The development of a PET radioligand selective for I 2 -imidazoline binding sites (I 2 BS) would enable, for the first time, specific, measurable in vivo imaging of this target protein, along with assessment of alterations in expression patterns of this protein in disease pathophysiology. Methods: BU99008 was identified as the most promising I 2 BS radioligand candidate and radiolabeled with 11 C via methylation. The in vivo binding properties of 11 C-BU99008 were assessed in rhesus monkeys to determine brain penetration, brain distribution, binding specificity and selectivity (via the use of the unlabeled blockers), and the most appropriate kinetic model for analyzing data generated with this PET radioligand. Results: 11 C-BU99008 was demonstrated to readily enter the brain, resulting in a heterogeneous distribution (globus pallidus . cortical regions . cerebellum) consistent with the reported regional I 2 BS densities as determined by human tissue section autoradiography and preclinical in vivo PET studies in the pig. In vivo competition studies revealed that 11 C-BU99008 displayed reversible kinetics specific for the I 2 BS. The multilinear analysis (MA1) model was the most appropriate analysis method for this PET radioligand in this species. The selective I 2 BS blocker BU224 was shown to cause a saturable, dose-dependent decrease in 11 C-BU99008 binding in all regions of the brain assessed, further demonstrating the heterogeneous distribution of I 2 BS protein in the rhesus brain and binding specificity for this radioligand. Conclusion: These data demonstrate that 11 C-BU99008 represents a specific and selective PET radioligand for imaging and quantifying the I 2 BS, in vivo, in the rhesus monkey. Further work is under way to translate the use of 11 C-BU99008 to the clinic.
Understanding the cellular processes underpinning the changes in binding observed during positron emission tomography neurotransmitter release studies may aid translation of these methodologies to other neurotransmitter systems. We compared the sensitivities of opioid receptor radioligands, carfentanil, and diprenorphine, to amphetamine-induced endogenous opioid peptide (EOP) release and methadone administration in the rat. We also investigated whether agonist-induced internalization was involved in reductions in observed binding using subcellular fractionation and confocal microscopy. After radioligand administration, significant reductions in [ 11 C]carfentanil, but not [ 3 H]diprenorphine, uptake were observed after methadone and amphetamine pretreatment. Subcellular fractionation and in vitro radioligand binding studies showed that amphetamine pretreatment only decreased total [11 C]carfentanil binding. In vitro saturation binding studies conducted in buffers representative of the internalization pathway suggested that m-receptors are significantly less able to bind the radioligands in endosomal compared with extracellular compartments. Finally, a significant increase in m-receptor-early endosome co-localization in the hypothalamus was observed after amphetamine and methadone treatment using double-labeling confocal microscopy, with no changes in d-or k-receptor co-localization. These data indicate carfentanil may be superior to diprenorphine when imaging EOP release in vivo, and that alterations in the ability to bind internalized receptors may be a predictor of ligand sensitivity to endogenous neurotransmitter release.
Nalmefene blunts BOLD response in the mesolimbic system during anticipation of monetary reward and an alcohol infusion. This is consistent with nalmefene's actions on opioid receptors, which modulate the mesolimbic dopaminergic system, and provides a neurobiological basis for its efficacy.
Various D2/3 receptor PET radioligands are sensitive to endogenous dopamine release in vivo. The Occupancy Model is generally used to interpret changes in binding observed in in vivo competition binding studies; an Internalisation Hypothesis may also contribute to these changes in signal. Extension of in vivo competition imaging to other receptor systems has been relatively unsuccessful. A greater understanding of the cellular processes underlying signal changes following endogenous neurotransmitter release may help translate this imaging paradigm to other receptor systems. To investigate the Internalisation Hypothesis we assessed the effects of different cellular environments, representative of those experienced by a receptor following agonist-induced internalisation, on the binding of three D2/3 PET ligands with previously reported sensitivities to endogenous dopamine in vivo, namely [3H]spiperone, [3H]raclopride and [3H]PhNO. Furthermore, we determined the contribution of each cellular compartment to total striatal binding for these D2/3 ligands. These studies suggest that sensitivity to endogenous dopamine release in vivo is related to a decrease in affinity in the endosomal environment compared with those found at the cell surface. In agreement with these findings we also demonstrate that ∼25% of total striatal binding for [3H]spiperone originates from sub-cellular, microsomal receptors, whereas for [3H]raclopride and [3H]PhNO, this fraction is lower, representing ∼14% and 17%, respectively. This pharmacological approach is fully translatable to other receptor systems. Assessment of affinity shifts in different cellular compartments may play a crucial role for understanding if a radioligand is sensitive to endogenous release in vivo, for not just the D2/3, but other receptor systems.
Low affinity α1/α2 containing GABAA receptors are significantly less able to bind [(11) C]/[(3) H]Ro15-4513 following translocation to the endosomal environment. The alterations in [(11) C]Ro15-4513 binding observed in vivo following perturbations in endogenous GABA are likely driven by both alterations in receptor binding parameters following agonist induced internalisation and the GABA Shift.
An evaluation was performed to assess effi cacy and resource utilisation of an elective inpatient alcohol detoxifi cation service at a large inner-city teaching hospital. Abstinence rates at 3, 6 and 12 months post-detoxifi cation were 68.1, 44.7 and 36.2%, respectively. Relapse was associated with referrals from acute hospital services, previous detoxifi cations, longer time between referral and admission for detoxifi cation, presence of alcohol in the blood on the day of admission and requirement for benzodiazepines during withdrawal. The service operates within the national 18-week referral target and runs at a cost substantially lower than that of residential alcohol detoxifi cation facilities but with similar sobriety rates. We demonstrate that elective detoxifi cation with specialist follow-up provides an effective service both in terms of patient outcomes and resource use. Further investment in these services at both local and national level should be considered.
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