likely to respond to AI therapy, while preventing unnecessary exposure to the adverse effects of AI (osteroporosis, hot flushes, musculoskeletal disorders, fatigue and mood disturbances among others, e.g. Mouridsen, 2006). Resistance to endocrine treatment is another clinical area where [11C]vorozole PET may have a significant impact. Although the mechanisms underlying resistance are not fully understood (Chumsri et al., 2014), treatment-related increases in aromatase expression (Catalano et al., 2014) is a likely mechanism which can be detected with aromatase imaging. [11C]vorozole PET will also provide a tool for early determination of target engagement, pharmacokinetics and pharmacodynamics of new AI drugs in development (Hietala, 1999, Waarde, 2000).