First-in-human use of 11C-CPPC with positron emission tomography for imaging the macrophage colony-stimulating factor 1 receptor Academic Article uri icon

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abstract

  • Abstract Purpose Study of the contribution of microglia to onset and course of several neuropsychiatric conditions is challenged by the fact that these resident immune cells often take on different phenotypes and functions outside the living brain. Imaging microglia with radiotracers developed for use with positron emission tomography (PET) allows researchers to study these cells in their native tissue microenvironment. However, many relevant microglial imaging targets such as the 18 kDa translocator protein are also expressed on non-microglial cells, which can complicate the interpretation of PET findings. 11C-CPPC was developed to image the macrophage colony-stimulating factor 1 receptor, a target that is expressed largely by microglia relative to other cell types in the brain. Our prior work with 11C-CPPC demonstrated its high, specific uptake in brains of rodents and nonhuman primates with neuroinflammation, which supports the current first-in-human evaluation of its pharmacokinetic behavior in the brains of healthy individuals. Methods Eight healthy nonsmoker adults completed a 90-min dynamic PET scan that began with bolus injection of 11C-CPPC. Arterial blood sampling was collected in order to generate a metabolite-corrected arterial input function. Tissue time-activity curves (TACs) were generated using regions of interest identified from co-registered magnetic resonance imaging data. One- and two-tissue compartmental models (1TCM and 2TCM) as well as Logan graphical analysis were compared. Results Cortical and subcortical tissue TACs peaked by 37.5 min post-injection of 11C-CPPC and then declined. The 1TCM was preferred. Total distribution volume (VT) values computed from 1TCM aligned well with those from Logan graphical analysis (t* = 30), with VT values relatively high in thalamus, striatum, and most cortical regions, and with relatively lower VT in hippocampus, total white matter, and cerebellar cortex. Conclusion Our results extend support for the use of 11C-CPPC with PET to study microglia in the human brain.

authors

  • Coughlin, Jennifer M
  • Du, Yong
  • Lesniak, Wojciech G
  • Harrington, Courtney K
  • Brosnan, Mary Katherine
  • O’Toole, Riley
  • Zandi, Adeline
  • Sweeney, Shannon Eileen
  • Abdallah, Rehab
  • Wu, Yunkou
  • Holt, Daniel P
  • Hall, Andrew W
  • Dannals, Robert F
  • Solnes, Lilja
  • Horti, Andrew G
  • Pomper, Martin G

publication date

  • September 30, 2022