The funders had no role in the design and conduct of the study; collection, management, analysis or interpretation of data; decision to submit, preparation, review, or approval of the manuscript for publication.

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.

Pretomanid is a nitroimidazole antimicrobial active against drug-resistant Mycobacterium tuberculosis and approved in combination with bedaquiline and linezolid (BPaL) to treat multidrug-resistant (MDR) pulmonary tuberculosis (TB). However, the penetration of these antibiotics into the central nervous system (CNS), and the efficacy of the BPaL regimen for TB meningitis, are not well established. Importantly, there is a lack of efficacious treatments for TB meningitis due to MDR strains, resulting in high mortality. We have developed new methods to synthesize 18F-pretomanid (chemically identical to the antibiotic) and performed cross-species positron emission tomography (PET) imaging to noninvasively measure pretomanid concentration-time profiles. Dynamic PET in mouse and rabbit models of TB meningitis demonstrates excellent CNS penetration of pretomanid but cerebrospinal fluid (CSF) levels does not correlate with those in the brain parenchyma. The bactericidal activity of the BPaL regimen in the mouse model of TB meningitis is substantially inferior to the standard TB regimen, likely due to restricted penetration of bedaquiline and linezolid into the brain parenchyma. Finally, first-in-human dynamic 18F-pretomanid PET in six healthy volunteers demonstrates excellent CNS penetration of pretomanid, with significantly higher levels in the brain parenchyma than in CSF. These data have important implications for developing new antibiotic treatments for TB meningitis.

Purpose: We report findings from the first-in-human study of [ 11 C]MDTC, a radiotracer developed to image the cannabinoid receptor type 2 (CB2R) with positron emission tomography (PET). Methods: Ten healthy adults were imaged according to a 90 min dynamic PET protocol after bolus intravenous injection of [ 11 C]MDTC. Five participants also completed a second [ 11 C]MDTC PET scan to assess test-retest reproducibility of receptor-binding outcomes. The kinetic behavior of [ 11 C]MDTC in human brain was evaluated using a metabolite-corrected arterial plasma input function with compartmental modeling and graphical analysis approaches. Four additional healthy adults completed whole-body [ 11 C]MDTC PET/CT to calculate organ doses and the whole-body effective dose. Results: [ 11 C]MDTC brain PET and [ 11 C]MDTC whole body PET/CT was well-tolerated. The model of choice for fitting the time activity curves (TACs) across brain regions of interest was a two-tissue compartment model with the blood volume fraction included as a fitting parameter (2TCM-vB). Regional distribution volume (V T ) values computed from Logan graphical analysis correlated well with those estimated using the 2TCM-vB model. Cortical regions and thalamus had higher V T than brainstem, striatum, hippocampus, and corpus callosum. Test-retest reliability of V T demonstrated a mean absolute variability of 7.13%, with an intraclass correlation coefficient 0.91. The measured effective dose of [ 11 C]MDTC was 5.29 µSv/MBq. Conclusion: These data support use of [ 11 C]MDTC PET for in vivo neuroimaging of CB2R in humans. Future in vivo studies using [ 11 C]MDTC PET in neuroinflammatory conditions are needed to assess the detection of high expression of the CB2R by activated microglia in human brain.