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

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.

Discovery of a High-Affinity Fluoromethyl Analog of [11C]5-Cyano-N-(4-(4-methylpiperazin-1-yl)-2-(piperidin-1-yl)phenyl)furan-2-carboxamide ([11C]CPPC) and Their Comparison in Mouse and Monkey as Colony-Stimulating Factor 1 Receptor Positron Emission Tomography Radioligands

“…5 Hz),54.63,51.95,47.11,46.09,36.65 (d,J = 18.7 Hz),27.88 (d,J = 6.2 Hz). 19 aniline (6a). 10% Pd/C (1.3 g, 1.24 mmol) was added to a mixture of 5a (3.9 g, 12.44 mmol) in MeOH (6 mL) under nitrogen.…”

“…Furthermore, the binding of [ 3 H] CPPC to post-mortem human brain was partially blocked by the known CSF1R inhibitors, PLX3397 , PLX5622 , and BLZ945 (<25%) . Results from a recent study of [ 11 C] CPPC in healthy human subjects extended support for the use of [ 11 C] CPPC to study microglia in the human brain …”

“…12 Results from a recent study of [ 11 C]CPPC in healthy human subjects extended support for the use of [ 11 C]CPPC to study microglia in the human brain. 19 V T values were somewhat higher in thalamus, striatum, and non-cerebellar cortical regions than in hippocampus, cerebellar cortex, and total white matter. Nonetheless, direct evidence for the specific binding of [ 11 C]CPPC to human brain CSF1R in vivo has not been demonstrated through rigorous pharmacological challenge experiments, there being no CSF1R inhibitors available for safe use in humans.…”

Recent Developments in Carbon-11 Chemistry and Applications for First-In-Human PET Studies

“…As discussed in this review, innovations continue in 11 C-radiolabelling strategies for applications in 11 C-tracer development. Within the past five years, to our knowledge at least 27 novel 11 C-labelled PET tracers have been translated for FIH PET studies (see Figure 1 ) [ 86 , 87 , 88 , 89 , 90 , 91 , 92 , 93 , 94 , 95 , 96 , 97 , 98 , 99 , 100 , 101 , 102 , 103 , 104 , 105 , 106 , 107 , 108 , 109 ]. Unsurprisingly, the vast majority of these PET tracers were designed to image targets within the CNS (see Table 1 ).…”

PET Imaging of Fructose Metabolism in a Rodent Model of Neuroinflammation with 6-[18F]fluoro-6-deoxy-D-fructose

“…Macrophage colony stimulating factor-1 receptor (CSF-1R) is one such target, which is predominantly found on microglia in the brain, with low-level expression occurring in neurons [ 15 , 16 ]. Several efforts to develop potent and selective CSF-1R targeted PET radiotracers for neuroimaging in preclinical and human studies are underway [ 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 ]. Two other targets of particular interest for PET imaging microglia are the purinergic receptors P2X 7 and P2Y 12 because they are found on M1 and M2 microglial phenotypes, respectively [ 26 ].…”