First-in-human study using [¹¹C]MDTC and positron emission tomography for imaging the cannabinoid receptor type 2

Background: Converging evidence supports a link between immune activation and several neuropsychiatric conditions, including psychosis and Alzheimer’s disease. It remains unclear however, whether the persistent activation of microglia, the brain’s resident immune cells, is mechanistically related to the pathophysiology of these conditions and whether its presence is an early harbinger of disease. The cannabinoid receptor type 2 (CB2) receptor is expressed by microglia at a low level in the healthy human brain. Since the CB2 receptor is increased in expression during microglial activation, imaging the CB2 receptor may yield insight into the relationship between the immune response and onset of neuropsychiatric disease, with potential for also informing and monitoring immune-modulating interventions. We recently developed [¹¹C]MDTC, a new radiotracer for use with PET to image CB2, and now evaluate its pharmacokinetic properties in human brain.

Methods: Ten healthy volunteers (ages 18-52, 6 male and 4 female) without history of substance abuse (including marijuana use) completed [¹¹C]MDTC dynamic PET neuroimaging on a High Resolution Research Tomograph scanner (HRRT, Siemens Healthcare, Knoxville,TN). Ninety minutes of dynamic emission data were collected after bolus injection of [¹¹C]MDTC, with collection of arterial blood samples for generation of a metabolite-corrected arterial input function. The average injected dose of radioactivity was 632.7 ± 76.8 MBq. The PET images were reconstructed into 30 frames (four 15 s, four 30 s, three 1 min, two 2 min, five 4 min, and twelve 5 min frames) using the iterative ordinary-Poisson ordered-subset expectation-maximization algorithm (6 iteration and 16 subsets, 2 mm post-smoothing), with correction for radioactive decay, dead time, attenuation, scatter and randoms. For each participant, time-activity curves (TACs) were generated for several regions of interest that were defined from each co-registered magnetic resonance image, including global gray matter, white matter, and various cortical regions that included cerebellar cortex. Model fitting was then performed to investigate the distribution of the radiotracer in the brain.

Results: Plasma activity peaked within 60 secs after injection and decreased to < 5% of the peak by 10 mins. RP-HPLC easily isolated [¹¹C]MDTC (retention time of 7.5 mins) from its radiolabeled metabolites, which were more polar and well-resolved from the parent compound. [¹¹C]MDTC represented 17.7 ± 2.8% of total plasma activity by 30 mins and 8.0 ± 1.5% by 90 mins. [¹¹C]MDTC rapidly entered the brain, and tissue TAC peaked at 1-2 mins post-injection and then declined to less than 20% of the peak after 20 mins post-injection. The PET SUV (from 1.5-10 mins) images demonstrated a pattern of higher activity in gray matter regions compared to white matter regions. The peak SUV values were 2.26 ± 0.60 and 1.79 ± 0.47 for gray matter and white matter, respectively. The two-tissue compartment model (2TCM) predicted the regional time-activity curves better than the one-tissue compartment model. The total distribution volume values computed from 2TCM were 0.85 ± 0.24, 0.74 ± 0.10, and 0.91 ± 0.29 for global gray matter, white matter, and cerebellar cortex, respectively.

Conclusions: For all healthy subjects, [¹¹C]MDTC PET data revealed a pattern of brain uptake in vivo that reflects the density of the CB2 receptor in the healthy human brain.