Enhancing Drug Discovery and Development through the Integration of Medicinal Chemistry, Chemical Biology, and Academia-Industry Partnerships: Insights from Roche's Endocannabinoid System Projects.

The endocannabinoid system (ECS) is a critical regulatory network composed of endogenous cannabinoids (eCBs), their synthesizing and degrading enzymes, and associated receptors. It is integral to maintaining homeostasis and orchestrating key functions within the central nervous and immune systems. Given its therapeutic significance, we have launched a series of drug discovery endeavors aimed at ECS targets, including peroxisome proliferator-activated receptors (PPARs), cannabinoid receptors types 1 (CB1R) and 2 (CB2R), and monoacylglycerol lipase (MAGL), addressing a wide array of medical needs.

Development of radiofluorinated MLN-4760 derivatives for PET imaging of the SARS-CoV-2 entry receptor ACE2.

Purpose: The angiotensin converting enzyme 2 (ACE2) plays a regulatory role in the cardiovascular system and serves SARS-CoV-2 as an entry receptor. The aim of this study was to synthesize and evaluate radiofluorinated derivatives of the ACE2 inhibitor MLN-4760. [F]F-MLN-4760 and [F]F-Aza-MLN-4760 were demonstrated to be suitable for non-invasive imaging of ACE2, potentially enabling a better understanding of its expression dynamics.

Comparison of the tolerability of Tb- and Lu-labeled somatostatin analogues in the preclinical setting.

Purpose: [Lu]Lu-DOTATATE is an established somatostatin receptor (SSTR) agonist for the treatment of metastasized neuroendocrine neoplasms, while the SSTR antagonist [Lu]Lu-DOTA-LM3 has only scarcely been employed in clinics. Impressive preclinical data obtained with [Tb]Tb-DOTA-LM3 in tumor-bearing mice indicated the potential of terbium-161 as an alternative to lutetium-177. The aim of the present study was to compare the tolerability of Tb- and Lu-based DOTA-LM3 and DOTATATE in immunocompetent mice.

Design and Preclinical Evaluation of a Novel Prostate-Specific Membrane Antigen Radioligand Modified with a Transthyretin Binder.

Transthyretin binders have previously been used to improve the pharmacokinetic properties of small-molecule drug conjugates and could, thus, be utilized for radiopharmaceuticals as an alternative to the widely explored "albumin binder concept". In this study, a novel PSMA ligand modified with a transthyretin-binding entity (TB-01) was synthesized and labeled with lutetium-177 to obtain [Lu]Lu-PSMA-TB-01. A high and specific uptake of [Lu]Lu-PSMA-TB-01 was found in PSMA-positive PC-3 PIP cells (69 ± 3% after 4 h incubation), while uptake in PSMA-negative PC-3 flu cells was negligible (<1%).

Towards the Magic Radioactive Bullet: Improving Targeted Radionuclide Therapy by Reducing the Renal Retention of Radioligands.

Targeted radionuclide therapy (TRT) is an emerging field and has the potential to become a major pillar in effective cancer treatment. Several pharmaceuticals are already in routine use for treating cancer, and there is still a high potential for new compounds for this application. But, a major issue for many radiolabeled low-to-moderate-molecular-weight molecules is their clearance via the kidneys and their subsequent reuptake.

Relaxed fibronectin: a potential novel target for imaging endometriotic lesions.

Background: Endometriosis is characterized by the ectopic occurrence of endometrial tissue. Though considered benign, endometriotic lesions possess tumor-like properties such as tissue invasion and remodeling of the extracellular matrix. One major clinical hurdle concerning endometriosis is its diagnosis.

Terbium-149 production: a focus on yield and quality improvement towards preclinical application.

Terbium-149 (T = 4.1 h, E = 3.98 MeV (16.

Brain cholesterol and Alzheimer's disease: challenges and opportunities in probe and drug development.

Cholesterol homeostasis is impaired in Alzheimer's disease; however, attempts to modulate brain cholesterol biology have not translated into tangible clinical benefits for patients to date. Several recent milestone developments have substantially improved our understanding of how excess neuronal cholesterol contributes to the pathophysiology of Alzheimer's disease. Indeed, neuronal cholesterol was linked to the formation of amyloid-β and neurofibrillary tangles through molecular pathways that were recently delineated in mechanistic studies.

Preclinical Evaluation of Gastrin-Releasing Peptide Receptor Antagonists Labeled with Tb and Lu: A Comparative Study.

To elucidate potential benefits of the Auger-electron-emitting radionuclide Tb, we compared the preclinical performance of the gastrin-releasing peptide receptor antagonists RM2 (DOTA-Pip-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH) and AMTG (α-Me-Trp-RM2), each labeled with both Lu and Tb. Tb/Lu labeling (90°C, 5 min) and cell-based experiments (PC-3 cells) were performed. In vivo stability (30 min after injection) and biodistribution studies (1-72 h after injection) were performed on PC-3 tumor-bearing CB17-SCID mice.

Prostate-Specific Membrane Antigen-Targeted Therapies for Prostate Cancer: Towards Improving Therapeutic Outcomes.

Context: Prostate-specific membrane antigen (PSMA) is a transmembrane glycoprotein overexpressed in most prostate cancers and exploited as a target for PSMA-targeted therapies. Different approaches to target PSMA-expressing cancer cells have been developed, showing promising results in clinical trials.

Objective: To discuss the regulation of PSMA expression and the main PSMA-targeted therapeutic concepts illustrating their clinical development and rationalizing combination approaches with examples.

Matrix Metalloproteinase-Responsive Delivery of PEGylated Fibroblast Growth Factor 2.

Attachment of polyethylene glycol (PEG) chains is a common, well-studied, and Food and Drug Administration-approved method to address the pharmacokinetic challenges of therapeutic proteins. Occasionally, PEGylation impairs the activity of pharmacodynamics (PD). To overcome this problem, disease-relevant cleavable linkers between the polymer and the therapeutic protein can unleash full PD by de-PEGylating the protein at its target site.

Synthesis and Biological Evaluation of Enantiomerically Pure () and ()[18F]OF-NB1 for Imaging the GluN2B Subunit-Containing NMDA Receptors.

GluN2B subunit-containing methyl-d-aspartate (NMDA) receptors have been implicated in various neurological disorders. Nonetheless, a validated fluorine-18 labeled positron emission tomography (PET) ligand for GluN2B imaging in the living human brain is currently lacking. The aim of this study was to develop a novel synthetic approach that allows an enantiomerically pure radiosynthesis of the previously reported PET radioligands ()[F]OF-NB1 and ()[F]OF-NB1 as well as to assess their and performance characteristics for imaging the GluN2B subunit-containing NMDA receptor in rodents.

Evaluation of [F]RoSMA-18-d as a CB2 PET Radioligand in Nonhuman Primates.

The cannabinoid type 2 receptor (CB2) has been implicated in a variety of central and peripheral inflammatory diseases, prompting significant interest in the development of CB2-targeted diagnostic and therapeutic agents. A validated positron emission tomography (PET) radioligand for imaging CB2 in the living human brain as well as in peripheral tissues is currently lacking. As part of our research program, we have recently identified the trisubstituted pyridine, [F]RoSMA-18-d, which proved to be highly suitable for and mapping of CB2 in rodents.

Investigations Using Albumin Binders to Modify the Tissue Distribution Profile of Radiopharmaceuticals Exemplified with Folate Radioconjugates.

Introducing an albumin-binding entity into otherwise short-lived radiopharmaceuticals can be an effective means to improve their pharmacokinetic properties due to enhanced blood residence time. In the current study, DOTA-derivatized albumin binders based on 4-(-iodophenyl)butanoate (DOTA-ALB-1 and DOTA-ALB-3) and 5-(-iodophenyl)pentanoate entities (DOTA-ALB-24 and DOTA-ALB-25) without and with a hydrophobic 4-(aminomethyl)benzoic acid (AMBA) linker unit, respectively, were synthesized and labeled with lutetium-177 for in vitro and in vivo comparison. Overall, [Lu]Lu-DOTA-ALB-1 demonstrated ~3-fold stronger in vitro albumin-binding affinity and a longer blood residence time (T ~8 h) than [Lu]Lu-DOTA-ALB-24 (T ~0.

Imaging increased metabolism in the spinal cord in mice after middle cerebral artery occlusion.

Emerging evidence indicates crosstalk between the brain and hematopoietic system following cerebral ischemia. Here, we investigated metabolism and oxygenation in the spleen and spinal cord in a transient middle cerebral artery occlusion (tMCAO) model. Sham-operated and tMCAO mice underwent [F]fluorodeoxyglucose (FDG)-positron emission tomography (PET) to assess glucose metabolism.

Albumin-Binding and Conventional PSMA Ligands in Combination with Tb: Biodistribution, Dosimetry, and Preclinical Therapy.

The favorable decay characteristics of Tb attracted the interest of clinicians in using this novel radionuclide for radioligand therapy (RLT). Tb decays with a similar half-life to Lu, but beyond the emission of β-particles and γ-rays, Tb also emits conversion and Auger electrons, which may be particularly effective to eliminate micrometastases. The aim of this study was to compare the dosimetry and therapeutic efficacy of Tb and Lu in tumor-bearing mice using SibuDAB and PSMA-I&T, which differ in their blood residence time and tumor uptake.

Synthesis and Biological Evaluation of Enantiomerically Pure ()- and ()-[F]OF-NB1 for Imaging the GluN2B Subunit-Containing NMDA receptors.

GluN2B subunit-containing -methyl-d-aspartate (NMDA) receptors have been implicated in various neurological disorders. Nonetheless, a validated fluorine-18 labeled positron emission tomography (PET) ligand for GluN2B imaging in the living human brain is currently lacking. As part of our PET ligand development program, we have recently reported on the preclinical evaluation of [F]OF-NB1 - a GluN2B PET ligand with promising attributes for potential clinical translation.

Determination of the half-life of gadolinium-148.

The half-life of the alpha-emitter Gd was measured using the "direct method", in which the number of atoms is directly determined and their activity is then measured. Pure Gd samples containing megabecquerels of Gd were obtained by reprocessing proton-irradiated tantalum material. Multicollector-inductively coupled plasma mass spectrometry was performed to determine the amount of Gd atoms retrieved.

New TMA (4,6,4'-Trimethyl angelicin) Analogues as Anti-Inflammatory Agents in the Treatment of Cystic Fibrosis Lung Disease.

A series of new-generation TMA (4,6,4'-trimethyl angelicin) analogues was projected and synthetized in order to ameliorate anti-inflammatory activity, with reduced or absent toxicity. Since the NF-κB transcription factor (TF) plays a critical role in the expression of IL-8 (Interluekin 8), a typical marker of lung inflammation in Cystic Fibrosis (CF), the use of agents able to interfere with the NF-κB pathway represents an interesting therapeutic strategy. Through preliminary EMSA experiments, we identified several new TMA derivatives able to inhibit the NF-κB/DNA complex.

[Ac]Ac-SibuDAB for Targeted Alpha Therapy of Prostate Cancer: Preclinical Evaluation and Comparison with [Ac]Ac-PSMA-617.

In the present study, SibuDAB, an albumin-binding PSMA ligand, was investigated in combination with actinium-225 and the data were compared with those of [Ac]Ac-PSMA-617. In vitro, [Ac]Ac-SibuDAB and [Ac]Ac-PSMA-617 showed similar tumor cell uptake and PSMA-binding affinities as their Lu-labeled counterparts. The in vitro binding to serum albumin in mouse and human blood plasma, respectively, was 2.

Targeting virulence regulation to disarm pathogenesis.

The development of anti-virulence drug therapy against infections would provide an alternative to traditional antibacterial therapy that are increasingly failing. Here, we demonstrate that the OmpR transcriptional regulator plays a pivotal role in the pathogenesis of diverse clinical strains in multiple murine and invertebrate infection models. We identified OmpR-regulated genes using RNA sequencing and further validated two genes whose expression can be used as robust biomarker to quantify OmpR inhibition in .

Improved Trimethylangelicin Analogs for Cystic Fibrosis: Design, Synthesis and Preliminary Screening.

A small library of new angelicin derivatives was designed and synthesized with the aim of bypassing the side effects of trimethylangelicin (TMA), a promising agent for the treatment of cystic fibrosis. To prevent photoreactions with DNA, hindered substituents were inserted at the 4 and/or 6 positions. Unlike the parent TMA, none of the new derivatives exhibited significant cytotoxicity or mutagenic effects.

Half-life measurement of Sc and Sc.

The half-lives of Sc and Sc were measured by following their decay rate using several measurement systems: two ionization chambers and three γ-spectrometry detectors with digital and/or analogue electronics. For Sc, the result was the combination of seven half-life values giving a result of 4.042(7) h, which agrees with the last reported value of 4.