title: Mechanistic and quantitative insight into cell surface targeted molecular imaging agent design.
abstract: Molecular imaging agent design involves simultaneously optimizing multiple probe properties. While several desired characteristics are straightforward, including high affinity and low non-specific background signal, in practice there are quantitative trade-offs between these properties. These include plasma clearance, where fast clearance lowers background signal but can reduce target uptake, and binding, where high affinity compounds sometimes suffer from lower stability or increased non-specific interactions. Further complicating probe development, many of the optimal parameters vary depending on both target tissue and imaging agent properties, making empirical approaches or previous experience difficult to translate. Here, we focus on low molecular weight compounds targeting extracellular receptors, which have some of the highest contrast values for imaging agents. We use a mechanistic approach to provide a quantitative framework for weighing trade-offs between molecules. Our results show that specific target uptake is well-described by quantitative simulations for a variety of targeting agents, whereas non-specific background signal is more difficult to predict. Two in vitro experimental methods for estimating background signal in vivo are compared - non-specific cellular uptake and plasma protein binding. Together, these data provide a quantitative method to guide probe design and focus animal work for more cost-effective and time-efficient development of molecular imaging agents.
authors.affiliation: Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, US.
authors.forename: Liang
authors.initials: L
authors.lastname: Zhang
authors.affiliation: Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, US.
authors.forename: Sumit
authors.initials: S
authors.lastname: Bhatnagar
authors.affiliation: Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, US.
authors.forename: Emily
authors.initials: E
authors.lastname: Deschenes
authors.affiliation: Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109, US.|Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI 48109, US.
authors.forename: Greg M
authors.initials: GM
authors.lastname: Thurber
mesh_terms: D000818:Animals; D002460:Cell Line; D003198:Computer Simulation; D015195:Drug Design; D006801:Humans; D051379:Mice; D008954:Models, Biological; D057054:Molecular Imaging / Q000379:methods*; D015335:Molecular Probes / Q000097:blood / Q000493:pharmacokinetics*; D011956:Receptors, Cell Surface / Q000378:metabolism*
chemical_list: D015335:Molecular Probes; D011956:Receptors, Cell Surface