Type II & III inhibitors of tropomyosin receptor kinase (Trk): a 2020-2022 patent update.

INTRODUCTION: The Trk family proteins are membrane-bound kinases predominantly expressed in neuronal tissues. Activated by neurotrophins, they regulate critical cellular processes through downstream signaling pathways. Dysregulation of Trk signaling can drive a range of diseases, making the design and study of Trk inhibitors a vital area of research. This review explores recent advances in the development of type II and III Trk inhibitors, with implications for various therapeutic applications. AREAS COVERED: Patents covering type II and III inhibitors targeting the Trk family are discussed as a complement of the previous review, Type I inhibitors of tropomyosin receptor kinase (Trk): a 2020-2022 patent update. Relevant patents were identified using the Web of Science database, Google, and Google Patents. EXPERT OPINION: While type II and III Trk inhibitor development has advanced more gradually compared to their type I counterparts, they hold significant promise in overcoming resistance mutations and achieving enhanced subtype selectivity - a critical factor in reducing adverse effects associated with pan-Trk inhibition. Recent interdisciplinary endeavors have marked substantial progress in the design of subtype selective Trk inhibitors, with impressive success heralded by the type III inhibitors. Notably, the emergence of mutant-selective Trk inhibitors introduces an intriguing dimension to the field, offering precise treatment possibilities.

Dosimetry of [18F]TRACK, the first PET tracer for imaging of TrkB/C receptors in humans.

BACKGROUND: Reduced expression or impaired signalling of tropomyosin receptor kinases (Trk receptors) are found in a vast spectrum of CNS disorders. [18F]TRACK is the first PET radioligand for TrkB/C with proven in vivo brain penetration and on-target specific signal. Here we report dosimetry data for [18F]TRACK in healthy humans. 6 healthy participants (age 22-61 y, 3 female) were scanned on a General Electric Discovery PET/CT 690 scanner. [18F]TRACK was synthesized with high molar activities (Am = 250 ± 75 GBq/µmol), and a dynamic series of 12 whole-body scans were acquired after injection of 129 to 147 MBq of the tracer. Images were reconstructed with standard corrections using the manufacturer's OSEM algorithm. Tracer concentration time-activity curves (TACs) were obtained using CT-derived volumes-of-interest. Organ-specific doses and the total effective dose were estimated using the Committee on Medical Internal Radiation Dose equation for adults and tabulated Source tissue values (S values). RESULTS: Average organ absorbed dose was highest for liver and gall bladder with 6.1E-2 (± 1.06E-2) mGy/MBq and 4.6 (± 1.18E-2) mGy/MBq, respectively. Total detriment weighted effective dose EDW was 1.63E-2 ± 1.68E-3 mSv/MBq. Organ-specific TACs indicated predominantly hepatic tracer elimination. CONCLUSION: Total and organ-specific effective doses for [18F]TRACK are low and the dosimetry profile is similar to other 18F-labelled radio tracers currently used in clinical settings.

CycloSiFA: The Next Generation of Silicon-Based Fluoride Acceptors for Positron Emission Tomography (PET).

The ring-opening Si-fluorination of a variety of azasilole derivatives cyclo-1-(iPr2 Si)-4-X-C6 H3 -2-CH2 NR (4: R=2,6-iPr2 C6 H3 , X=H; 4 a: R=2,4,6-Me3 C6 H2 , X=H; 9: R=2,6-iPr2 C6 H3 , X=tBuMe2 SiO; 10: R=2,6-iPr2 C6 H3 , X=OH; 13: R=2,6-iPr2 C6 H3 , X=HCCCH2 O; 22: R=2,6-iPr2 C6 H3 , X=tBuMe2 SiCH2 O) with different 19 F-fluoride sources was studied, optimized and the experience gained was used in a translational approach to create a straightforward 18 F-labelling protocol for the azasilole derivatives [18 F]6 and [18 F]14. The latter constitutes a potential clickable CycloSiFA prosthetic group which might be used in PET tracer development using Cu-catalysed triazole formation. Based on our findings, CycloSiFA has the potential to become a new entry into non-canonical labelling methodologies for radioactive PET tracer development.

Type I inhibitors of tropomyosin receptor kinase (Trk): a 2020-2022 patent update.

INTRODUCTION: Trk inhibitors are significant in the realm of personalized medicine as they target specific genetic alterations, such as NTRK gene fusions, leading to improved treatment outcomes for cancer patients. By tailoring the treatment to the genetic characteristics of the tumor rather than the tumor type, Trk inhibitors offer the potential for more effective and precise therapies, resulting in enhanced response rates and prolonged survival for patients with NTRK fusion-positive cancers. AREAS COVERED: Patents covering type I inhibitors targeting the Trk family are discussed, building upon our prior review series on Trk inhibitors. Relevant patents were identified through the Web of Science database, Google, and Google Patents. EXPERT OPINION: The field of Trk inhibitors has evolved significantly, as reflected in the current patent literature, which emphasizes the selective structural refinement of clinical champions. Efforts now concentrate on enhancing efficacy against on-target resistance mechanisms, with modifications made to improve potency, reduce toxicity, and enhance pharmacokinetics. Combination therapies show potential to address off-target resistance mechanisms and improve treatment outcomes. Challenges remain in accurately diagnosing NTRK gene alterations and integrating screening into routine clinical practice. Trk inhibitors have surpassed their conventional role of inhibition and are now seeing new applications in radiopharmaceutical development and as molecular targeting agents.

Recent Advances in the Clinical Translation of Silicon Fluoride Acceptor (SiFA) 18F-Radiopharmaceuticals.

The incorporation of silicon fluoride acceptor (SiFA) moieties into a variety of molecules, such as peptides, proteins and biologically relevant small molecules, has improved the generation of 18F-radiopharmaceuticals for medical imaging. The efficient isotopic exchange radiofluorination process, in combination with the enhanced [18F]SiFA in vivo stability, make it a suitable strategy for fluorine-18 incorporation. This review will highlight the clinical applicability of [18F]SiFA-labeled compounds and discuss the significant radiotracers currently in clinical use.

Tropomyosin receptor kinase inhibitors: an updated patent review for 2016-2019.

Introduction: Tropomyosin receptor kinases (Trks) control processes in the fields of growth, survival, and differentiation of neuronal processes. They also play a crucial role in neurodegenerative diseases as well as different types of cancer. Interest in developing Trk inhibitors to target NTRK fusion-driven cancers has escalated in the last decade, leading to the FDA approval of the pan-Trk inhibitors entrectinib and larotrectinib. The development of next-generation inhibitors that overcome resistance mutations arising from treatment with these first generation inhibitors has been the focus in recent years.Area covered: In this updated patent review for 2016-2019, patents covering inhibitors targeting the Trk family are discussed as a continuation of the previous reviews, Tropomyosin receptor kinase inhibitors: an updated patent review for 2010-2016 - Parts 1 & 2. The status of Trk inhibitors in clinical trials is also evaluated. For the identification of relevant patents and clinical trials, Web of Science, Google, Google Patents, and patent referencing were used.Expert opinion: The FDA approval of larotrectinib and entrectinib is a prime example of how basket clinical trial design targeting oncogenic drivers, regardless of tumor histology, is a viable approach to drug discovery and embodies the shift toward personalized medicine.