Christin Y. Sander

The dopamine D ₂ -receptor antagonist prochlorperazine is approved clinically as both an antipsychotic and an antiemetic. Classical antipsychotics like prochlorperazine have been shown to treat the positive symptoms of schizophrenia at occupancies higher than 60% with extrapyramidal symptoms occurring at occupancies over 80%. As an antiemetic, this drug is known to carry a high risk of akathisia and some risk for more severe extrapyramidal symptoms, but the relationship between dosage and D ₂ receptor occupancies has not been reported. The functional consequences of D ₂ receptor binding at different occupancy levels also remain unexplored in human subjects. In this study, we performed simultaneous PET and MRI to measure receptor occupancy by competition with [ ¹¹ C]raclopride and to assess the concurrent functional hemodynamic response versus prochlorperazine dosage. Additional studies in non-human primates (NHP) were performed for comparison and dose flexibility. In human subjects, the effective dose to achieve 50% occupancy was 1.2 mg/100-kg, indicating that a clinical dose of 10 mg will achieve occupancies greater than 80% in virtually all subjects. In both human subjects and NHP, functional MRI responses showed a rapidly escalating response at occupancies larger than about 60%, a response consistent with autoreceptor-mediated dopamine release. These results provide a functional correlate for the lower edge of the antipsychotic therapeutic occupancy window and confirm that D ₂ receptor antagonism is ineffective at attenuating post-synaptic function at low occupancies.

Background/Objectives: Quantitative PET imaging of μ-opioid receptor (MOR) availability and pharmacologic engagement can advance in vivo studies of opioid receptor biology. We previously evaluated a series of ¹⁸F-labeled carfentanil analogs and prioritized the regioisomer [¹⁸F]fluorocarfentanil ([¹⁸F]FCFN) based on favorable brain kinetics, regional distribution, and naloxone-sensitive binding. Here, we provide proof-of-concept evaluation of [¹⁸F]FCFN in rhesus macaques to assess its potential for quantitative, pharmacologically responsive MOR PET. Methods: [¹⁸F]FCFN was produced by automated radiosynthesis. Dynamic [¹⁸F]FCFN PET scans were performed in two rhesus macaques under baseline conditions, after low- (0.005 mg/kg) and high-dose (0.2 mg/kg) naloxone pretreatment, and during within-scan intravenous or intranasal naloxone challenge. For arterial input scans, two-tissue compartment modeling with metabolite-corrected arterial input functions was used to estimate total distribution volume (V_T). Nondisplaceable binding potential (BP_ND) was estimated using multilinear reference tissue model 2 with the cerebellum as the candidate reference region. Results: Automated radiosynthesis produced [¹⁸F]FCFN in high radiochemical yield and molar activity, enabling low-mass PET injections (0.09–0.32 μg). [¹⁸F]FCFN showed rapid brain uptake and MOR-consistent regional distribution, with lowest uptake in the cerebellum. Regional BP_ND correlated positively with V_T at baseline (R² = 0.983, p < 0.0001) and after high-dose blockade (R² = 0.522, p < 0.004). Naloxone pretreatment reduced regional BP_ND in a dose-dependent manner. Within-scan intravenous and intranasal naloxone challenges also produced marked reductions in BP_ND. Conclusions: [¹⁸F]FCFN enables quantitative, pharmacologically sensitive MOR PET imaging in nonhuman primates at low injected masses. Concordant plasma-input and reference-tissue measures, dose-dependent blockade, and proof-of-concept within-scan displacement support its use for measuring MOR availability and dynamic antagonist engagement across administration routes.

Sleep entails significant changes in cerebral hemodynamics and metabolism. Yet, the way these processes evolve throughout wakefulness and sleep and their spatiotemporal dependence remain largely unknown. Here, by integrating a functional PET technique with simultaneous EEG-fMRI, we reveal a tightly coupled temporal progression of global hemodynamics and metabolism during the descent into NREM sleep, with large hemodynamic fluctuations emerging as global glucose metabolism declines, both of which track EEG arousal dynamics. Furthermore, we identify two distinct network patterns that emerge during NREM sleep: a ~0.02-Hz oscillating, high-metabolism sensorimotor network remains active and dynamic, whereas hemodynamic and metabolic activity in the default-mode network is suppressed. These results elucidate how sleep diminishes awareness while preserving sensory responses, and uncover a complex, alternating balance of neuronal, hemodynamic, and metabolic dynamics in the sleeping brain. This work also demonstrates the potential of EEG-PET-MRI to explore neuro-metabolic-hemodynamic mechanisms underlying cognition and arousal in humans.

Cognitive ageing is marked by progressive decline in episodic memory and dopaminergic function, yet the extent to which individual differences in dopaminergic system integrity influence memory under motivational contexts remains unclear. In this study, we investigated how baseline D2/D3 receptor availability (BP _ND ⁰ ) in key dopaminergic pathways relates to reward-modulated memory performance in healthy older adults. Thirty-three healthy seniors (aged 64-85) underwent two session concurrent MR-PET imaging with [ ¹ F]fallypride involving scene categorisation task with high- and low-motivational contexts. We quantified BP _ND ⁰ across nine dopaminergic regions of interest and examined their relationships with recognition memory performance at short (∼15m) and long (∼24h) delays. Baseline D2/D3 receptor availability showed high test-retest reliability and regionally distinct profiles, suggesting it reflects a stable neurochemical characteristic in healthy ageing, and principal axis factor analysis revealed two partially independent dopaminergic subsystems (dorsal striatal vs mesolimbic) based on interindividual patterns in receptor densities. Region-specific associations further linked D2/D3 receptor availability to distinct memory outcomes. Higher caudate D2/D3 receptor availability was associated with a liberal response bias (increased hits and false alarms both), whereas higher putamen D2/D3 predicted more durable long-term memory retention. Greater thalamic D2/D3 receptor availability correlated with fewer short-term false memories, while greater D2/D3 receptor availability in the amygdala was associated with better recognition at longer delays. In contrast, higher midbrain (substantia nigra and ventral tegmental area) D2/D3 availability which was linked to poorer reward-related memory performance. These findings suggest several complementary dopaminergic circuits supporting episodic memory. Our results highlight dopaminergic neuromodulation as a key factor in cognitive ageing and a potential target for interventions to bolster memory in late life. Patient consent and ethics approval: All subjects who were included in this study have provided their consent prior to their participation, following the guidelines of the ethics committee at University Hospital Magdeburg in Magdeburg, Germany.

Understanding neuromodulatory effects of serotonin 2A receptor (5-HT _2A R) agonists with diverse pharmacological profiles is relevant to advancing psychedelic-related drug applications. We performed simultaneous positron emission tomography (PET) and pharmacological magnetic resonance imaging (phMRI) in anesthetized nonhuman primates (NHP; N = 3) to examine partial agonists with varying 5-HT _2A R affinities and selectivity profiles: psilocybin (30, 60, and 90 µg/kg), lisuride (5 µg/kg), and 25CN-NBOH (15 µg/kg). Receptor occupancy was assessed with [ ¹¹ C]MDL-100907 PET, and cerebral blood volume (CBV) changes were measured with phMRI. Mixed partial agonists psilocybin and lisuride evoked biphasic CBV responses, whereas the selective 25CN-NBOH produced monophasic CBV increases. Cortical occupancy for psilocybin plateaued at 60 µg/kg (32%), whereas a lower dose of lisuride (5 µg/kg) resulted in similar occupancy (31%). Administration of 25CN-NBOH resulted in lower occupancy (7%) but larger changes in CBV compared to psilocybin and lisuride. The associations between CBV and 5-HT _2A R occupancy appear linear for lisuride and 25CN-NBOH, but not for psilocybin. We speculate that the temporal and spatial differences in hemodynamic responses of the three agonists could stem from mixed affinity profiles. This work provides an understanding of pharmacological impacts of mixed serotonergic agonists being pursued as therapeutics for psychiatric conditions, offering valuable insights for future drug applications and development strategies.

The dopamine system plays a significant role in drug reward and the pathogenesis of addiction. Psychostimulant drugs acutely increase dopamine levels, triggering receptor internalization. In vitro data suggest that dopamine D ₁ receptors (D ₁ R) recycle, whereas D ₂ receptors (D ₂ R) degrade in response to activation. Yet, receptor fates in vivo remain unclear. This study bridges in vitro mechanisms and in vivo measurements of stimulant-induced modulation of receptor states using longitudinal multi-modal imaging combined with neuropharmacology. We demonstrate how repeated amphetamine administration differentially modulates D ₁ R vs. D ₂ R signaling in nonhuman primates over 24 hours using simultaneous positron emission tomography and functional magnetic resonance imaging. In contrast to predominantly inhibitory D ₂ R signaling due to an initial amphetamine challenge, excitatory D ₁ R functional signaling prevails three hours later, while D ₂ Rs stay internalized. These results demonstrate differential externalization mechanisms of the D ₁ R and D ₂ R in vivo and a shift in receptor subtype activation after a dopamine surge.

We report a novel forward-model implementation of the full reference tissue model (fFTRM) that addresses the fast-exchange approximation employed by the simplified reference tissue model (SRTM) by incorporating a non-zero dissociation time constant from the specifically bound compartment. The forward computational approach avoided errors associated with noisy and nonorthogonal basis functions using an inverse linear model. Compared to analysis by a multilinear single-compartment reference tissue model (MRTM), fFTRM provided improved accuracy for estimation of binding potentials at early times in the scan, with no worse reproducibility across sessions. To test the model’s ability to identify small focal changes in binding potential using a within-scan challenge, we employed a nonhuman primate model of focal dopamine release elicited by deep brain microstimulation remote to ventral striatum (VST) during imaging by simultaneous PET and fMRI. The new model reported an unambiguously lateralized response in VST consistent with fMRI, whereas the MRTM-derived response was not lateralized and was consistent with simulations of model bias. The proposed model enabled better accuracy in PET [¹¹C]raclopride displacement studies and may also facilitate challenges sooner after injection, thereby recovering some sensitivity lost to radioactive decay of the PET tracer.

The positron emission tomography (PET) radiotracer [¹¹C]PBR28 has been increasingly used to image the translocator protein (TSPO) as a marker of neuroinflammation in a variety of brain disorders. Interrelatedly, similar clinical populations can also exhibit altered brain perfusion, as has been shown using arterial spin labelling in magnetic resonance imaging (MRI) studies. Hence, an unsolved debate has revolved around whether changes in perfusion could alter delivery, uptake, or washout of the radiotracer [¹¹C]PBR28, and thereby influence outcome measures that affect interpretation of TSPO upregulation. In this simultaneous PET/MRI study, we demonstrate that [¹¹C]PBR28 signal elevations in chronic low back pain patients are not accompanied, in the same regions, by increases in cerebral blood flow (CBF) compared to healthy controls, and that areas of marginal hypoperfusion are not accompanied by decreases in [¹¹C]PBR28 signal. In non-human primates, we show that hypercapnia-induced increases in CBF during radiotracer delivery or washout do not alter [¹¹C]PBR28 outcome measures. The combined results from two methodologically distinct experiments provide support from human data and direct experimental evidence from non-human primates that changes in CBF do not influence outcome measures reported by [¹¹C]PBR28 PET imaging studies and corresponding interpretations of the biological meaning of TSPO upregulation.