Positron Emission Tomography Radioligand Research Articles

Rimota-Gd: Paramagnetic Probe for In Vivo MRI Studies of the Cannabinoid 1 Receptor Distribution in the Mouse Brain.

The cannabinoid 1 receptor (CB1) is highly expressed in the central nervous system, where its physiological functions include the regulation of energy balance, pain, and addiction. Herein, we develop and validate a technique to use magnetic resonance imaging (MRI) to investigate the distribution of CB1 across mouse brains with high spatial resolution, expanding previously described in vitro studies and in vivo studies with positron emission tomography (PET). To support the MRI investigations, we developed a ligand that is specific for in vivo neuroimaging of CB1. By chemically conjugating the CB1 antagonist rimonabant acid to a gadolinium chelator, we obtained the paramagnetic probe Rimota-Gd. The specificity of binding of rimonabant acid to CB1 and the relaxation enhancement by the paramagnetic gadolinium permit MRI-based localization of CB1. We used Rimota-Gd to investigate the spatial distribution of CB1 across the mouse brain and compared the results with an investigation using the PET radioligand [18F]MK-9470. Rimota-Gd opens the door for in vivo MRI imaging of CB1 and provides a roadmap for the study of other receptors by whole-brain images with high spatial and temporal resolution.

Identification and In Vitro and In Vivo Characterization of KAC-50.1 as a Potential α-Synuclein PET Radioligand.

The accumulation of aggregated α-synuclein (α-syn) is a pathological hallmark of Parkinson's disease (PD) and other synucleinopathies. Here within, we report the in vitro characterization targeting site 2 of α-syn fibrils and in vivo evaluation of NHPs of KAC-50.1 as a potential α-syn positron emission tomography (PET) radioligand. Preclinical studies were performed using a multidimensional approach of post-mortem brain imaging techniques, radioligand binding, and biochemical studies. These experiments were followed by PET imaging in cynomolgus monkeys using [11C]KAC-50.1. [3H]KAC-50.1 displayed a KD of 35 nM toward site 2 in recombinant α-syn fibrils. Specific binding of [3H]KAC-50.1 was observed in brain tissues with abundant α-syn pathology but also in AD, PSP, and CBD cases, indicating binding to amyloid β (Aβ) and tau pathology. PET studies showed a rapid entrance of [11C]KAC-50.1 into the brain and relatively rapid washout from cortical brain regions, with slower washout in subcortical regions. [3H]KAC-50.1 is a ligand that binds to fibrillar α-syn but shows limited selectivity for α-syn versus Aβ and tau fibrils. PET studies in NHPs indicate that [11C]KAC-50.1, despite reversible kinetic properties, displays retention in white matter. Altogether, the in vitro and in vivo properties do not support further development of [11C]KAC-50.1 as a PET imaging agent.

Synthesis of K+ channel radioligand [18F]5-methyl-3-fluoro-4-aminopyridine and PET imaging in mice

[18F]3-fluoro-4-aminopyridine ([18F]3F4AP) is the first positron emission tomography (PET) radioligand that targets voltage-gated potassium (K+) channels in the brain for imaging demyelination. [18F]3F4AP exhibits high brain penetration, favorable kinetics for PET imaging, and high sensitivity to demyelinating lesions. However, recent studies in awake human subjects indicate lower metabolic stability than in anesthetized animals, resulting in reduced brain uptake. Therefore, there is a need for novel radioligands for K+ channels with suitable pharmacological properties and enhanced metabolic stability. Recent in vitro studies demonstrate that 5-methyl-3-fluoro-4-aminopyridine (5Me3F4AP) exhibits comparable binding affinity to K+ channels, pKa, logD, and membrane permeability as 3F4AP, and a slower enzymatic metabolic rate, suggesting its potential as a K+ channel PET tracer. In this study, we describe the radiochemical synthesis of [18F]5Me3F4AP using an isotope exchange method from the corresponding 3-fluoro-5-methyl-4-nitropyridine N-oxide, followed by a palladium on carbon mediated hydrogenation of the nitro and N-oxide groups. This method yielded [18F]5Me3F4AP with high purity and acceptable molar activity. PET/CT studies using naïve mice demonstrate that [18F]5Me3F4AP effectively crosses the blood–brain barrier and has comparable kinetics to [18F]3F4AP. These findings strongly suggest that [18F]5Me3F4AP is a promising candidate for neuroimaging applications and warrant further studies to investigate its sensitivity to lesions and in vivo metabolic stability.

Whole‐body MRI for staging prostate cancer: a narrative review

ObjectiveTo present a narrative review regarding the diagnostic accuracy of whole‐body magnetic resonance imaging (WBMRI) in staging patients with high‐risk prostate cancer (HRPCa) and compare it to established imaging modalities.MethodsA narrative review was carried out using PubMed using the following keywords: ‘whole body’, ‘magnetic resonance imaging’, ‘MRI’, ‘prostate cancer’, ‘risk stratification’, and ‘staging’. Articles that evaluated WBMRI as the imaging modality to stage patients with HRPCa were included, while studies that solely assessed for biochemical recurrence or metastatic disease progression were excluded.ResultsIn the evaluation of lymphatic metastases, WBMRI has demonstrated a comparable, if not improved, sensitivity and specificity compared to conventional imaging of computed tomography (CT). Furthermore, WBMRI demonstrates improved sensitivity and specificity in detecting bone metastases compared to bone scintigraphy (BS). However, with advent of prostate‐specific membrane antigen (PSMA) radioligands for positron emission tomography (PET), the diagnostic performance of WBMRI to detect metastatic disease appears inferior.ConclusionsThe diagnostic capabilities of WBMRI exceed that of conventional imaging of CT and BS in detecting metastatic disease in patients with HRPCa. However, WBMRI does not perform as well as PSMA PET/CT. Further study on cost comparisons between WBMRI and PSMA PET/CT are needed, as well as evaluations of combined PSMA PET/MRI are needed.

PET imaging in rat brain shows opposite effects of acute and chronic alcohol exposure on phosphodiesterase-4B, an indirect biomarker of cAMP activity.

The cyclic adenosine monophosphate (cAMP) cascade is thought to play an important role in regulating alcohol-dependent behaviors, with potentially opposite effects following acute versus chronic administration. Phosphodiesterase 4 (PDE4) is the primary brain enzyme that metabolizes cAMP, thereby terminating its signal. Radioligand binding to PDE4 serves as an indirect biomarker of cAMP activity, as cAMP-protein kinase A (PKA)-mediated phosphorylation of PDE4 increases its affinity for radioligand binding ~10-fold. Of the four PDE4 subtypes, PDE4B polymorphisms are known to be strongly associated with alcohol and substance use disorders. This study imaged rats with the PDE4B-preferring positron emission tomography (PET) radioligand [18F]PF-06445974 following acute and chronic ethanol administration, aiming to explore the potential of PDE4B PET imaging for future human studies. Compared to the control group treated with saline, acute alcohol administration (i.p. ethanol 0.5 g/kg) significantly increased whole brain uptake of [18F]PF-06445974 as early as 30 minutes post-exposure. This effect persisted at 2 hours, peaked at 4 hours, and diminished at 6 hours and 24 hours post-exposure. In contrast, in a rat model of alcohol dependence, [18F]PF-06445974 brain uptake was significantly reduced at 5 hours post-exposure and was normalized by 3 days. This reduction may reflect long-term adaptation to repeated alcohol-induced activation of cAMP signaling with chronic exposure. Taken together, the results suggest that PET imaging of PDE4B in individuals with alcohol use disorder (AUD) should be considered in conjunction with ongoing trials of PDE4 inhibitors to treat alcohol withdrawal and reduce alcohol consumption.

Development and Evaluation of [11C]I-58: A Novel PET Radiotracer Targeting BRD4 BD2 for Advanced Epigenetic Imaging.

The paired bromodomains (BD1 and BD2), located in the bromodomain and extra-terminal (BET) family proteins, perform specific functions in gene transcriptional control and expression. Targeting specific bromodomains with inhibitors holds promise for achieving therapeutic benefits with reduced side effects. However, the comprehension of this target related to the disease is still restricted. Positron emission tomography (PET) imaging is a powerful tool that provides a valuable avenue for exploring the BD2 bromodomain. This investigation introduces a novel radioligand, [11C]I-58, for PET targeting the BET BD2 domain. The synthesis of compound I-58, along with its radiosynthetic process for C11 labeling, is detailed, and the suitability of [11C]I-58 for PET imaging of the BD2 bromodomain is evaluated. Initial PET study findings in mice indicate that [11C]I-58 exhibits suitable biodistribution in peripheral organs and tissues. Additionally, in vitro autoradiography studies and blocking experiments provide compelling evidence supporting the specific binding of [11C]I-58 to the BD2 bromodomain. These results establish [11C]I-58 as a promising instrument for the PET imaging of the BD2 bromodomain. This research not only holds the potential to pave the path for developing PET radioligands precisely targeting the BD2 bromodomain but also adds to a more profound comprehension of the biological mechanisms linked to the BD bromodomain.

Advances and Insights in Positron Emission Tomography Tracers for Metabotropic Glutamate Receptor 4 Imaging.

Positron emission tomography (PET) imaging employs positron-emitting radioisotopes to visualize biological processes in living subjects with high sensitivity and quantitative accuracy. As the most translational molecular imaging modality, PET can detect and image a wide range of radiotracers with minimal or no modification to parent drugs or targeting molecules. This Perspective provides a comprehensive analysis of developing PET radioligands using allosteric modulators for the metabotropic glutamate receptor subtype 4 (mGluR4) as a therapeutic target for neurological disorders. We focus on the selection of lead compounds from various chemotypes of mGluR4 positive allosteric modulators (PAMs) and discuss the challenges and systematic characterization required in developing brain-penetrant PET tracers specific for mGluR4. Through this analysis, we offer insights into the development and evaluation of PET ligands. Our review concludes that further research and development in this field hold great promise for discovering effective treatments for neurological disorders.

Development of a New Positron Emission Tomography Imaging Radioligand Targeting RIPK1 in the Brain and Characterization in Alzheimer's Disease.

Targeting receptor-interacting protein kinase 1 (RIPK1) has emerged as a promising therapeutic stratagem for neurodegenerative disorders, particularly Alzheimer's disease (AD). A positron emission tomography (PET) probe enabling brain RIPK1 imaging can provide a powerful tool to unveil the neuropathology associated with RIPK1. Herein, the development of a new PET radioligand, [11C]CNY-10 is reported, which may enable brain RIPK1 imaging. [11C]CNY-10 is radiosynthesized with a high radiochemical yield (41.8%) and molar activity (305 GBq/µmol). [11C]CNY-10 is characterized by PET imaging in rodents and a non-human primate, demonstrating good brain penetration, binding specificity, and a suitable clearance kinetic profile. It is performed autoradiography of[11C]CNY-10 in human AD and healthy control postmortem brain tissues, which shows strong radiosignal in AD brains higher than healthy controls. Subsequently, it is conducted further characterization of RIPK1 in AD using [11C]CNY-10-based PET studies in combination with immunohistochemistry leveraging the 5xFAD mouse model. It is found that AD mice revealed RIPK1 brain signal significantly higher than WT control mice and that RIPK1 is closely related to amyloid plaques in the brain. The studies enable further translational studies of [11C]CNY-10 for AD and potentially other RIPK1-related human studies.

Examining iron-related off-target binding effects of 18F-AV1451 PET in the cortex of Aβ+ individuals.

The presence of neurofibrillary tangles containing hyper-phosphorylated tau is a characteristic of Alzheimer's disease (AD) pathology. The positron emission tomography (PET) radioligand sensitive to tau neurofibrillary tangles (18F-AV1451) also binds with iron. This off-target binding effect may be enhanced in older adults on the AD spectrum, particularly those with amyloid-positive biomarkers. Here, we examined group differences in 18F-AV1451 PET after controlling for iron-sensitive measures from magnetic resonance imaging (MRI) and its relationships to tissue microstructure and cognition in 40 amyloid beta positive (Aβ+) individuals, 20 amyloid beta negative (Aβ-) with MCI and 31 Aβ- control participants. After controlling for iron, increased 18F-AV1451 PET uptake was found in the temporal lobe and hippocampus of Aβ+ participants compared to Aβ- MCI and control participants. Within the Aβ+ group, significant correlations were seen between 18F-AV1451 PET uptake and tissue microstructure and these correlations remained significant after controlling for iron. These findings indicate that off-target binding of iron to the 18F-AV1451 ligand may not affect its sensitivity to Aβ status or cognition in early-stage AD.

GMP production of [18F]FE-PE2I on a TRACERLab FX2 N synthesis module, a radiotracer for in vivo PET imaging of the dopamine transport

BackgroundParkinson's disease is a neurodegenerative disorder that is characterized by a degeneration of the dopaminergic system. Dopamine transporter (DAT) positron emission tomography (PET) imaging has emerged as a powerful and non-invasive method to quantify dopaminergic function in the living brain. The PET radioligand, [18F]FE-PE2I, a cocaine chemical derivative, has shown promising properties for in vivo PET imaging of DAT, including high affinity and selectivity for DAT, excellent brain permeability, and favorable metabolism. The aim of the current study was to scale up the production of [18F]FE-PE2I to fulfil the increasing clinical demand for this tracer.ResultsThus, a fully automated and GMP-compliant production procedure has been developed using a commercially available radiosynthesis module GE TRACERLab FX2 N. [18F]FE-PE2I was produced with a radiochemical yield of 39 ± 8% (n = 4, relative [18F]F− delivered to the module). The synthesis time was 70 min, and the molar activity was 925.3 ± 763 GBq/µmol (250 ± 20 Ci/µmol). The produced [18F]FE-PE2I was stable over 6 h at room temperature.ConclusionThe protocol reliably provides a sterile and pyrogen–free GMP-compliant product.

Synthesis and preclinical evaluation of 11C-labeled 7-Oxo-2,4,5,7-tetrahydro-6H-pyrazolo[3,4-c]pyridine radioligands for RIPK1 positron emission tomography imaging

Targeting receptor-interacting protein kinase 1 (RIPK1) has emerged as a promising therapeutic strategy for various neurodegenerative disorders. The development of a positron emission tomography (PET) probe for brain RIPK1 imaging could offer a valuable tool to assess therapeutic effectiveness and uncover the neuropathology associated with RIPK1. In this study, we present the development and characterization of two new PET radioligands, [11C]PB218 and [11C]PB220, which have the potential to facilitate brain RIPK1 imaging. [11C]PB218 and [11C]PB220 were successfully synthesized with a high radiochemical yield (34 % − 42 %) and molar activity (293 – 314 GBq/µmol). PET imaging characterization of two radioligands was conducted in rodents, demonstrating that both newly developed tracers have good brain penetration (maximum SUV = 0.9 – 1.0) and appropriate brain clearance kinetic profiles. Notably, [11C]PB218 has a more favorable binding specificity than [11C]PB220. A PET/MR study of [11C]PB218 in a non-human primate exhibited good brain penetration, desirable kinetic properties, and a safe profile, thus supporting the translational applicability of our new probe. These investigations enable further translational exploration of [11C]PB218 for drug discovery and PET probe development targeting RIPK1.

Preclinical Evaluation of Azabenzimidazole-Based PET Radioligands for γ-8 Dependent Transmembrane AMPA Receptor Regulatory Protein Imaging.

AMPA glutamate receptors (AMPARs) play a pivotal role in excitatory neurotransmission, particularly in the hippocampus where the TARP γ-8 subunit is enriched and serves as a target for emerging anti-epileptic drugs. To enable in vivo visualization of TARP γ-8 distribution and expression by positron emission tomography (PET), this study focuses on the development of novel 18 F-labeled TARP γ-8 inhibitors and their corresponding precursors, stemming from the azabenzimidazole scaffold. The resulting radioligands [18 F]TARP-2204 and [18 F]TARP-2205 were successfully synthesized with acceptable radiochemical yield, high molar activity, and excellent radiochemical purity. In vitro autoradiography demonstrates high level of specific binding of [18 F]TARP-2205 to TARP γ-8 in both rat and nonhuman primate brain tissues. However, unexpected radiodefluorination in PET imaging studies of rodents emphasizes the need for further structural refinement. This work serves as an excellent starting point for the development of future 18 F-labeled TARP γ-8 PET tracers, offering valuable insights into medicinal chemistry design, radiosynthesis and subsequent PET evaluation.

Synthesis and preclinical evaluation of [11C]uPSEM792 for PSAM4-GlyR based chemogenetics

Chemogenetic tools are designed to control neuronal signaling. These tools have the potential to contribute to the understanding of neuropsychiatric disorders and to the development of new treatments. One such chemogenetic technology comprises modified Pharmacologically Selective Actuator Modules (PSAMs) paired with Pharmacologically Selective Effector Molecules (PSEMs). PSAMs are receptors with ligand-binding domains that have been modified to interact only with a specific small-molecule agonist, designated a PSEM. PSAM4 is a triple mutant PSAM derived from the α7 nicotinic receptor (α7L131G,Q139L,Y217F). Although having no constitutive activity as a ligand-gated ion channel, PSAM4 has been coupled to the serotonin 5-HT3 receptor (5-HT3R) and to the glycine receptor (GlyR). Treatment with the partner PSEM to activate PSAM4-5-HT3 or PSAM4-GlyR, causes neuronal activation or silencing, respectively. A suitably designed radioligand may enable selective visualization of the expression and location of PSAMs with positron emission tomography (PET). Here, we evaluated uPSEM792, an ultrapotent PSEM for PSAM4-GlyR, as a possible lead for PET radioligand development. We labeled uPSEM792 with the positron-emitter, carbon-11 (t1/2 = 20.4 min), in high radiochemical yield by treating a protected precursor with [11C]iodomethane followed by base deprotection. PET experiments with [11C]uPSEM792 in rodents and in a monkey transduced with PSAM4-GlyR showed low peak radioactivity uptake in brain. This low uptake was probably due to high polarity of the radioligand, as evidenced by physicochemical measurements, and to the vulnerability of the radioligand to efflux transport at the blood–brain barrier. These findings can inform the design of a more effective PSAM4 based PET radioligand, based on the uPSEM792 chemotype.

3D-QSAR Studies on High-affinity Phosphodiestera.

Recent studies have found that Phosphodiesterase-4 (PDE4) is closely related to the pathogenesis of depression, cognitive impairment and neurological impairment. Our objective is to develop potent inhibitors of the high-affinity phosphodiesterase 4D isoform (PDE4D) that can serve as radioligands for Positron Emission Tomography (PET) imaging, thereby advancing research in the field of neurological diseases. We employed a multi-step approach combining three-dimensional quantitative structure-activity relationship (3D-QSAR) modeling, molecular docking, classification techniques, and CoMSIA analysis to investigate the conformational relationship of highaffinity PDE4D inhibitors as PET ligands. ADMET and Drug-likeness predictions were also conducted. By utilizing these methods, our aim was to identify more potent PDE4D inhibitors. The results showed that the CoMSIA model with the best principal component scores (n=7) had a cross-validated Q2 value of 0.602 and a non-cross-validated R2 value of 0.976. These results affirmed the excellent predictive capability of the established CoMSIA model. Analysis of the generated 3D-QSAR contour plots highlighted specific regions in the molecular structure of the compounds that can be further optimized and modified. Guided by the contour plots, we designed 100 novel PDE4D inhibitors, and molecular docking was performed for the top 4 compounds with high activity. The molecular docking scores were promising, and ADMET and drug similarity predictions yielded satisfactory results. Taking into consideration these factors, compound 51c was determined to be the optimal compound, laying a solid foundation for further research. For the continued development of PDE4D PET radioligand, these models and new compounds' developing methodology offer a theoretical foundation and crucial references.

A facile synthesis of precursor for the σ-1 receptor PET radioligand [18 F]FTC-146 and its radiofluorination.

The σ-1 receptor is a non-opioid transmembrane protein involved in various human pathologies including neurodegenerative diseases, inflammation, and cancer. The previously published ligand [18 F]FTC-146 is among the most promising tools for σ-1 molecular imaging by positron emission tomography (PET), with a potential for application in clinical diagnostics and research. However, the published six- or four-step synthesis of the tosyl ester precursor for its radiosynthesis is complicated and time-consuming. Herein, we present a simple one-step precursor synthesis followed by a one-step fluorine-18 labeling procedure that streamlines the preparation of [18 F]FTC-146. Instead of a tosyl-based precursor, we developed a one-step synthesis of the precursor analog AM-16 containing a chloride leaving group for the SN 2 reaction with 18 F-fluoride. 18 F-fluorination of AM-16 led to a moderate decay-corrected radiochemical yield (RCY = 7.5%) with molar activity (Am ) of 45.9GBq/μmol. Further optimization of this procedure should enable routine radiopharmaceutical production of this promising PET tracer.

PET Imaging to Measure Neuroinflammation In Vivo.

This paper provides an overview of the role of neuroinflammation in Alzheimer's disease and other neurodegenerative diseases, highlighting the potential of anti-inflammatory treatments to slow or prevent decline. This research focuses on the use of positron emission tomography (PET) imaging to visualize and quantify molecular brain changes in patients, specifically microglial activation and reactive astrogliosis. We discuss the development and application of several PET radioligands, including first-generation ligands like PK11195 and Ro5-4864, as well as second- and third-generation ligands such as [11C]PBR28, [18F]DPA-714, [18F]GE-180, and [11C]ER176. These ligands target the 18-kDa translocator protein (TSPO), which is overexpressed in activated microglia and upregulated in astrocytes. We also address the limitations of these ligands, such as low brain uptake, poor penetration of the blood-brain barrier, short half-life, and variable kinetic behavior. Furthermore, we demonstrate the impact of genetic polymorphisms on ligand binding.

Microglial Positron Emission Tomography Imaging In Vivo : Positron Emission Tomography Radioligands: Utility in Research and Clinical Practice.

Microglia, the resident immune cells of the central nervous system (CNS) play a key role in regulating and maintaining homeostasis in the brain. However, the CNS is also vulnerable to infections and inflammatory processes. In response to CNS perturbations, microglia become reactive, notably with expression of the translocator protein (TSPO), primarily on their outer mitochondrial membrane. Despite TSPO being commonly used as a marker for microglia, it is also present in other cell types such as astrocytes. Positron emission tomography (PET) ligands that target the TSPO enable the noninvasive detection and quantification of glial reactivity. While some limitations were raised, TSPO PET remains an attractive biomarker of CNS infection and inflammation. This book chapter delves into the development and application of microglial PET imaging with a focus on the TSPO PET. First, we provide an overview of the evolution of TSPO PET radioligands from first-generation to second-generation ligands and their applications in studying neuroinflammation (or CNS inflammation). Subsequently, we discuss the limitations and challenges associated with TSPO PET. Then we go on to explore non-TSPO targets for microglial PET imaging. Finally, we conclude with future directions for research and clinical practice in this field.

Design and Discovery of Novel NLRP3 Inhibitors and PET Imaging Radiotracers Based on a 1,2,3-Triazole-Bearing Scaffold.

The NOD-like receptor (NLR) family pyrin-domain-containing 3 (NLRP3) inflammasome, an essential component of the innate immune system, has been emerging as a viable drug target and a potential biomarker for human diseases. In our efforts to develop novel small molecule NLRP3 inhibitors, a 1-(5-chloro-2-methoxybenzyl)-4-phenyl-1H-1,2,3-triazole scaffold was designed via a rational approach based on our previous leads. Structure-activity relationship studies and biophysical studies identified a new lead compound 8 as a potent (IC50: 0.55 ± 0.16 μM), selective, and direct NLRP3 inhibitor. Positron emission tomography (PET) imaging studies of [11C]8 demonstrated its rapid and high brain uptake as well as fast washout in mice and rhesus macaque. Notably, plasma kinetic analysis of this radiotracer from the PET/magnetic resonance imaging studies in rhesus macaque suggested radiometabolic stability. Collectively, our data not only encourage further studies of this lead compound but also warrant further optimization to generate additional novel NLRP3 inhibitors and suitable central nervous system PET radioligands with translational promise.

Dose reduction in dynamic synaptic vesicle glycoprotein 2A PET imaging using artificial neural networks

Objective. Reducing dose in positron emission tomography (PET) imaging increases noise in reconstructed dynamic frames, which inevitably results in higher noise and possible bias in subsequently estimated images of kinetic parameters than those estimated in the standard dose case. We report the development of a spatiotemporal denoising technique for reduced-count dynamic frames through integrating a cascade artificial neural network (ANN) with the highly constrained back-projection (HYPR) scheme to improve low-dose parametric imaging. Approach. We implemented and assessed the proposed method using imaging data acquired with 11C-UCB-J, a PET radioligand bound to synaptic vesicle glycoprotein 2A (SV2A) in the human brain. The patch-based ANN was trained with a reduced-count frame and its full-count correspondence of a subject and was used in cascade to process dynamic frames of other subjects to further take advantage of its denoising capability. The HYPR strategy was then applied to the spatial ANN processed image frames to make use of the temporal information from the entire dynamic scan. Main results. In all the testing subjects including healthy volunteers and Parkinson’s disease patients, the proposed method reduced more noise while introducing minimal bias in dynamic frames and the resulting parametric images, as compared with conventional denoising methods. Significance. Achieving 80% noise reduction with a bias of −2% in dynamic frames, which translates into 75% and 70% of noise reduction in the tracer uptake (bias, −2%) and distribution volume (bias, −5%) images, the proposed ANN+HYPR technique demonstrates the denoising capability equivalent to a 11-fold dose increase for dynamic SV2A PET imaging with 11C-UCB-J.

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

GluN2B subunit-containing N-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 (R)-[18F]OF-NB1 and (S)-[18F]OF-NB1 as well as to assess their in vitro and in vivo performance characteristics for imaging the GluN2B subunit-containing NMDA receptor in rodents. A novel synthetic approach was successfully developed, which allows for the enantiomerically pure radiosynthesis of (R)-[18F]OF-NB1 and (S)-[18F]OF-NB1 and the translation of the probe to the clinic. While both enantiomers were selective over sigma2 receptors in vitro and in vivo, (R)-[18F]OF-NB1 showed superior GluN2B subunit specificity by in vitro autoradiography and higher volumes of distribution in the rodent brain by small animal PET studies.