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Peptides that are composed of dextrorotary (d)-amino acids have gained increasing attention as a potential therapeutic class. However, our understanding of the in vivo fate of d -peptides is limited. This highlights the need for whole-body, quantitative tracking of d -peptides to better understand how they interact with the living body. Here, we used mouse models to track the movement of a programmed death-ligand 1 (PD-L1)-targeting d -dodecapeptide antagonist (DPA) using positron emission tomography (PET). More specifically, we profiled the metabolic routes of [64Cu]DPA and investigated the tumor engagement of [64Cu/68Ga]DPA in mouse models. Our results revealed that intact [64Cu/68Ga]DPA was primarily eliminated by the kidneys and had a notable accumulation in tumors. Moreover, a single dose of [64Cu]DPA effectively delayed tumor growth and improved the survival of mice. Collectively, these results not only deepen our knowledge of the in vivo fate of d -peptides, but also underscore the utility of d -peptides as radiopharmaceuticals. The in vivo fate and target engagement of a PD-L1 binding D-peptide, DPA, were comprehensively tracked by PET imaging, revealing that DPA is a superior targeting vehicle for radiotheranostic agents. [Display omitted] [ABSTRACT FROM AUTHOR]

As a serine hydrolase, monoacylglycerol lipase (MAGL) is principally responsible for the metabolism of 2-arachidonoylglycerol (2-AG) in the central nervous system (CNS), leading to the formation of arachidonic acid (AA). Dysfunction of MAGL has been associated with multiple CNS disorders and symptoms, including neuroinflammation, cognitive impairment, epileptogenesis, nociception and neurodegenerative diseases. Inhibition of MAGL provides a promising therapeutic direction for the treatment of these conditions, and a MAGL positron emission tomography (PET) probe would greatly facilitate preclinical and clinical development of MAGL inhibitors. Herein, we design and synthesize a small library of fluoropyridyl-containing MAGL inhibitor candidates. Pharmacological evaluation of these candidates by activity-based protein profiling identified 14 as a lead compound, which was then radiolabeled with fluorine-18 via a facile S N Ar reaction to form 2-[18F]fluoropyridine scaffold. Good blood–brain barrier permeability and high in vivo specific binding was demonstrated for radioligand [18F] 14 (also named as [18F]MAGL-1902). This work may serve as a roadmap for clinical translation and further design of potent 18F-labeled MAGL PET tracers. A highly potent irreversible MAGL PET tracer [18F] 14 was described, which exhibited favorable in vitro and in vivo characteristics, including excellent affinity, high brain uptake, and good binding specificity. [Display omitted] [ABSTRACT FROM AUTHOR]

The 18 kDa translocator protein (TSPO), previously known as the peripheral benzodiazepine receptor, is predominately localized to the outer mitochondrial membrane in steroidogenic cells. Brain TSPO expression is relatively low under physiological conditions, but is upregulated in response to glial cell activation. As the primary index of neuroinflammation, TSPO is implicated in the pathogenesis and progression of numerous neuropsychiatric disorders and neurodegenerative diseases, including Alzheimer's disease (AD), amyotrophic lateral sclerosis (ALS), Parkinson's disease (PD), multiple sclerosis (MS), major depressive disorder (MDD) and obsessive compulsive disorder (OCD). In this context, numerous TSPO-targeted positron emission tomography (PET) tracers have been developed. Among them, several radioligands have advanced to clinical research studies. In this review, we will overview the recent development of TSPO PET tracers, focusing on the radioligand design, radioisotope labeling, pharmacokinetics, and PET imaging evaluation. Additionally, we will consider current limitations, as well as translational potential for future application of TSPO radiopharmaceuticals. This review aims to not only present the challenges in current TSPO PET imaging, but to also provide a new perspective on TSPO targeted PET tracer discovery efforts. Addressing these challenges will facilitate the translation of TSPO in clinical studies of neuroinflammation associated with central nervous system diseases. The 18 kDa translocator protein (TSPO) expression in the central nervous system is upregulated in response to glial cell activation. There is a great potential for the future application of TSPO radioligands as diagnostic and prognostic tools, as well as for assessing therapeutic interventions for neurologic diseases. Image 1 [ABSTRACT FROM AUTHOR]

The use of photothermal agents (PTAs) in cancer photothermal therapy (PTT) has shown promising results in clinical studies. The rapid degradation of PTAs may address safety concerns but usually limits the photothermal stability required for efficacious treatment. Conversely, PTAs with high photothermal stability usually degrade slowly. The solutions that address the balance between the high photothermal stability and rapid degradation of PTAs are rare. Here, we report that the inherent Cu2+-capturing ability of black phosphorus (BP) can accelerate the degradation of BP, while also enhancing photothermal stability. The incorporation of Cu2+ into BP@Cu nanostructures further enables chemodynamic therapy (CDT)-enhanced PTT. Moreover, by employing 64Cu2+, positron emission tomography (PET) imaging can be achieved for in vivo real-time and quantitative tracking. Therefore, our study not only introduces an "ideal" PTA that bypasses the limitations of PTAs, but also provides the proof-of-concept application of BP-based materials in PET-guided, CDT-enhanced combination cancer therapy. A balance between high stability and rapid degradation is required for effective photothermal anti-cancer agents. Here, the authors use Cu2+ to accelerate the degradation of black phosphorus nanosheets while enhancing its photothermal ability and apply this material for PET-guided, CDT-enhanced combination cancer therapy in mice. [ABSTRACT FROM AUTHOR]

Monoacylglycerol lipase (MAGL) is a major serine hydrolase that hydrolyses 2-arachidonoylglycerol (2-AG) into arachidonic acid (AA) and glycerol in the brain. Because 2-AG and AA are endogenous biologically active ligands in the brain, the inhibition of MAGL is an attractive therapeutic target for neurodegenerative diseases. In this study, to visualize MAGL via positron emission tomography (PET), we report a new carbon-11-labeled radiotracer, namely 1,1,1,3,3,3-hexafluoropropan-2-yl-3-(1-benzyl-1 H -pyrazol-3-yl)azetidine-1-[11C]carboxylate ([11C] 6). Compound 6 exhibited high in vitro binding affinity (IC 50 = 0.41 nM) to MAGL in the brain with a suitable lipophilicity (cLogD = 3.29). [11C] 6 was synthesized by reacting 1,1,1,3,3,3-hexafluoropropanol (7) with [11C]phosgene ([11C]COCl 2), followed by a reaction with 3-(1-benzyl-1 H -pyrazol-3-yl)azetidine hydrochloride (8), which resulted in a 15.0 ± 6.8% radiochemical yield (decay-corrected, n = 7) based on [11C]CO 2 and a 45 min synthesis time from the end of bombardment. A biodistribution study in mice showed high uptake of radioactivity in MAGL-rich organs, including the lungs, heart, and kidneys. More than 90% of the total radioactivity was irreversibly bound in the brain homogenate of rats 5 min and 30 min after the radiotracer injection. PET summation images of rat brains showed high radioactivity in all brain regions. Pretreatment with 6 or MAGL-selective inhibitor JW642 significantly reduced the uptake of radioactivity in the brain. [11C] 6 is a promising PET tracer which offers in vivo specific binding and selectivity for MAGL in rodent brains. [ABSTRACT FROM AUTHOR]

Selective metabotropic glutamate receptor 2 (mGluR2) inhibitors have been demonstrated to show therapeutic effects by improving alleviating symptoms of schizophrenic patients in clinical studies. Herein we report the synthesis and preliminary evaluation of a 11C-labeled positron emission tomography (PET) tracer originating from a mGluR2 inhibitor, 3-(cyclopropylmethyl)-7-((4-(4-methoxyphenyl)piperidin-1-yl)methyl)-8-(trifluoromethyl)-[1,2,4]triazolo[4,3- a ]pyridine (CMTP, 1a). [11C]CMTP ([11C] 1a) was synthesized by O-[11C]methylation of desmethyl precursor 1b with [11C]methyl iodide in 19.7 ± 8.9% (n = 10) radiochemical yield (based on [11C]CO 2) with >98% radiochemical purity and >74 GBq/μmol molar activity. Autoradiography study showed that [11C] 1a possessed moderate in vitro specific binding to mGluR2 in the rat brain, with a heterogeneous distribution of radioactive accumulation in the mGluR2-rich brain tissue sections, such as the cerebral cortex and striatum. PET study indicated that [11C] 1a was able to cross the blood–brain barrier and enter the brain, but had very low specific binding in the rat brain. Further optimization for the chemical structure of 1a is necessary to increase binding affinity to mGluR2 and then improve in vivo specific binding in brain. [ABSTRACT FROM AUTHOR]

• Efficient radiosynthetic route to a 18F-labeled M4 PET ligand. • High radiochemical yield and high molar activity. • Modest in vitro binding specificity by autoradiography studies. • Limited brain penetration in rodents. Positive allosteric modulators of muscarinic acetylcholine receptor subtype 4 have been identified as promising activators for the treatment of neurological disorders and neurodegenerative diseases, including schizophrenia, Alzheimer's disease (AD) and dementia with Lewy bodies (DLB). Herein we report the synthesis and preliminary evaluation of a 18F-labeled positron emission tomography ligand based on a M 4 activator (7). 18F-Isotopologue of 7 was prepared in a reasonable radiochemical yield with high radiochemical purity (>99%) and high molar activity (>37 GBq/µmol). In vitro autoradiography studies indicated that the ligand possessed moderate in vitro specific binding. Dynamic PET studies in vivo demonstrated that 18F] 7 (also named as 18F]M 4 R-1911) failed to cross the blood–brain barrier. Therefore, further chemical scaffold optimization in chemotype of 7 is necessary to overcome limited brain permeability and improve specific binding. [ABSTRACT FROM AUTHOR]

Transmembrane AMPA Receptor Regulatory Proteins (TARPs) are a recently discovered family of proteins that modulate the activity of AMPA receptors in the ionotropic glutamate system. TARPs exhibit regional specific expression in the brain, leading to physiological differentiation and modulation of AMPA activity. Herein we develop a novel PET ligand based on a novel TARP subtype γ-8 dependent antagonist and perform preliminary evaluation by PET. Transmembrane AMPA receptor regulatory proteins (TARPs) are a recently discovered family of proteins that modulate AMPA receptors activity. Based on a potent and selective TARP subtype γ-8 antagonist, 6-(methyl(4-(pyridin-2-yl)thiazol-2-yl)amino)benzo[ d ]thiazol-2(3H)-one (compound 9), we perform the radiosynthesis of its 11C-isotopologue 1 and conduct preliminary PET evaluation to test the feasibility of imaging TARP γ-8 dependent receptors in vivo. [ABSTRACT FROM AUTHOR]