PET Imaging of the cannabinoid receptor type 2 in humans using [11C]MDTC

Abstract

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.

Synthesis and Preclinical Evaluation of Fluorinated 5-Azaindoles as CB2 PET Radioligands

“…37 Recently, Du et al reported the first-in-human study of [ 11 C]A836339 in healthy subjects. 38,39 The radiotracer displayed promising pharmacokinetic properties, supporting further studies in conditions with hCB2 upregulation. 38,39 To date, no ideal CB2 PET-radioligand has been characterized in the clinical setting.…”

“…2-Oxoquinoline [ 11 C]­NE40 was evaluated in healthy volunteers and AD patients, however the tracer failed to show colocalized binding in the area of Aβ-plaques (Figure A) . Recently, Du et al reported the first-in-human study of [ 11 C]­A836339 in healthy subjects. , The radiotracer displayed promising pharmacokinetic properties, supporting further studies in conditions with hCB2 upregulation. , To date, no ideal CB2 PET-radioligand has been characterized in the clinical setting.…”

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 ).…”

Evaluation of cannabinoid type 2 receptor expression and pyridine-based radiotracers in brains from a mouse model of Alzheimer’s disease

“…Several CB 2 R ligands have been developed and evaluated (Ni et al, 2019b), including [ 11 C]NE40 (Vandeputte et al, 2012), [ 11 C]A-836339 (MDTC) (Pottier et al, 2017;Du et al, 2022), [ 18 F]MA3 (Attili et al, 2019), [ 18 F]FC0324 (Caillé et al, 2017), [ 18 F]JHU94620 (Moldovan et al, 2016), [ 18 F]LU13 (Gündel et al, 2022), [ 18 F]DM102 (Modemann et al, 2022), [ 18 F]CRA13 (Hassan et al, 2020), [ 11 C]RS-016 (Meletta et al, 2017), [ 11 C]RS-028 (Haider et al, 2018), [ 11 C]RSR-056 (Slavik et al, 2015), and [ 18 F]RoSMA-18-d6 (Haider et al, 2020). Thus far, only one in-human in vivo CB 2 R PET using [ 11 C]NE40 (Ahmad et al, 2016) in patients with AD and healthy controls has been reported, showing no group difference.…”