Purpose The purpose of this study was to assess, in a large sample of healthy young adults, sex differences in the binding potential of [ 11 C]ABP688, a positron emission tomography (PET) tracer selective for the metabotropic glutamate type 5 (mGlu5) receptor. Methods High resolution [ 11 C]ABP688 PET scans were acquired in 74 healthy volunteers (25 male, 49 female, mean age 20 ± 3.0). Mean binding potential (BP ND = f ND * (B avail / K D )) values were calculated in the prefrontal cortex, striatum, and limbic regions using the simplified reference tissue model with cerebellar grey matter as the reference region. Results [ 11 C]ABP688 BP ND was significantly higher in men compared to women in the prefrontal cortex ( p < 0.01), striatum ( p < 0.001), and hippocampus ( p < 0.05). Whole-brain BP ND was 17% higher in men. BP ND was not related to menstrual phase in women. Conclusions Binding availability of mGlu5 receptors as measured by PET [ 11 C]ABP688 is higher in healthy men than women. This likely represents a source of variability in [ 11 C]ABP688 studies and could have relevance for sex differences in cognitive-behavioral functions and neuropsychiatric disorders.

The neurobiological traits that confer risk for addictions remain poorly understood. However, dopaminergic function throughout the prefrontal cortex, limbic system, and upper brainstem has been implicated in behavioral features that influence addiction vulnerability, including poor impulse control, and altered sensitivity to rewards and punishments (i.e., externalizing features). To test these associations in humans, we measured type-2/3 dopamine receptor (DA 2/3 R) availability in youth at high vs. low risk for substance use disorders (SUDs). In this study, N = 58 youth (18.5 ± 0.6 years) were recruited from cohorts that have been followed since birth. Participants with either high (high EXT; N = 27; 16 F/11 M) or low pre-existing externalizing traits (low EXT; N = 31; 20 F/11 M) underwent a 90-min positron emission tomography [ 18 F]fallypride scan, and completed the Barratt Impulsiveness Scale (BIS-11), Substance Use Risk Profile scale (SURPS), and Sensitivity to Punishment (SP) and Sensitivity to Reward (SR) questionnaire. We found that high vs. low EXT trait participants reported elevated substance use, BIS-11, SR, and SURPS impulsivity scores, had a greater prevalence of psychiatric disorders, and exhibited higher [ 18 F]fallypride binding potential (BP ND) values in prefrontal, limbic and paralimbic regions, even when controlling for substance use. Group differences were not evident in midbrain dopamine cell body regions, but, across all participants, low midbrain BP ND values were associated with low SP scores. Together, the results suggest that altered DA 2/3 R availability in terminal extra-striatal and dopamine cell body regions might constitute biological vulnerability traits, generating an EXT trajectory for addictions with and without co-occurring alterations in punishment sensitivity (i.e., an internalizing feature).

The excitatory neurotransmitter glutamate has been implicated in experience-dependent neuroplasticity and drug-seeking behaviors. Type 5 metabotropic glutamate (mGlu5) receptors might be particularly important. They are critically involved in synaptic plasticity and their availability has been reported to be lower in people with alcohol, tobacco, and cocaine use disorders. Since these reductions could reflect effects of drug use or pre-existing traits, we used positron emission tomography to measure mGlu5 receptor availability in young adults at elevated risk for addictions. Fifty-nine participants (age 18.5 ± 0.6) were recruited from a longitudinal study that has followed them since birth. Based on externalizing traits that predict future substance use problems, half were at low risk, half were at high risk. Cannabis use histories varied markedly and participants were divided into three subgroups: zero, low, and high use. Compared to low risk volunteers, those at elevated risk had lower [11C]ABP688 binding potential (BPND) values in the striatum, amygdala, insula, and orbitofrontal cortex (OFC). Cannabis use by risk group interactions were observed in the striatum and OFC. In these regions, low [11C]ABP688 BPND values were only seen in the high risk group that used high quantities of cannabis. When these high risk, high cannabis use individuals were compared to all other participants, [11C]ABP688 BPND values were lower in the striatum, OFC, and insula. Together, these results provide evidence that mGlu5 receptor availability is low in youth at elevated risk for addictions, particularly those who frequently use cannabis.

Purpose: To determine how the low-affinity (Z)-isomer of the radiotracer [ 11 C]ABP688 affects binding potential values in vivo in humans. Methods:High resolution [ 11 C]ABP688 PET scans were acquired on 74 healthy volunteers (25 male, 49 female, mean age 20±3.0). Relative content of (E)-and (Z)-isomer were determined prior to injection using analytical high performance liquid chromatography (rt(E) = 10 minutes, rt(Z) = 8.5 minutes). Mean binding potential (BPND= fND * (Bavail / KD)) values were calculated in the striatum, limbic regions, and prefrontal cortex using the simplified reference tissue model with cerebellar grey matter as reference.Results: Mean±SD (E)-isomer content in [ 11 C]ABP688 production was 92±3.8% (range 78-97%). Percent (E)-isomer was positively correlated with BPND in the striatum (ρ=0.28, p=0.015) and limbic regions (ρ=0.25, p=0.036). In multiple regression analysis, sex (b=0.39, p=0.001) and (E)-isomer content (b=0.23, p=0.040) were significant predictors of BPND. Conclusions:Even modest levels of (Z)-[ 11 C]ABP688 can reduce estimates of tracer binding in vivo. Future studies should use production methods that enrich levels of (E)-[ 11 C]ABP688, report tracer isomer ratios, and account for this factor in their analyses.