The Non-Anhydrous, Minimally Basic Synthesis of the Dopamine D2 Agonist [18F]MCL-524

The dopamine D2 agonist MCL-524 is selective for the D2 receptor in the high-affinity state (D2high), and, therefore, the PET analogue, [18F]MCL-524, may facilitate the elucidation of the role of D2high in disorders such as schizophrenia. However, the previously reported synthesis of [18F]MCL-524 proved difficult to replicate and was lacking experimental details. We therefore developed a new synthesis of [18F]MCL-524 using a “non-anhydrous, minimally basic” (NAMB) approach. In this method, [18F]F− is eluted from a small (10–12 mg) trap-and-release column with tetraethylammonium tosylate (2.37 mg) in 7:3 MeCN:H2O (0.1 mL), rather than the basic carbonate or bicarbonate solution that is most often used for [18F]F− recovery. The tosylated precursor (1 mg) in 0.9 mL anhydrous acetonitrile was added directly to the eluate, without azeotropic drying, and the solution was heated (150 °C/15 min). The catechol was then deprotected with the Lewis acid In(OTf)3 (10 equiv.; 150 °C/20 min). In contrast to deprotection with protic acids, Lewis-acid-based deprotection facilitated the efficient removal of byproducts by HPLC and eliminated the need for SPE extraction prior to HPLC purification. Using the NAMB approach, [18F]MCL-524 was obtained in 5–9% RCY (decay-corrected, n = 3), confirming the utility of this improved method for the multistep synthesis of [18F]MCL-524 and suggesting that it may applicable to the synthesis of other 18F-labeled radiotracers.

Conscious perception and the modulatory role of dopamine: no effect of the dopamine D2 agonist cabergoline on visual masking, the attentional blink, and probabilistic discrimination

Rationale Conscious perception is thought to depend on global amplification of sensory input. In recent years, striatal dopamine has been proposed to be involved in gating information and conscious access, due to its modulatory influence on thalamocortical connectivity. Objectives Since much of the evidence that implicates striatal dopamine is correlational, we conducted a double-blind crossover pharmacological study in which we administered cabergoline—a dopamine D2 agonist—and placebo to 30 healthy participants. Under both conditions, we subjected participants to several well-established experimental conscious-perception paradigms, such as backward masking and the attentional blink task. Results We found no evidence in support of an effect of cabergoline on conscious perception: key behavioral and event-related potential (ERP) findings associated with each of these tasks were unaffected by cabergoline. Conclusions Our results cast doubt on a causal role for dopamine in visual perception. It remains an open possibility that dopamine has causal effects in other tasks, perhaps where perceptual uncertainty is more prominent.

Conscious perception and the modulatory role of dopamine: no effect of the dopamine D2 agonist cabergoline on visual masking, the attentional blink, and probabilistic discrimination

RationaleConscious perception is thought to depend on global amplification of sensory input. In recent years, striatal dopamine has been proposed to be involved in gating information and conscious access, due to its modulatory influence on thalamocortical connectivity.ObjectivesSince much of the evidence that implicates striatal dopamine is correlational, we conducted a double-blind crossover pharmacological study in which we administered cabergoline – a dopamine D2 agonist – and placebo to 30 healthy participants. Under both conditions, we subjected participants to several well-established experimental conscious-perception paradigms, such as backward masking and the attentional blink task.ResultsWe found no evidence in support of an effect of cabergoline on conscious perception: key behavioral and event-related potential (ERP) findings associated with each of these tasks were unaffected by cabergoline.ConclusionsOur results cast doubt on a causal role for dopamine in visual perception. It remains an open possibility that dopamine has causal effects in other tasks, perhaps where perceptual uncertainty is more prominent.

The prolactin receptor long isoform regulates nociceptor sensitization and opioid-induced hyperalgesia selectively in females

Pain is more prevalent in women for reasons that remain unclear. We have identified a mechanism of injury-free nociceptor sensitization and opioid-induced hyperalgesia (OIH) promoted by prolactin (PRL) in females. PRL signals through mutually inhibitory long (PRLR-L) and short (PRLR-S) receptor isoforms, and PRLR-S activation induces neuronal excitability. PRL and PRLR expression were higher in females. CRISPR-mediated editing of PRLR-L promoted nociceptor sensitization and allodynia in naïve, uninjured female mice that depended on circulating PRL. Opioids, but not trauma-induced nerve injury, decreased PRLR-L promoting OIH through activation of PRLR-S in female mice. Deletion of both PRLR-L and PRLR-S (total PRLR) prevented, whereas PRLR-L overexpression rescued established OIH selectively in females. Inhibition of circulating PRL with cabergoline, a dopamine D2 agonist, up-regulated PRLR-L and prevented OIH only in females. The PRLR-L isoform therefore confers protection against PRL-promoted pain in females. Limiting PRL/PRLR-S signaling pharmacologically or with gene therapies targeting the PRLR may be effective for reducing pain in a female-selective manner.