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 ¹¹C-labeled antagonist radiotracers with high affinity and selectivity toward KOR. What is limiting their wide applications is the short half-life of ¹¹C. Herein, we report the synthesis of a first ¹⁸F-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‑[¹⁸F]Fluorobenzyl)-4-[(tetrahydrofuran-2-yl)methyl]piperazine: A Novel Suitable Radioligand with Low Lipophilicity for Imaging σ₁ Receptors in the Brain

We have designed and synthesized novel piperazine compounds with low lipophilicity as σ₁ receptor ligands. 1-(4-Fluorobenzyl)-4-[(tetrahydrofuran-2-yl)­methyl]­piperazine (<b>10</b>) possessed a low nanomolar σ₁ receptor affinity and a high selectivity toward the vesicular acetylcholine transporter (>2000-fold), σ₂ receptors (52-fold), and adenosine A_2A, adrenergic α₂, cannabinoid CB₁, dopamine D₁, D_2L, γ-aminobutyric acid A (GABA_A), NMDA, melatonin MT₁, MT₂, and serotonin 5-HT₁ receptors. The corresponding radiotracer [¹⁸F]<b>10</b> demonstrated high brain uptake and extremely high brain-to-blood ratios in biodistribution studies in mice. Pretreatment with the selective σ₁ receptor agonist SA4503 significantly reduced the level of accumulation of the radiotracer in the brain. No radiometabolite of [¹⁸F]<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 [¹⁸F]<b>10</b> to σ₁ receptors in rat brain. <i>Ex vivo</i> autoradiography showed a reduced level of binding of [¹⁸F]<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 σ₁ receptors in Alzheimer’s disease

Quantitative projection of human brain penetration of the H₃ antagonist PF-03654746 by integrating rat-derived brain partitioning and PET receptor occupancy

<p>1. Unbound brain drug concentration (<i>C</i>_b,u), a valid surrogate of interstitial fluid drug concentration (<i>C</i>_ISF), cannot be directly determined in humans, which limits accurately defining the human <i>C</i>_b,u:<i>C</i>_p,u of investigational molecules.</p> <p>2. For the H₃R 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>_b,u:<i>C</i>_p,u 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>_b,u:<i>C</i>_p,u of 2.11).</p> <p>4. In NHP and humans, the PET receptor occupancy-based <i>C</i>_p,u IC₅₀ 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 H₃ <i>K</i>_i (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>_b,u:<i>C</i>_p,u of <b>PF-03654746</b> was integrated with <i>C</i>_p,u IC₅₀ to identify unbound (neuro) potency of <b>PF-03654746</b>, <i>n</i>IC₅₀.</p> <p>6. The <i>n</i>IC₅₀ 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 H₃ <i>K</i>_i (2.3 nM).</p> <p>7. This correlation of the <i>n</i>IC₅₀ and <i>in vitro h</i>H₃ <i>K</i>_i 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>_p,u as a reliable surrogate of <i>C</i>_b,u.</p> <p>8. Thus, <i>n</i>IC₅₀ quantitatively informed the human <i>C</i>_b,u:<i>C</i>_p,u 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