We aimed to develop
radioligands for PET imaging of brain phosphodiesterase
subtype 4D (PDE4D), a potential target for developing cognition enhancing
or antidepressive drugs. Exploration of several chemical series gave
four leads with high PDE4D inhibitory potency and selectivity, optimal
lipophilicity, and good brain uptake. These leads featured alkoxypyridinyl
cores. They were successfully labeled with carbon-11 (t
1/2 = 20.4 min) for evaluation with PET in monkey. Whereas
two of these radioligands did not provide PDE4D-specific signal in
monkey brain, two others, [11C]T1660 and [11C]T1650, provided sizable specific signal, as judged by pharmacological
challenge using rolipram or a selective PDE4D inhibitor (BPN14770)
and subsequent biomathematical analysis. Specific binding was highest
in prefrontal cortex, temporal cortex, and hippocampus, regions that
are important for cognitive function. [11C]T1650 was progressed
to evaluation in humans with PET, but the output measure of brain
enzyme density (V
T) increased with scan
duration. This instability over time suggests that radiometabolite(s)
were accumulating in the brain. BPN14770 blocked PDE4D uptake in human
brain after a single dose, but the percentage occupancy was difficult
to estimate because of the unreliability of measuring V
T. Overall, these results show that imaging of PDE4D in
primate brain is feasible but that further radioligand refinement
is needed, most likely to avoid problematic radiometabolites.
Angiotensin-converting enzyme (ACE) regulates blood pressure by cleaving angiotensin I to produce angiotensin II. In the brain, ACE is especially abundant in striatal tissue, but the function of ACE in striatal circuits remains poorly understood. We found that ACE degrades an unconventional enkephalin heptapeptide, Met-enkephalin-Arg-Phe, in the nucleus accumbens of mice. ACE inhibition enhanced µ-opioid receptor activation by Met-enkephalin-Arg-Phe, causing a cell type–specific long-term depression of glutamate release onto medium spiny projection neurons expressing the Drd1 dopamine receptor. Systemic ACE inhibition was not intrinsically rewarding, but it led to a decrease in conditioned place preference caused by fentanyl administration and an enhancement of reciprocal social interaction. Our results raise the enticing prospect that central ACE inhibition can boost endogenous opioid signaling for clinical benefit while mitigating the risk of addiction.
Translocator
protein 18 kDa (TSPO) is a biomarker of neuroinflammation.
[11C]ER176 robustly quantifies TSPO in the human brain
with positron emission tomography (PET), irrespective of subject genotype.
We aimed to develop an ER176 analog with potential for labeling with
longer-lived fluorine-18 (t
1/2 = 109.8
min). New fluoro and trifluoromethyl analogs of ER176 were prepared
through a concise synthetic strategy. These ligands showed high TSPO
affinity and low human genotype sensitivity. Each ligand was initially
labeled by a generic 11C-methylation procedure, thereby
enabling speedy screening in mice. Each radioligand was rapidly taken
up and well retained in the mouse brain at baseline after intravenous
injection. Preblocking of TSPO showed that high proportions of brain
uptake were specifically bound to TSPO at baseline. Overall, the 3-fluoro
analog of [11C]ER176 ([11C]3b)
displayed the most promising imaging properties. Therefore, a method
was developed to label 3b with [18F]fluoride
ion. [18F]3b gave similarly promising PET
imaging results and deserves evaluation in higher species.
Previous work found that [11C]deschloroclozapine ([11C]DCZ) is superior to [11C]clozapine ([11C]CLZ) for imaging Designer Receptors Exclusively Activated by Designer Drugs (DREADDs). This study used PET to quantitatively and separately measure the signal from transfected receptors, endogenous receptors/targets, and non-displaceable binding in other brain regions to better understand this superiority. A genetically-modified muscarinic type-4 human receptor (hM4Di) was injected into the right amygdala of a male rhesus macaque. [11C]DCZ and [11C]CLZ PET scans were conducted 2–24 months later. Uptake was quantified relative to the concentration of parent radioligand in arterial plasma at baseline (n = 3 scans/radioligand) and after receptor blockade (n = 3 scans/radioligand). Both radioligands had greater uptake in the transfected region and displaceable uptake in other brain regions. Displaceable uptake was not uniformly distributed, perhaps representing off-target binding to endogenous receptor(s). After correction, [11C]DCZ signal was 19% of that for [11C]CLZ, and background uptake was 10% of that for [11C]CLZ. Despite stronger [11C]CLZ binding, the signal-to-background ratio for [11C]DCZ was almost two-fold greater than for [11C]CLZ. Both radioligands had comparable DREADD selectivity. All reference tissue models underestimated signal-to-background ratio in the transfected region by 40%–50% for both radioligands. Thus, the greater signal-to-background ratio of [11C]DCZ was due to its lower background uptake.
As the additive manufacturing industry grows, it is compounding the global plastic waste problem. Distributed recycling and additive manufacturing (DRAM) offers an economic solution to this challenge, but it has been relegated to either small-volume 3D printers (limiting waste recycling throughput) or expensive industrial machines (limiting accessibility and lateral scaling). To overcome these challenges, this paper provides proof-of-concept for a novel open-source hybrid 3D printer that combines a low-cost hanging printer design with a compression screw-based end-effector that allows direct extrusion of recycled plastic waste in large expandable printing volumes. Mechanical testing of the resultant prints from 100% waste plastic, however, showed that combining challenges of non-uniform feedstocks and a heavy printhead for a hangprinter reduced the strength of the parts compared to fused filament fabrication. The preliminary results are technologically promising, however, and provide opportunities to improve on the open source design to help process the volumes of waste plastic needed for DRAM to address the negative environmental impacts of global plastic use.
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