[18F]fluoromannitol: A novel imaging agent to delineate osteomyelitis in sickle cell disease - ABSTRACT: Sickle cell disease (SCD) is the most common inherited hematological disorder, affecting millions of patients worldwide and predominantly underserved populations with strained access to healthcare. Patients with SCD are at increased risk for bacterial infection, called osteomyelitis, which requires prompt diagnosis to avoid potentially severe outcomes, such as permanent disability or even death. Osteomyelitis can be very difficult to impossible to distinguish from other SCD-prone risks, such as vaso-occlusive crisis (VOC), but the treatment plans and success of these two diseases diverge considerably. This investigation seeks to develop a clinically- translatable novel positron emission tomography (PET) imaging agent capable of specifically identifying infection in the body. We have identified a lead small molecule, [18F]fluoromannitol, which shows preliminary evidence of specific accumulation of bacteria in cultures and an animal model of musculoskeletal infection. We will commence our study by developing a streamlined radiosynthesis, which will facilitate automation of [18F]fluromannitol and ensure robust access to this tracer for our in vitro characterization of this agent in SCD osteomyelitis causative organisms (Specific Aim 1). As [18F]fluoromannitol is a new chemical entity, we will validate its ability to diagnose bacterial infection in a SCD mouse model of osteomyelitis (Specific Aim 2A). In addition, we will investigate [18F]fluoromannitol’s ability to quantify antibiotic efficacy in vivo using PET (Aim 2B, establish its sensitivity for bacteria in vivo (2C), and perform predictive dosimetry studies to support an IND application for human research (2D). Finally, with our new PET agent fully characterized for its bacterial specificity and biological activity, we will perform first-in-human studies to quantify [18F]fluoromannitol’s biodistribution in healthy volunteers (Specific Aim 3) to gather dosimetry and safety data to support future clinical research studies in SCD osteomyelitis and other cases of bacterial infection of diverse etiologies.
