7 research outputs found
Fluorine-18-Labeled Antagonist for PET Imaging of Kappa Opioid Receptors
Kappa opioid receptor
(KOR) antagonists are potential drug candidates
for diseases such as treatment-refractory depression, anxiety, and
addictive disorders. PET imaging radiotracers for KOR can be used
in occupancy study to facilitate drug development, and to investigate
the roles of KOR in health and diseases. We have previously developed
two <sup>11</sup>C-labeled antagonist radiotracers with high affinity
and selectivity toward KOR. What is limiting their wide applications
is the short half-life of <sup>11</sup>C. Herein, we report the synthesis
of a first <sup>18</sup>F-labeled KOR antagonist radiotracer and the
initial PET imaging study in a nonhuman primate
sj-docx-1-jop-10.1177_02698811221140008 – Supplemental material for Neurotransmitter transporter occupancy following administration of centanafadine sustained-release tablets: A phase 1 study in healthy male adults
Supplemental material, sj-docx-1-jop-10.1177_02698811221140008 for Neurotransmitter transporter occupancy following administration of centanafadine sustained-release tablets: A phase 1 study in healthy male adults by David Matuskey, Jean-Dominique Gallezot, Nabeel Nabulsi, Shannan Henry, Kristen Torres, Mark Dias, Gustavo A Angarita, Yiyun Huang, Susan E Shoaf, Richard E Carson and Shailly Mehrotra in Journal of Psychopharmacology</p
sj-pdf-1-jcb-10.1177_0271678X231153730 - Supplemental material for In vivo synaptic density loss correlates with impaired functional and related structural connectivity in Alzheimer’s disease
Supplemental material, sj-pdf-1-jcb-10.1177_0271678X231153730 for In vivo synaptic density loss correlates with impaired functional and related structural connectivity in Alzheimer’s disease by Junfang Zhang, Jie Wang, Xiaomeng Xu, Zhiwen You, Qi Huang, Yiyun Huang, Qihao Guo, Yihui Guan, Jun Zhao, Jun Liu, Wei Xu, Yulei Deng, Fang Xie and Binyin Li in Journal of Cerebral Blood Flow & Metabolism</p
1‑(4‑[<sup>18</sup>F]Fluorobenzyl)-4-[(tetrahydrofuran-2-yl)methyl]piperazine: A Novel Suitable Radioligand with Low Lipophilicity for Imaging σ<sub>1</sub> Receptors in the Brain
We have designed and synthesized
novel piperazine compounds with
low lipophilicity as σ<sub>1</sub> receptor ligands. 1-(4-Fluorobenzyl)-4-[(tetrahydrofuran-2-yl)methyl]piperazine
(<b>10</b>) possessed a low nanomolar σ<sub>1</sub> receptor
affinity and a high selectivity toward the vesicular acetylcholine
transporter (>2000-fold), σ<sub>2</sub> receptors (52-fold),
and adenosine A<sub>2A</sub>, adrenergic α<sub>2</sub>, cannabinoid
CB<sub>1</sub>, dopamine D<sub>1</sub>, D<sub>2L</sub>, γ-aminobutyric
acid A (GABA<sub>A</sub>), NMDA, melatonin MT<sub>1</sub>, MT<sub>2</sub>, and serotonin 5-HT<sub>1</sub> receptors. The corresponding
radiotracer [<sup>18</sup>F]<b>10</b> demonstrated high brain
uptake and extremely high brain-to-blood ratios in biodistribution
studies in mice. Pretreatment with the selective σ<sub>1</sub> receptor agonist SA4503 significantly reduced the level of accumulation
of the radiotracer in the brain. No radiometabolite of [<sup>18</sup>F]<b>10</b> was observed to enter the brain. Positron emission
tomography and magnetic resonance imaging confirmed suitable kinetics
and a high specific binding of [<sup>18</sup>F]<b>10</b> to
σ<sub>1</sub> receptors in rat brain. <i>Ex vivo</i> autoradiography showed a reduced level of binding of [<sup>18</sup>F]<b>10</b> in the cortex and hippocampus of the senescence-accelerated
prone (SAMP8) compared to that of the senescence-accelerated resistant
(SAMR1) mice, indicating the potential dysfunction of σ<sub>1</sub> receptors in Alzheimer’s disease
Quantitative projection of human brain penetration of the H<sub>3</sub> antagonist PF-03654746 by integrating rat-derived brain partitioning and PET receptor occupancy
<p>1. Unbound brain drug concentration (<i>C</i><sub>b,u</sub>), a valid surrogate of interstitial fluid drug concentration (<i>C</i><sub>ISF</sub>), cannot be directly determined in humans, which limits accurately defining the human <i>C</i><sub>b,u</sub>:<i>C</i><sub>p,u</sub> of investigational molecules.</p> <p>2. For the H<sub>3</sub>R antagonist (1<i>R</i>,3<i>R</i>)-<i>N</i>-ethyl-3-fluoro-3-[3-fluoro-4-(pyrrolidin-1-lmethyl)phenyl]cyclobutane-1-carboxamide (<b>PF-03654746</b>), we interrogated <i>C</i><sub>b,u</sub>:<i>C</i><sub>p,u</sub> in humans and nonhuman primate (NHP).</p> <p>3. In rat, <b>PF-03654746</b> achieved net blood–brain barrier (BBB) equilibrium (<i>C</i><sub>b,u</sub>:<i>C</i><sub>p,u</sub> of 2.11).</p> <p>4. In NHP and humans, the PET receptor occupancy-based <i>C</i><sub>p,u</sub> IC<sub>50</sub> of <b>PF-03654746</b> was 0.99 nM and 0.31 nM, respectively, which were 2.1- and 7.4-fold lower than its <i>in vitro</i> human H<sub>3</sub> <i>K</i><sub>i</sub> (2.3 nM).</p> <p>5. In an attempt to understand this higher-than-expected potency in humans and NHP, rat-derived <i>C</i><sub>b,u</sub>:<i>C</i><sub>p,u</sub> of <b>PF-03654746</b> was integrated with <i>C</i><sub>p,u</sub> IC<sub>50</sub> to identify unbound (neuro) potency of <b>PF-03654746</b>, <i>n</i>IC<sub>50</sub>.</p> <p>6. The <i>n</i>IC<sub>50</sub> of <b>PF-03654746</b> was 2.1 nM in NHP and 0.66 nM in human which better correlated (1.1- and 3.49-fold lower) with <i>in vitro</i> human H<sub>3</sub> <i>K</i><sub>i</sub> (2.3 nM).</p> <p>7. This correlation of the <i>n</i>IC<sub>50</sub> and <i>in vitro h</i>H<sub>3</sub> <i>K</i><sub>i</sub> suggested the translation of net BBB equilibrium of <b>PF-03654746</b> from rat to NHP and humans, and confirmed the use of <i>C</i><sub>p,u</sub> as a reliable surrogate of <i>C</i><sub>b,u</sub>.</p> <p>8. Thus, <i>n</i>IC<sub>50</sub> quantitatively informed the human <i>C</i><sub>b,u</sub>:<i>C</i><sub>p,u</sub> of <b>PF-03654746</b>.</p
Additional file 1 of Drug characteristics derived from kinetic modeling: combined 11C-UCB-J human PET imaging with levetiracetam and brivaracetam occupancy of SV2A
Additional file 1: Fig. S1. 11C-UCB-J activity curves in putamen (closed circles) with model fits (solid curves). a and b Displacement (LEV, 1500 mg at 60 min) and post-dose scans, c and d displacement (BRV, 200 mg at 60 min) and post-dose scans. CND(t) and CS(t) was displayed in the dotted curves and break curves, respectively. Fig. S2. 11C-UCB-J activity curves in cerebellum (closed circles) with model fits (solid curves). a and b displacement (LEV, 1500 mg at 60 min) and post-dose scans, c and d displacement (BRV, 200 mg at 60 min) and post-dose scans. CND(t) and CS(t) was displayed in the dotted curves and break curves, respectively. Fig. S3. Concentrations of AED in the plasma and non-displaceable AED in the putamen (DND(t)) and occupancy curves by LEV (a, b) and BRV (c, d). Insets in (b) and (d) show the occupancy curves for the first 2 h. Fig. S4. Concentrations of AED in the plasma and non-displaceable AED in the cerebellum (DND(t)) and occupancy curves by LEV (a, b) and BRV (c, d). Insets in (b) and (d) show the occupancy curves for the first 2 h. Table S1. Kinetic parameters estimated using the one-tissue compartment model (LEV: n = 4, BRV: n = 5)
Increased Nanoparticle Delivery to Brain Tumors by Autocatalytic Priming for Improved Treatment and Imaging
The
blood–brain barrier (BBB) is partially disrupted in
brain tumors. Despite the gaps in the BBB, there is an inadequate
amount of pharmacological agents delivered into the brain. Thus, the
low delivery efficiency renders many of these agents ineffective in
treating brain cancer. In this report, we proposed an “autocatalytic”
approach for increasing the transport of nanoparticles into the brain.
In this strategy, a small number of nanoparticles enter into the brain <i>via</i> transcytosis or through the BBB gaps. After penetrating
the BBB, the nanoparticles release BBB modulators, which enables more
nanoparticles to be transported, creating a positive feedback loop
for increased delivery. Specifically, we demonstrated that these autocatalytic
brain tumor-targeting poly(amine-<i>co</i>-ester) terpolymer
nanoparticles (ABTT NPs) can readily cross the BBB and preferentially
accumulate in brain tumors at a concentration of 4.3- and 94.0-fold
greater than that in the liver and in brain regions without tumors,
respectively. We further demonstrated that ABTT NPs were capable of
mediating brain cancer gene therapy and chemotherapy. Our results
suggest ABTT NPs can prime the brain to increase the systemic delivery
of therapeutics for treating brain malignancies