Clinical MAO PET Imaging via Trapped Metabolites

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Activated monoamine oxidase-B (MAO-B) has been implicated in Alzheimer’s disease and related disorders (ADRD). In order to capitalize upon MAO-B dysfunction as a potential therapeutic target for ADRD, imaging agents for quantifying MAO-B enzymatic activity using positron emission tomography (PET) are required. Despite historical attempts at developing MAO-B imaging agents, key challenges remain for the widespread clinical application of MAO PET in ADRD. Prior research focused upon radiolabeled suicide inhibitors ([11C]L- deprenyl-D2) and reversible inhibitors ([11C]SL25.1188). However, imaging agents based on MAO-B inhibitors have limitations, as they may quantify MAO-B levels but provide no information on enzymatic activity. To address this critical gap in brain PET, the overall objective of this R21 proposal is to translate a first-in-class substrate- based imaging agent for clinical imaging of MAO-B dysfunction in ADRD. Our central hypothesis is that PET imaging with [11C]COU, an MAO-B substrate that forms a trapped metabolite, is uniquely positioned to quantify MAO-B activity with PET for the first time. The proposed research will complete preclinical experiments (pharm- tox, dosimetry, chemistry validation) and documentation (IND and IRB) necessary for clinical translation (Aim 1), conduct essential first-in-human (FIH) PET studies to establish human dosimetry, determine our kinetic modeling approach, and validate the PET signal is dependent on MAO-B activity in blocking studies (Aim 2), and carry out proof-of-concept MAO PET imaging in AD patients (Aim 3). The research is significant because [11C]COU PET could solve the problem of quantifying MAO-B activity in the brain that has been unfeasible since the earliest days of MAO PET imaging in the 1980s. Clinical translation of [11C]COU is justified by extensive preclinical results that provide groundwork for the exciting FIH studies proposed by this R21 grant. Our team at the University of Michigan has worked together for decades at the cutting edge of brain PET and has been collaborating for 8 years on preclinical proof-of-concept studies with [11C]COU. Our expertise in radiochemistry and preclinical imaging (Scott, Brooks, Kilbourn), kinetic modeling and PET image quantitation (Koeppe), as well as ADRD research and clinical nuclear medicine (Frey) uniquely positions us to accomplish the proposed research. The project goals will be realized through quantitation of MAO-B activity using PET via an innovative trapped metabolite approach. [11C]COU is CNS permeable and, once in the brain, gets oxidized by MAO-B and fragments to generate [11C]1-methyl-2,3-dihydropyridin-4(1H)-one ([11C]MDHP). Since [11C]MDHP cannot penetrate the blood-brain barrier, it is trapped in the CNS and we expect that evaluating kinetics using a standard two-tissue compartment model (with irreversible trapping of [11C]MDHP), will allow use of k3 rate constant estimates as an index of MAO activity. Overall, this project will deliver a new technique for quantitating MAO activity with PET that will improve our understanding of MAO-B function in aging as well as ADRD (and other diseases) and, ultimately, aid in utilizing MAO-B imaging for the detection and treatment of disease.