Yasuyuki Kimura

Microglia, the immune cells in the brain, play a significant role in the pathophysiology of neurodegenerative diseases. To visualize these cells in the living brain, we developed a PET ligand, [11C]NCGG401 (4-{2-[((1R,2R)-2-hydroxycyclohexyl)(methyl)amino]benzothiazol-6-yloxy}-N-methylpicolinamide, NCGG401), that targets colony-stimulating factor 1 receptor (CSF1R). In this study, we present the first-in-human evaluation of [11C]NCGG401 to assess its safety profile and then to evaluate its kinetics to quantify CSF1R in the human brain. Methods: Head to upper thigh PET scans were conducted in 3 healthy men to estimate the effective dose of [11C]NCGG401. Brain PET scans were performed on 6 healthy men, combined with arterial blood sampling and metabolite analyses. Compartmental and graphical models were used to quantify CSF1R in the human brain. [11C]NCGG401 PET data were indirectly compared with regional CSF1R protein levels after death that were reported in a proteomics study. In addition, the results of this study were directly compared with the PET imaging of 18-kDa translocator protein using [11C]DPA-713 (N,N-diethyl-2-[2-(4-methoxyphenyl)-5,7-dimethylpyrazolo[1,5-a]pyrimidin-3-yl]acetamide, DPA-713). Results: The administration of [11C]NCGG401 did not result in severe adverse events. The effective doses per injected activity were 5.1 ± 0.2 µSv/MBq for men and 6.1 ± 0.3 µSv/MBq for women. [11C]NCGG401 demonstrated good brain permeability, with peak uptake reaching an SUV of 3. Regional total distribution volumes were reliably quantified using the 2-tissue compartment model and a Logan plot with 60 min of scan data. The resulting parametric images reflected the known distribution of CSF1R in the brain. Furthermore, regional total distribution volume values of [11C]NCGG401 showed good correlation with regional CSF1R protein levels. The [11C]NCGG401 images showed regional distributions different from those of [11C]DPA-713. Conclusion: [11C]NCGG401 images appear to reflect regional microglia-specific distributions of CSF1R in the brain, consistent with the findings of a CSF1R proteomics study by others. However, ultimate confirmation of specific CSF1R binding should be validated by evaluating, in suitable preclinical or human experiments, pharmacologic blockade of its binding in the brain in vivo.