Brain Penetration Research Articles

SCR-6852, an oral and highly brain-penetrating estrogen receptor degrader (SERD), effectively shrinks tumors both in intracranial and subcutaneous ER + breast cancer models

BackgroundTargeted estrogen receptor degradation has been approved to effectively treat ER + breast cancers. Due to the poor bioavailability of fulvestrant, the first generation of SERD, many efforts were made to develop oral SERDs. With the approval of Elacestrant, oral SERDs demonstrated superior efficacy than fulvestrant. However, due to the poor ability of known SERDs to penetrate the blood–brain barrier (BBB), breast cancer patients with brain metastasis cannot benefit from clinical SERDs.MethodsThe ER inhibitory effects were evaluated on ERα protein degradation, and target genes downregulation. And anti-proliferation activities were further determined in a panel of ER + breast cancer cell lines. The subcutaneous and intracranial ER + tumor models were used to evaluate the efficacy of anti-tumor effects. Brain penetrability was determined in multiple animal species.ResultsSCR-6852 is a novel SERD and currently is under early clinical evaluation. In vitro studies demonstrated that it strongly induced both wildtype and mutant ERα degradation. It potently inhibited cell proliferation in a panel of ER + breast cancer cell lines, including the cell lines containing ESR1 mutations (Y537 and D538). Furthermore, SCR-6852 exhibited pure antagonistic activities on the ERɑ signal axis identified both in vitro and in vivo. Oral administration of SCR-6852 at 10 mg/kg resulted in tumor shrinkage which was superior to Fulvestrant at 250 mg/kg, notably, in the intracranial tumor model, SCR-6852 effectively inhibited tumor growth and significantly prolonged mice survival, which correlated well with the high exposure in brains. In addition to mice, SCR-6852 also exhibited high brain penetrability in rats and dogs.ConclusionsSCR-6852 is a novel SERD with high potency in inducing ERα protein degradation and pure antagonistic activity on ERɑ signaling in vitro and in vivo. Due to the high brain penetrability, SCR-6852 could be used to treat breast patients with brain metastasis.

Pharmacokinetics of the KRASG12C inhibitor adagrasib is limited by CYP3A and ABCB1, and influenced by binding to mouse plasma carboxylesterase 1c

Adagrasib (Krazati™) is the second FDA-approved specific KRASG12C inhibitor for non-small cell lung cancer (NSCLC) patients harboring this mutation. The impact of the drug efflux transporters ABCB1 and ABCG2, and the drug-metabolizing enzymes CYP3A and carboxylesterase 1 (CES1) on the pharmacokinetics of oral adagrasib were studied using genetically modified mouse models. Adagrasib was potently transported by human ABCB1 and modestly by mouse Abcg2 in vitro. In Abcb1a/b-/- and Abcb1a/b;Abcg2-/- mice, the brain-to-plasma ratios were enhanced by 33- and 55-fold, respectively, compared to wild-type mice, whereas ratios in Abcg2-/- mice remained unchanged. The influence of ABC transporters was completely reversed by coadministration of the dual ABCB1/ABCG2 inhibitor elacridar, increasing the brain penetration in wild-type mice by 41-fold while no signs of acute CNS toxicity were observed. Tumor ABCB1 overexpression may thus confer adagrasib resistance. Whereas the ABC transporters did not affect adagrasib plasma exposure, CYP3A and Ces1 strongly impacted its apparent oral availability. The plasma AUC0–8 h was significantly enhanced by 2.3-fold in Cyp3a-/- compared to wild-type mice, and subsequently 4.3-fold reduced in transgenic CYP3A4 mice, indicating substantial CYP3A-mediated metabolism. Adagrasib plasma exposure was strongly reduced in Ces1-/- compared to wild-type mice, but tissue exposure was slightly increased, suggesting that adagrasib binds to plasma Ces1c in mice and is perhaps metabolized by Ces1. This binding could complicate interpretation of mouse studies, especially since humans lack circulating CES1 enzyme(s). Our results may be useful to further optimize the clinical safety and efficacy of adagrasib, and give more insight into potential drug-drug interactions risks.

Development of a Dihydroquinoline-Pyrazoline GluN2C/2D-Selective Negative Allosteric Modulator of the N-Methyl-d-aspartate Receptor.

Subunit-selective inhibition of N-methyl-d-aspartate receptors (NMDARs) is a promising therapeutic strategy for several neurological disorders, including epilepsy, Alzheimer's and Parkinson's disease, depression, and acute brain injury. We previously described the dihydroquinoline-pyrazoline (DQP) analogue 2a (DQP-26) as a potent NMDAR negative allosteric modulator with selectivity for GluN2C/D over GluN2A/B. However, moderate (<100-fold) subunit selectivity, inadequate cell-membrane permeability, and poor brain penetration complicated the use of 2a as an in vivo probe. In an effort to improve selectivity and the pharmacokinetic profile of the series, we performed additional structure-activity relationship studies of the succinate side chain and investigated the use of prodrugs to mask the pendant carboxylic acid. These efforts led to discovery of the analogue (S)-(-)-2i, also referred to as (S)-(-)-DQP-997-74, which exhibits >100- and >300-fold selectivity for GluN2C- and GluN2D-containing NMDARs (IC50 0.069 and 0.035 μM, respectively) compared to GluN2A- and GluN2B-containing receptors (IC50 5.2 and 16 μM, respectively) and has no effects on AMPA, kainate, or GluN1/GluN3 receptors. Compound (S)-(-)-2i is 5-fold more potent than (S)-2a. In addition, compound 2i shows a time-dependent enhancement of inhibitory actions at GluN2C- and GluN2D-containing NMDARs in the presence of the agonist glutamate, which could attenuate hypersynchronous activity driven by high-frequency excitatory synaptic transmission. Consistent with this finding, compound 2i significantly reduced the number of epileptic events in a murine model of tuberous sclerosis complex (TSC)-induced epilepsy that is associated with upregulation of the GluN2C subunit. Thus, 2i represents a robust tool for the GluN2C/D target validation. Esterification of the succinate carboxylate improved brain penetration, suggesting a strategy for therapeutic development of this series for NMDAR-associated neurological conditions.

Identification of potential inhibitors against Alzheimer-related proteins in Cordyceps militaris ethanol extract: experimental evidence and computational analyses.

Laboratory experiments were carried out to identify the chemical composition of Cordyceps militaris and reveal the first evidence of their Alzheimer-related potential. Liquid chromatography-mass spectrometry analysis identified 21 bioactive compounds in the ethanol extract (1-21). High-performance liquid chromatography quantified the content of cordycepin (0.32%). Bioassays revealed the overall anti-Alzheimer potential of the extract against acetylcholinesterase (IC50 = 115.9 ± 11.16µgmL-1). Multi-platform computations were utilized to predict the biological inhibitory effects of its phytochemical components against Alzheimer-related protein structures: acetylcholinesterase (PDB-4EY7) and β-amyloid protein (PDB-2LMN). In particular, 7 is considered as a most effective inhibitor predicted by its chemical stability in dipole-based environments (ground state - 467.26302 a.u.; dipole moment 11.598 Debye), inhibitory effectiveness ( - 13.6kcalmol-1), polarized compatibility (polarizability 25.8 Å3; logP - 1.01), and brain penetrability (logBB - 0.244; logPS - 3.047). Besides, 3 is promising as a brain-penetrating agent (logBB - 0.257; logPS - 2.400). The results preliminarily suggest further experimental attempts to verify the pro-cognitive effects of l(-)-carnitine (7). The online version contains supplementary material available at 10.1007/s13205-023-03714-9.

Assessing extent of brain penetration in vivo (Kp,uu,brain) in Göttingen minipig using a diverse set of reference drugs

The application of Göttingen minipigs for non-rodent pharmacokinetics (PK) and drug safety testing has seen a dramatic increase in recent years. The aim of this study was to determine the total and unbound brain-to-plasma ratios (Kp,brain and Kp,uu,brain) for a diverse set of reference compounds in female Göttingen minipigs and compare these with Kp,uu,brain values from other species to assess the suitability of Göttingen minipigs as a model for CNS drug safety testing and brain PK in clinical translation. The reference set consisted of 17 compounds with varying physico-chemical properties and included known human P-glycoprotein (P-gp) substrates. The results of the study showed, that minipig Kp,brain and Kp,uu,brain values for the tested compounds were in the range 0.03–86 and 0.02–2.4 (n = 3–4) respectively. The Kp,uu,brain values were comparable between minipig and rat for a large proportion of the compounds (71% within 2-fold, n = 17). Comparisons of brain penetration across several species for a subset of reference compounds revealed that minipig values were quite similar to those of rat, dog, monkey and human. The study highlighted that the largest Kp,uu,brain species differences were observed for compounds classified as transporter substrates (e.g. cimetidine, risperidone, Way-100635 and altanserin). In conclusion these brain penetration data add substantially to the available literature on PK and drug disposition for minipigs and support use of Göttingen minipig as a non-rodent drug safety model for CNS drug candidates and as a brain PK model for clinical translation.

Lipid nanocarrier targeting activated macrophages for antiretroviral therapy of HIV reservoir.

Aim: To develop lipid nano-antiretrovirals (LNAs) for the treatment of HIV-infected macrophages. Materials & methods: LNAswere prepared with docosahexaenoic acid to facilitate brain penetration and surface-decorated with folate considering that infected macrophages often overexpress folate receptors. Results: Folate-decorated LNAs loading rilpivirine (RPV) wereefficiently taken up byfolate receptor-expressing cell types including activated macrophages. The intracellular Cmax of theRPV-LNAs in activated macrophages was 2.54-fold and the area under thecurve was3.4-fold versus free RPV, translating to comparable or higher (p<0.01; RPV ≤6.5ng/ml) activities against HIV infectivity and superior protection (p<0.05) against HIV cytotoxicity. LNAs were also effective in monocyte-derived macrophages. Conclusion: These findings demonstratethe potential of LNAs for the treatment of infected macrophages, which are key players in HIV reservoirs.

Synthesis and anti-cancer potential of potent peripheral MAOA inhibitors designed to limit blood:brain penetration

Monoamine oxidases (MAOA/MAOB) are enzymes known for their role in neurotransmitter regulation in the central nervous system (CNS). Irreversible and non-selective MAO inhibitors (MAOi’s) were the first class of antidepressants, thus subsequent work on drugs such as the selective MAOA inhibitor clorgyline has focussed on selectivity and increased CNS penetration. MAOA is highly expressed in high grade and metastatic prostate cancer with a proposed effect on prostate cancer growth, recurrence, and drug resistance. A Phase II Clinical Trial has demonstrated the therapeutic effects of the irreversible nonselective MAOi phenelzine for prostate cancer. However, neurologic adverse effects led to early withdrawal in 25% of the enrolled patient-population. In this work, we revised the clorgyline scaffold with the goal of decreasing CNS penetration to minimize CNS-related side effects while retaining or enhancing MAOA inhibition potency and selectivity. Using the known co-crystal structure of clorgyline bound with FAD co-factor in the hMAOA active site as a reference, we designed and synthesized a series of compounds predicted to have lower CNS penetration (logBB). All synthesized derivatives displayed favorable drug-like characteristics such as predicted Caco-2 permeability and human oral absorption, and exhibited highly selective hMAOA binding interactions. Introduction of an HBD group (NH2 or OH) at position 5 of the phenyl ring clorgyline resulted in 3x more potent hMAOA inhibition with equivalent or better hMAOB selectivity, and similar prostate cancer cell cytotoxicity. In contrast, introduction of larger substituents at this position or at the terminal amine significantly reduced the hMAOA inhibition potency, attributed in part to a steric clash within the binding pocket of the MAOA active site. Replacement of the N-methyl group by a more polar, but larger 2-hydroxyethyl group did not enhance potency. However, introduction of a polar 2-hydroxy in the propyl chain retained the highly selective MAOA inhibition and cancer cell cytotoxicity of clorgyline while reducing its CNS score from 2 to 0. We believe that these results identify a new class of peripherally directed MAOIs that may allow safer therapeutic targeting of MAOA for a variety of anti-cancer and anti-inflammatory indications.

In Silico Discovery and Subsequent Characterization of Potent 4R-Tauopathy Positron Emission Tomography Radiotracers.

A chemical fingerprint search identified Z3777013540 (1-(5-(6-fluoro-1H-indol-2-yl)pyrimidin-2-yl)piperidin-4-ol; 1) as a potential 4R-tau binding ligand. Binding assays in post-mortem Alzheimer's disease (AD), progressive supranuclear palsy (PSP), and corticobasal degeneration (CBD) brain with [3H]1 provided KD (nM) values in AD = 4.0, PSP = 5.1, and CBD = 4.5. In vivo positron emission tomography (PET) imaging in rats with [18F]1 demonstrated good brain penetration and rapid clearance from normal brain tissues. A subsequent molecular similarity search using 1 as the query revealed an additional promising compound, Z4169252340 (4-(5-(6-fluoro-1H-indol-2-yl)pyrimidin-2-yl)morpholine; 21). Binding assays with [3H]21 provided KD (nM) values in AD = 1.2, PSP = 1.6, and CBD = 1.7 and lower affinities for binding aggregated α-synuclein and amyloid-beta. PET imaging in rats with [18F]21 demonstrated a higher brain penetration than [18F]1 and rapid clearance from normal brain tissues. We anticipate that 1 and 21 will be useful for the identification of other potent novel 4R-tau radiotracers.

Discovery of Novel Oleamide Analogues as Brain-Penetrant Positive Allosteric Serotonin 5-HT2C Receptor and Dual 5-HT2C/5-HT2A Receptor Modulators.

The serotonin 5-HT2A receptor (5-HT2AR) and 5-HT2CR localize to the brain and share overlapping signal transduction facets that contribute to their roles in cognition, mood, learning, and memory. Achieving selective targeting of these receptors is challenged by the similarity in their 5-HT orthosteric binding pockets. A fragment-based discovery approach was employed to design and synthesize novel oleamide analogues as selective 5-HT2CR or dual 5-HT2CR/5-HT2AR positive allosteric modulators (PAMs). Compound 13 (JPC0323) exhibited on-target properties, acceptable plasma exposure and brain penetration, as well as negligible displacement to orthosteric sites of ∼50 GPCRs and transporters. Furthermore, compound 13 suppressed novelty-induced locomotor activity in a 5-HT2CR-dependent manner, suggesting 5-HT2CR PAM, but not 5-HT2AR, activity at the level of the whole organism at the employed doses of 13. We discovered new selective 5-HT2CR PAMs and first-in-class 5-HT2CR/5-HT2AR dual PAMs that broaden the pharmacological toolbox to explore the biology of these vital receptors.

Therapeutical Options in ROS1-Rearranged Advanced Non Small Cell Lung Cancer.

ROS proto-oncogene 1 (ROS1) rearrangements occur in 0.9-2.6% of patients with non small cell lung cancer (NSCLC), conferring sensitivity to treatment with specific tyrosine-kinase inhibitors (TKI). Crizotinib, a first-generation TKI, was the first target-therapy approved for the first-line treatment of ROS1-positive NSCLC. Recently, entrectinib, a multitarget inhibitor with an anti-ROS1 activity 40 times more potent than crizotinib and better activity on the central nervous system (CNS), received approval for treatment-naive patients. After a median time-to-progression of 5.5-20 months, resistance mechanisms can occur, leading to tumor progression. Therefore, newer generation TKI with greater potency and brain penetration have been developed and are currently under investigation. This review summarizes the current knowledge on clinicopathological characteristics of ROS1-positive NSCLC and its therapeutic options.

Solubility-Permeability Interplay in Facilitating the Prediction of Drug Disposition Routes, Extent of Absorption, Food Effects, Brain Penetration and Drug Induced Liver Injury Potential

Here I detail the use of measures of permeability rate and solubility in predicting drug disposition characteristics through the utilization of the Biopharmaceutics Drug Disposition Classification System (BDDCS) and the Extended Clearance Classification System (ECCS) as well as the accuracy of the systems in predicting the major route of elimination and the extent of oral absorption of a new small molecule therapeutics. I compare the BDDCS and ECCS with the FDA Biopharmaceutics Classification System (BCS). I also detail the use of the BCS in predicting food effects and the BDDCS in predicting brain disposition of small molecule therapeutics and in validating DILI predictive metrics. This review provides an update of the current status of these classification systems and their uses in the drug development process.

Novel series of tunable µOR modulators with enhanced brain penetration for the treatment of opioid use disorder, pain and neuropsychiatric indications

Structural optimization of a previously reported agonist of µOR, PZM21 is described resulting in the discovery of a novel series of amides with at least 4-folds enhanced CNS penetration in rat. Furthermore, these efforts yielded compounds with varying levels of efficacy on the receptor ranging from high efficacy agonists such as compound 20 to antagonists, such as 24. The correlation between in vitro activation of µOR and relative activity in models of analgesia for these compounds is discussed. The compelling results obtained in these studies demonstrate the potential utility of these newly discovered compounds in the treatment of pain and opioid use disorder.

Population Pharmacokinetic Modeling of Free Plasma and Free Brain Concentrations of Ceftaroline in Healthy and Methicillin-Resistant Staphylococcus aureus-Infected Wistar Rats.

A population pharmacokinetic model was developed to describe alterations in ceftaroline brain disposition caused by meningitis in healthy and methicillin-resistant Staphylococcus aureus (MRSA)-infected rats. Blood and brain microdialysate samples were obtained after a single bolus dose of ceftaroline fosamil (20 mg/kg) administered intravenously. Plasma data were modeled as one compartment, and brain data were added to the model as a second compartment, with bidirectional drug transport between plasma and brain (Qin and Qout). The cardiac output (CO) of the animals showed a significant correlation with the relative recovery (RR) of plasma microdialysis probes, with animals with greater CO presenting lower RR values. The Qin was approximately 60% higher in infected animals, leading to greater brain exposure to ceftaroline. Ceftaroline brain penetration was influenced by MRSA infection, increasing from 17% (Qin/Qout) in healthy animals to 27% in infected animals. Simulations of a 2-h intravenous infusion of 50 mg/kg every 8 h achieved >90% probability of target attainment (PTA) in plasma and brain for the modal MRSA MIC (0.25 mg/L), suggesting that the drug should be considered an option for treating central nervous system infections.

Efficacy of lazertinib for symptomatic or asymptomatic brain metastases in treatment-naive patients with advanced EGFR mutation-positive non-small cell lung cancer: Protocol of an open-label, single-arm phase II trial.

Non-small cell lung cancer (NSCLC) with epidermal growth factor receptor (EGFR) mutation has a higher incidence of brain metastases than wild-type EGFR mutations. Osimertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), targets both EGFR-TKI sensitizing and T790M-resistance mutations and has a higher brain penetration rate relative to first- and second-generation EGFR-TKIs. Therefore, osimertinib has become a preferred first-line therapy for advanced EGFR mutation-positive NSCLC. However, lazertinib, an emerging EGFR-TKI, has shown higher selectivity toward EGFR mutations and improved penetration of the blood-brain barrier compared to osimertinib in preclinical studies. This trial will evaluate the efficacy of lazertinib as a first-line therapy in patients with EGFR mutation-positive NSCLC who have brain metastases, with or without additional local therapy. This is a single-center, open-label, single-arm phase II trial. A total of 75 patients with advanced EGFR mutation-positive NSCLC will be recruited. Eligible patients will receive oral lazertinib 240 mg, once daily until disease progression or intolerable toxicity is detected. Patients with moderate to severe symptoms related to brain metastasis will simultaneously receive local therapy for the brain. The primary endpoints are progression-free survival and intracranial progression-free survival. Lazertinib, in combination with local therapy for the brain, if necessary, is expected to improve the clinical benefit in advanced EGFR mutation-positive NSCLC with brain metastases, as a first-line treatment.

Modeling and Simulation as a Tool to Assess Voriconazole Exposure in the Central Nervous System.

Voriconazole is a triazole antifungal used empirically for the treatment of complicated meningitis associated with Cryptococcus neoformans. Biopsy studies show that the drug exhibits adequate brain penetration although levels of cerebral spinal fluid (CSF) are highly variable. Considering that CSF is one of the main surrogates for CNS exposure, the present work proposed the building of a population pharmacokinetic modeling (popPK) model able to describing the exposure achieved by voriconazole in the plasma, interstitial cerebral fluid and CSF of healthy and infected rats. The developed popPK model was described by four compartments, including total plasma, free brain and total CSF concentrations. The following PK parameters were determined: Km = 4.76 mg/L, Vmax = 1.06 mg/h, Q1 = 2.69 L, Qin = 0.81 h-1 and Qout = 0.63 h-1. Infection was a covariate in the Michaelis-Menten constant (Km) and intercompartmental clearance from the brain tissue compartment to central compartment (Qout). Simulations performed with the popPK model to determine the probability of reaching the therapeutic target of fAUC > MIC showed that VRC has sufficient tissue exposure in the interstitial fluid and in the CSF for the treatment of fungal infections in these tissues at prevalent minimum inhibitory concentrations.

P-glycoprotein (MDR1/ABCB1) Restricts Brain Penetration of the Main Active Heroin Metabolites 6-monoacetylmorphine (6-MAM) and Morphine in Mice.

Heroin (diacetylmorphine; diamorphine) is a highly addictive opioid prodrug. Heroin prescription is possible in some countries for chronic, treatment-refractory opioid-dependent patients and as a potent analgesic for specific indications. We aimed to study the pharmacokinetic interactions of heroin and its main pharmacodynamically active metabolites, 6-monoacetylmorphine (6-MAM) and morphine, with the multidrug efflux transporters P-glycoprotein/ABCB1 and BCRP/ABCG2 using wild-type, Abcb1a/1b and Abcb1a/1b;Abcg2 knockout mice. Upon subcutaneous (s.c.) heroin administration, its blood levels decreased quickly, making it challenging to detect heroin even shortly after dosing. 6-MAM was the predominant active metabolite present in blood and most tissues. At 10 and 30min after heroin administration, 6-MAM and morphine brain accumulation were increased about 2-fold when mouse (m)Abcb1a/1b and mAbcg2 were ablated. Fifteen minutes after direct s.c. administration of an equimolar dose of 6-MAM, we observed good intrinsic brain penetration of 6-MAM in wild-type mice. Still, mAbcb1 limited brain accumulation of 6-MAM and morphine without affecting their blood exposure, and possibly mediated their direct intestinal excretion. A minor contribution of mAbcg2 to these effects could not be excluded. We show that mAbcb1a/1b can limit 6-MAM and morphine brain exposure. Pharmacodynamic behavioral/postural observations, while non-quantitative, supported moderately increased brain levels of 6-MAM and morphine in the knockout mouse strains. Variation in ABCB1 activity due to genetic polymorphisms or environmental factors (e.g., drug interactions) might affect 6-MAM/morphine exposure in individuals, but only to a limited extent.

MDB-38. COMPUTATIONAL DRUG SENSITIVITY PREDICTS MEDULLOBLASTOMA SUBGROUP-SPECIFIC THERAPEUTICS

Abstract Medulloblastoma is the most common malignant pediatric brain tumor. Tumors are typically characterized as Group 3, Group 4, SHH, or WNT. Current standard-of-care includes surgery, radiation, and chemotherapy; however, treatment response and prognosis vary widely between subgroups. Additionally, surviving children frequently suffer from lifelong neurocognitive deficits. Therefore, novel therapeutic options are urgently needed. Despite extensive characterization of medulloblastoma tumors into four molecular subgroups, few subgroup specific therapies have advanced to the clinic. To address this, we have developed a novel platform called DrugSeq, which predicts drug sensitivities in patients and can stratify tumors by subgroup. DrugSeq also identifies key pharmacotranscriptomic differences between primary and recurrent tumors. We first calculated disease signatures for each patient by normalizing gene expression to low grade glioma samples from the posterior fossa. Using previously developed transcriptional consensus signatures (TCSs) that represent the affect that a drug has on the gene expression across a panel of cancer cell lines, we then calculated the discordance between each patient disease signature and drug TCS. Finally, using an ANOVA analysis we identified drugs which are predicted to differentially target each medulloblastoma subgroup. Among our top predicted anti-cancer compounds we found several kinase inhibitors, bromodomain inhibitors, and several psychiatric drugs with known brain penetrance. Additionally, we show distinct differences in drug sensitivity predictions between newly diagnosed and recurrent tumors, such as sensitivity to BET inhibition for recurrent Group 3 and Group 4 tumors despite no predicted sensitivity in the newly diagnosed tumors. Future studies with larger datasets may be able to further subdivide patients by age or molecular features within subgroups. Collectively, we show that DrugSeq may identify novel therapies and facilitate patient stratification in clinical trials, leading to more successful targeted medulloblastoma therapies.

Design, Radiosynthesis, and Evaluation of New Fluorinated Analogs of MeDAS for Myelin PET Imaging.

Positron emission tomography (PET) imaging of the myelin sheath is a powerful tool to investigate multiple sclerosis, monitor its evolution, and support drug development. Radiotracers based on N,N-dimethylaminostilbene (MeDAS) fluorinated analogs have been designed for myelin PET imaging but were never translated to humans. We have synthesized three original fluorinated analogs of MeDAS with low metabolic rates for which binding to myelin in a healthy rat brain was demonstrated by fluorescence microscopy. A tosyl precursor was synthesized for the lead compound PEGMeDAS and automated fluorine-18 radiolabeling afforded [18F]PEGMeDAS in 25 ± 5% radiochemical yield and 102 ± 15 GBq/μmol molar activity. Biodistribution in healthy rats demonstrated the brain penetration with low penetration of radiometabolites. However, E to Z isomerization observed in plasma hampers further investigations of this family of molecules and requires complementary data on the in vivo behavior of the Z isomer.

Discovery of Dimethyl Shikonin Oxime 5a, a Potent, Selective Bombesin Receptor Subtype-3 Agonist for the Treatment of Type 2 Diabetes Mellitus.

Bombesin receptor subtype-3 (BB3, BRS-3) is an orphan Gαq protein-coupled receptor. The characterization of novel synthetic ligands for BB3 is an alternative and attractive strategy to study its diverse physiological functions. Here, we uncovered the intimate pairing of DMAKO-00 and its derivatives with BB3. Dimethyl shikonin oxime 5a (DSO-5a) was identified as the most potent agonist for BB3 (pEC50 = 8.422 in IP-1 accumulation), which was 898-fold more potent than DMAKO-00. Importantly, without brain penetration, DSO-5a improved glucose tolerance in C57BL/6 mice through BB3 and ameliorated glucose homeostasis in diabetic db/db mice. We further revealed that DSO-5a upregulated PPAR-gamma activity via BB3 through a quantitative proteomics approach. Collectively, our study demonstrated that DSO-5a, a representative compound of DMAKO-00 derivatives, is a potent, selective, and low-brain-penetrating agonist for BB3, and BB3 is a promising treatment target for type 2 diabetes mellitus.

C-Abl tyrosine kinase down-regulation as target for memory improvement in Alzheimer's disease.

Growing evidence suggests that the non-receptor tyrosine kinase, c-Abl, plays a significant role in the pathogenesis of Alzheimer's disease (AD). Here, we analyzed the effect of c-Abl on the cognitive performance decline of APPSwe/PSEN1ΔE9 (APP/PS1) mouse model for AD. We used the conditional genetic ablation of c-Abl in the brain (c-Abl-KO) and pharmacological treatment with neurotinib, a novel allosteric c-Abl inhibitor with high brain penetrance, imbued in rodent's chow. We found that APP/PS1/c-Abl-KO mice and APP/PS1 neurotinib-fed mice had improved performance in hippocampus-dependent tasks. In the object location and Barnes-maze tests, they recognized the displaced object and learned the location of the escape hole faster than APP/PS1 mice. Also, APP/PS1 neurotinib-fed mice required fewer trials to reach the learning criterion in the memory flexibility test. Accordingly, c-Abl absence and inhibition caused fewer amyloid plaques, reduced astrogliosis, and preserved neurons in the hippocampus. Our results further validate c-Abl as a target for AD, and the neurotinib, a novel c-Abl inhibitor, as a suitable preclinical candidate for AD therapies.