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PD-1/PD-L1 immune checkpoint blockade for cancer therapy showed promising results in clinical studies. Further endeavors are required to enhance patient stratification, as, at present, only a small portion of patients with PD-L1-positive tumors (as determined by PD-L1 targeted immunohistochemistry; IHC) benefit from anti-PD-1/PD-L1 immunotherapy. This can be explained by the heterogeneity of tumor lesions and the intrinsic limitation of multiple biopsies. Consequently, non-invasive in vivo quantification of PD-L1 on tumors and metastases throughout the entire body using positron emission tomography (PET) imaging holds the potential to augment patient stratification. Within the scope of this work, six new small molecules were synthesized by following a ligand-based drug design approach supported by computational docking utilizing lead structures based on the (2-methyl-[1,1′-biphenyl]-3-yl)methanol scaffold and evaluated in vitro for potential future use as PD-L1 PET tracers. The results demonstrated binding affinities in the nanomolar to micromolar range for lead structures and newly prepared molecules, respectively. Carbon-11 labeling was successfully and selectively established and optimized with very good radiochemical conversions of up to 57%. The obtained insights into the significance of polar intermolecular interactions, along with the successful radiosyntheses, could contribute substantially to the future development of small-molecule PD-L1 PET tracers. [ABSTRACT FROM AUTHOR]

PD-1/PD-L1 immune checkpoint blockade for cancer therapy showed promising results in clinical studies. Further endeavors are required to enhance patient stratification, as, at present, only a small portion of patients with PD-L1-positive tumors (as determined by PD-L1 targeted immunohistochemistry; IHC) benefit from anti-PD-1/PD-L1 immunotherapy. This can be explained by the heterogeneity of tumor lesions and the intrinsic limitation of multiple biopsies. Consequently, non-invasive in vivo quantification of PD-L1 on tumors and metastases throughout the entire body using positron emission tomography (PET) imaging holds the potential to augment patient stratification. Within the scope of this work, six new small molecules were synthesized by following a ligand-based drug design approach supported by computational docking utilizing lead structures based on the (2-methyl-[1,1′-biphenyl]-3-yl)methanol scaffold and evaluated in vitro for potential future use as PD-L1 PET tracers. The results demonstrated binding affinities in the nanomolar to micromolar range for lead structures and newly prepared molecules, respectively. Carbon-11 labeling was successfully and selectively established and optimized with very good radiochemical conversions of up to 57%. The obtained insights into the significance of polar intermolecular interactions, along with the successful radiosyntheses, could contribute substantially to the future development of small-molecule PD-L1 PET tracers.

Positron emission tomography (PET) is a highly sensitive and versatile molecular imaging modality that leverages radiolabeled molecules, known as radiotracers, to interrogate biochemical processes such as metabolism, enzymatic activity, and receptor expression. The ability to probe specific molecular and cellular events longitudinally in a noninvasive manner makes PET imaging a particularly powerful technique for studying the central nervous system (CNS) in both health and disease. Unfortunately, developing and translating a single CNS PET tracer for clinical use is typically an extremely resource-intensive endeavor, often requiring synthesis and evaluation of numerous candidate molecules. While existing in vitro methods are beginning to address the challenge of derisking molecules prior to costly in vivo PET studies, most require a significant investment of resources and possess substantial limitations. In the context of CNS drug development, significant time and resources have been invested into the development and optimization of computational methods, particularly involving machine learning, to streamline the design of better CNS therapeutics. However, analogous efforts developed and validated for CNS radiotracer design are conspicuously limited. In this Perspective, we overview the requirements and challenges of CNS PET tracer design, survey the most promising computational methods for in silico CNS drug design, and bridge these two areas by discussing the potential applications and impact of computational design tools in CNS radiotracer design.

The military conflicts of the last decade have highlighted the growing problem of traumatic brain injury in combatants returning from the battlefield. The considerable evidence pointing at the accumulation of tau aggregates and its recognition as a risk factor in neurodegenerative conditions such as Alzheimer's disease have led to a major effort to develop selective tau ligands that would allow research into the physiopathologic underpinnings of traumatic brain injury and chronic traumatic encephalopathy in military personnel and the civilian population. These tracers will allow new insights into tau pathology in the human brain, facilitating research into causes, diagnosis, and treatment of traumatic encephalopathy and major neurodegenerative dementias, such as Alzheimer's disease and some variants of frontotemporal lobar degeneration, in which tau plays a role. The field of selective tau imaging has to overcome several obstacles, some of them associated with the idiosyncrasies of tau aggregation and others related to radiotracer design. A worldwide effort has focused on the development of imaging agents that will allow selective tau imaging in vivo. Recent progress in the development of these tracers is enabling the noninvasive assessment of the extent of tau pathology in the brain, eventually allowing the quantification of changes in tau pathology over time and its relation to cognitive performance, brain volumetrics, and other biomarkers, as well as assessment of efficacy and patient recruitment for antitau therapeutic trials. [ABSTRACT FROM AUTHOR]

The military conflicts of the last decade have highlighted the growing problem of traumatic brain injury in combatants returning from the battlefield. The considerable evidence pointing at the accumulation of tau aggregates and its recognition as a risk factor in neurodegenerative conditions such as Alzheimer's disease have led to a major effort to develop selective tau ligands that would allow research into the physiopathologic underpinnings of traumatic brain injury and chronic traumatic encephalopathy in military personnel and the civilian population. These tracers will allow new insights into tau pathology in the human brain, facilitating research into causes, diagnosis, and treatment of traumatic encephalopathy and major neurodegenerative dementias, such as Alzheimer's disease and some variants of frontotemporal lobar degeneration, in which tau plays a role. The field of selective tau imaging has to overcome several obstacles, some of them associated with the idiosyncrasies of tau aggregation and others related to radiotracer design. A worldwide effort has focused on the development of imaging agents that will allow selective tau imaging in vivo. Recent progress in the development of these tracers is enabling the noninvasive assessment of the extent of tau pathology in the brain, eventually allowing the quantification of changes in tau pathology over time and its relation to cognitive performance, brain volumetrics, and other biomarkers, as well as assessment of efficacy and patient recruitment for antitau therapeutic trials., (Copyright © 2014 The Alzheimer's Association. Published by Elsevier Inc. All rights reserved.)