Next generation PET neuroimaging for safe, accessible measurement of opioid addiction neurobiology

About This Grant

Project Summary/Abstract The “Opioid Crisis Response Act of 2018” is a key legislative effort to address the opioid epidemic in United States, recognizing opioid overdoses as one of the nation’s most pressing public health threats. Opioid related deaths have surged since 1999, with over 82,000 deaths in 2022 alone, driven primarily by synthetic opioids like fentanyl. To combat this crisis, there is an urgent need for new translational tools and strategies to better understand the neurobiology of opioid addiction. The mu opioid receptor (MOR) plays a critical role in regulating the respiratory system and neuropsychiatric functions, directly impacting the key concerns of the opioid epidemic – respiratory failure and addiction. Despite its importance in various diseases, the full scope of its role of MOR and its ligands in complex addiction mechanism in human brains remains unclear. To address this, we are developing a new translational tool to study the molecular and cellular mechanisms of receptor dysregulation that contribute to substance abuse and mental health disorders. Non-invasive, quantitative positron emission tomography (PET) imaging of MOR in the human brain will provide crucial perspective into how MOR density and occupancy are linked to its dysregulation. While a handful of conventional MOR-PET probes exist and offer valuable insights through preclinical and clinical imaging studies, they are either too potent or not sensitive enough for studying neurobiology of MOR in the living brain. This proposal focuses on the final preclinical evaluation of a safe, widely accessible PET neuroimaging probe18F-fluorocarfentanil (18F-FCFN). Our team recently developed four derivatives of 18F-FCFN and validated their in vivo suitability as PET neuroimaging probes in rats through proof-of-concept studies. Based on our prior findings, published in 2025, two 18F-FCFN candidates emerged with promising features – high brain uptake, favorable selectivity and specific binding to MOR. We now propose completing final evaluations in higher species to select the best 18F-FCFN candidates for clinical translation. In AIM 1, we will assess the in vivo pharmacokinetics, selectivity, and binding potential (BPND) of these two 18F-FCFN candidates in non-human primates (NHPs) and select the top candidate for further evaluations. In AIM 2, we will determine the whole-body biodistribution and radiation dosimetry of the selected 18F-FCFN candidate in NHPs, along with conducting acute toxicology studies to assess its safety for human use. This work is critical for selecting and advancing the top 18F-FCFN candidate to first-in-human trials.