Positron Emission Tomography Ligand Research Articles

Comparison of discovery rates and prognostic utility of [68Ga]Ga-PSMA-11 PET/CT and circulating tumor DNA in prostate cancer-a cross-sectional study.

Circulating-tumor DNA (ctDNA) and prostate-specific membrane antigen (PSMA) ligand positron-emission tomography (PET) enable minimal-invasive prostate cancer (PCa) detection and survival prognostication. The present study aims to compare their tumor discovery abilities and prognostic values. One hundred thirty men with confirmed PCa (70.5 ± 8.0years) who underwent [68Ga]Ga-PSMA-11 PET/CT (184.8 ± 19.7MBq) imaging and plasma sample collection (March 2019-August 2021) were included. Plasma-extracted cell-free DNA was subjected to whole-genome-based ctDNA analysis. PSMA-positive tumor lesions were delineated and their quantitative parameters extracted. ctDNA and PSMA PET/CT discovery rates were compared, and the prognostic value for overall survival (OS) was evaluated. PSMA PET discovery rates according to castration status and PSA ranges did differ significantly (P = 0.013, P < 0.001), while ctDNA discovery rates did not (P = 0.311, P = 0.123). ctDNA discovery rates differed between localized and metastatic disease (P = 0.013). Correlations between ctDNA concentrations and PSMA-positive tumor volume (PSMA-TV) were significant in all (r = 0.42, P < 0.001) and castration-resistant (r = 0.65, P < 0.001), however not in hormone-sensitive patients (r = 0.15, P = 0.249). PSMA-TV and ctDNA levels were associated with survival outcomes in the Logrank (P < 0.0001, P < 0.0001) and multivariate Cox regression analysis (P = 0.0023, P < 0.0001). These findings suggest that PSMA PET imaging outperforms ctDNA analysis in detecting prostate cancer across the whole spectrum of disease, while both modalities are independently highly prognostic for survival outcomes.

18F] AlF-NOTA-FAPI-04 PET/CT for non-invasive assessment of tubular injury in kidney diseases.

[18F] AlF-NOTA-FAPI-04 is a novel positron emission tomography (PET) ligand, which specifically targets fibroblast activation protein (FAP) expression as a FAP inhibitor (FAPI). We analysed the diagnostic value of [18F] AlF-NOTA-FAPI-04 PET/CT for the non-invasive assessment of kidney interstitial inflammation and fibrosis in different renal pathologies. Twenty-six patients (14 males and 12 females; mean age, 50.5±16.5 years) with a wide range of kidney diseases and 10 patients (six males and four females; mean age, 55.4±8.6 years) without known evidence of renal disease as disease controls underwent [18F] AlF-NOTA-FAPI-04 PET/CT imaging. Kidney tissues obtained from kidney biopsies were stained with haematoxylin and eosin, periodic acid-Schiff, Masson's trichome, and periodic acid-silver methenamine. Immunohistochemical staining was also performed to assess the expression of α-smooth muscle actin (αSMA) and FAP. Renal parenchymal FAPI uptake reflected by maximum standardized uptake value (SUVmax) and mean standardized uptake value (SUVmean) measurements on PET/CT was analysed against pathohistological findings. We found that renal parenchymal FAPI uptake was significantly higher in patients with various kidney diseases than in control patients in this study (SUVmax=4.3±1.8vs 1.9±0.4, SUVmean=3.9±1.7vs 1.5±0.4, respectively; all P<0.001). All kidney diseases, both in acute and chronic kidney disease, had increased renal parenchymal uptake to varying degrees. The correlation analysis indicated a positive association between the SUVmax and the tubulointerstitial inflammation (TII), interstitial fibrosis and tubular atrophy (IF/TA), and TII+IF/TA scores (r=0.612, 0.681, and 0.754, all P<0.05), and between the SUVmean and the TII, IF/TA, and TII+IF/TA scores (r=0.603, 0.700, and 0.748, all P<0.05). Furthermore, we found significant positive correlations between both SUVmax and the SUVmean with SMA and FAP staining scores (r=0.686 and 0.732, r=0.667 and 0.739, respectively; both P<0.001). [18F] AlF-NOTA-FAPI-04 PET/CT is clinically available for the comprehensive and non-invasive assessment of tubular injury in various kidney diseases.

Development and In Vivo Evaluation of Small-Molecule Ligands for Positron Emission Tomography of Immune Checkpoint Modulation Targeting Programmed Cell Death 1 Ligand 1.

A substantial portion of patients do not benefit from programmed cell death protein 1/programmed cell death 1 ligand 1 (PD-1/PD-L1) checkpoint inhibition therapies, necessitating a deeper understanding of predictive biomarkers. Immunohistochemistry (IHC) has played a pivotal role in assessing PD-L1 expression, but small-molecule positron emission tomography (PET) tracers could offer a promising avenue to address IHC-associated limitations, i.e., invasiveness and PD-L1 expression heterogeneity. PET tracers would allow for improved quantification of PD-L1 through noninvasive whole-body imaging, thereby enhancing patient stratification. Here, a large series of PD-L1 targeting small molecules were synthesized, leveraging advantageous substructures to achieve exceptionally low nanomolar affinities. Compound 5c emerged as a promising candidate (IC50 = 10.2 nM) and underwent successful carbon-11 radiolabeling. However, a lack of in vivo tracer uptake in xenografts and notable accumulation in excretory organs was observed, underscoring the challenges encountered in small-molecule PD-L1 PET tracer development. The findings, including structure-activity relationships and in vivo biodistribution data, stand to illuminate the path forward for refining small-molecule PD-L1 PET tracers.

Preclinical validation of a novel brain-penetrant PET ligand for visualization of histone deacetylase 6: a potential imaging target for neurodegenerative diseases.

Histone deacetylase 6 (HDAC6) has emerged as a therapeutic target for neurodegenerative diseases such as Alzheimer's disease. Noninvasive imaging of HDAC6 in the brain by positron emission tomography (PET) would accelerate research into its roles in these diseases. We recently discovered an 18F-labeled derivative of the selective HDAC6 inhibitor SW-100 ([18F]FSW-100) as a potential candidate for brain HDAC6 radioligand. As a mandatory step prior to clinical translation, we performed preclinical validation of [18F]FSW-100. Process validation of [18F]FSW-100 radiosynthesis for clinical use and assessment of preclinical toxicity and radiation dosimetry estimated from mouse distribution data were performed. In vitro selectivity of FSW-100 for 28 common receptors in the brain and HDAC isoforms was characterized. [18F]FSW-100 PET imaging was performed in non-human primates in a conscious state to estimate the feasibility of HDAC6 imaging in humans. Three consecutive validation runs of the automated radiosynthesis gave [18F]FSW-100 injections with radiochemical yields of 12%, and the injections conformed to specified quality control criteria for batch release. No acute toxicity was observed for non-radiolabeled FSW-100 or radioactivity decayed [18F]FSW-100 injection, and the former was negative in the Ames test. The whole-body effective dose estimated from biodistribution in mice was within the range of that of previously reported 18F-radioligands in humans. In vitro selectivity against common receptors and other HDAC isoforms was confirmed. [18F]FSW-100 demonstrated good penetration in monkey brain, and in vivo blocking studies suggested that the uptake was specific. These results support the clinical utility of [18F]FSW-100 for in vivo imaging of HDAC6 in the brain.

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.

Radiodifluoromethylation of well-functionalized molecules.

The strategic installation of a [18F]fluorine atom at the specific position of the lead molecule is a never-ending challenge for radiochemists in their endeavour to develop novel positron emission tomography (PET) imaging applications. Although the radiosynthesis of [18F]CF2H-containing molecules has been explored in the past decade, more methods need to be explored for various well-functionalized compounds. Recently, two novel strategies of radiodifluoromethylation were reported, namely the utilization of [18F]difluorocarbene building block and frustrated Lewis pair-mediated C-18F bond formation, respectively. These methods provide an efficient radiofunctionalization of complex CF2H-containing molecules for drug discovery and PET ligand development.

Discovery and optimization of the first‐in‐class TDP‐43 PET tracer

AbstractBackgroundIntracellular aggregation of TDP‐43 is found in most patients with amyotrophic lateral sclerosis (ALS), 45% of patients with frontotemporal dementia (FTD) and 30‐50% of patients with clinical diagnosis of Alzheimer’s disease. Sensitive fluid or imaging biomarkers of TDP‐43 pathology are currently not available. Direct detection of TDP‐43 aggregates by positron emission tomography (PET) holds promise for a more accurate diagnosis, patient stratification and assessment of therapeutic efficacy in clinical trials.MethodsUsing ACI’s Morphomer® small molecule library focused on brain penetrant and beta sheet binding compounds, initial hits were identified, and iterative medicinal chemistry applied to discover compounds with optimized properties. Radiobinding and autoradiography experiments on FTLD‐TDP brain samples were used to evaluate affinity and target engagement. These techniques were also used to assess selectivity over other aggregation‐prone proteins using brain material from Alzheimer’s (AD) and Parkinson’s disease (PD) cases. Brain pharmacokinetic (PK) profile was obtained in mice, followed by assessment of brain uptake, distribution and washout for selected 18F radiolabeled compounds in non‐human primates (NHP).ResultsSeveral chemical series showing nanomolar binding affinity to aggregated TDP‐43 from patient brain samples were identified. The specificity of binding was further confirmed by high resolution autoradiography enabling visualization of target engagement on TDP‐43 inclusions in FTLD‐TDP brain sections. In addition, the most advanced compounds differentiated FTLD‐TDP from control by classical autoradiography on patient brain sections. Selectivity over amyloid beta, alpha‐synuclein and Tau was observed. The compounds with the most favorable brain penetrantion properties demonstrated fast and substantial brain uptake and fast and complete washout in NHPs.ConclusionsFirst‐in‐class TDP‐43 PET ligands have been discovered with the potential to identify FTLD‐TDP pathology by PET. These tools may finally allow the ability to detect and follow the progression of TDP‐43 pathology in the brains of living patients with certain TDP‐43 proteinopathies.

Neuropathological characterization of PiB binding in postmortem striatum in Down syndrome

AbstractBackgroundAmyloid‐beta plaques form in the brain throughout life in people with Down syndrome (DS) and are one of the hallmarks of Alzheimer disease (AD) neuropathology. The regional progression of amyloid buildup in DS is similar to that of late onset AD (LOAD) in the neurotypical population. The development of positron emission tomography (PET) ligands like Pittsburgh Compound B (PiB) has allowed researchers and clinicians to visualize and track amyloid accumulation in the brain throughout life. Using this technology, a unique pattern emerges in people with DS, where the earliest and strongest PiB PET retention is in the striatum, unlike LOAD but similar to autosomal dominant AD. Frontal cortex PiB PET retention is similar in all groups. We used a fluorescent derivative of PiB, cyano‐PiB (CN‐PiB), to investigate PiB labeling postmortem in DS striatum. We hypothesized that striatal CN‐PiB load increases with age and is greater than in the frontal cortex, similar to observations from PiB PET studies of adults with DS.MethodWe conducted CN‐PiB labeling in postmortem striatum and frontal cortex from 44 cases with DS ages ranging from 42 to 70 years (25F/19M, mean PMI 7.4 hours). Whole slide imaging and automated image analysis were used to derive individual plaque‐level information regarding load, size, and distribution of CN‐PiB+ plaques in DS with age.ResultCN‐PiB labeled plaques in both the striatum and frontal cortex were also positive for amyloid‐beta antibodies targeting epitopes 1‐16, 17‐24, and x‐42. Preliminary data suggest that striatal CN‐PiB load (median = 2.3%) is not higher compared to the frontal cortex in DS (median = 10%). Striatal CN‐PiB load did not change with age from 42 to 70 years, suggesting an early saturation (IQR = 3.5%).ConclusionCN‐PiB labeled amyloid‐beta plaque load in the striatum in DS is comparable to conventional neuropathologic analysis and does not differ from frontal cortical load. Other aspects of PiB‐binding or pathologies may contribute to the early and prominent striatal PiB PET retention reported in DS. It will be important in future studies to include younger cases with DS.

Positron emission tomography (PET) imaging of neuroinflammation in healthy and Alzheimer disease participants using TSPO tracers

AbstractBackgroundAlzheimer’s disease (AD) is the most common type of dementia. In addition to the widely recognized accumulation of amyloid and tau protein being the core pathology of AD, neuroinflammation is another cause of brain dysfunction and structural change. Expression of translocator protein (TSPO) on the outer mitochondrial membrane of activated microglia is strongly associated with neuroinflammation. With the development of TSPO positron emission tomography (PET) tracer, we were able to evaluate neuroinflammation non‐invasively in a clinical cohort of AD spectrum.MethodCognitively impaired patients (including AD and mild cognitive impairment (MCI)) and cognitively normal controls (CN) were recruited from single dementia clinic. [18F]FEPPA, the second‐generation PET ligand specifically binds TSPO was synthesized fully automated. Structural brain MRI and functional PET imaging were performed simultaneously with a PET/MR scanner (SIGNA, GE Company, USA). Kinetic analyses were performed using PMOD 4.2 modeling software. Total distribution volume (VT) in each ROI, including frontal, temporal, inferiolateral parietal, occipital, hippocampus and cerebellum, were derived from a two‐tissue compartment model (2‐TCM). In addition, APOE and rs6971 polymorphism genotyping were conducted in all subjects. Mann‐Whitney U Tet, Kruskal‐Wallis Test and linear correlation were performed.ResultA total of 39 participants (23 males and 16 females) participated, including 13 cognitively normal, 9 with MCI and 17 with Alzheimer’s disease. The rs6971 genotype had no significant effect on [18F]FEPPA binding to TSPO. The amount of TSPO expression was independent of age, gender, and APOE ε4 carrier status. The VT of each ROI did not differ significantly between cognitive groups. VT of frontal, temporal, inferiolateral parietal and occipital lobe were all negatively correlated with MMSE, Boston Naming Test and Trial Making A performance. However, such association was not observed between VT of hippocampus and cognitive tests.ConclusionAlthough there was no difference between TSPO expression in each ROI among cognitive groups, we still observed that higher TSPO expression in the cortex was associated with worse performance in certain cognitive tests. This implied that the increase in neuroinflammation was related to the decline of cognitive performance regardless of cognitive diagnosis.

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.

Visualizing reactive astrocytes: Positron emission tomography imaging ligands for imidazoline‐2 binding sites

AbstractImidazoline‐2 binding sites (I2BS) exhibit specific expression in reactive astrocytes of the brain and are implicated in various pathophysiological processes, including analgesia, inflammation, Alzheimer's disease, Parkinson's disease, and glial tumors. However, the lack of available protein structural data poses a challenge in the exploration of I2BS functions and pharmacological characterizations, indicating the need for the discovery of selective ligands. As a non‐invasive and translational molecular imaging tool, positron emission tomography (PET) has found wide application in clinical diagnosis and drug discovery. Consequently, several PET ligands have been developed to “visualize” I2BS in the living brain, thereby elucidating the biological implications of I2BS and facilitating I2BS‐directed drug development. This review offers a comprehensive update on I2BS PET ligands, with a focus on their chemotypes and PET imaging outcomes. Furthermore, the review provides a summary of recent I2BS drug discoveries, which could serve as a catalyst for the development of more potent PET ligands.

The α-synuclein PET tracer [18F] ACI-12589 distinguishes multiple system atrophy from other neurodegenerative diseases

A positron emission tomography (PET) tracer detecting α-synuclein pathology will improve the diagnosis, and ultimately the treatment of α-synuclein-related diseases. Here we show that the PET ligand, [18F]ACI-12589, displays good in vitro affinity and specificity for pathological α-synuclein in tissues from patients with different α-synuclein-related disorders including Parkinson’s disease (PD) and Multiple-System Atrophy (MSA) using autoradiography and radiobinding techniques. In the initial clinical evaluation we include 23 participants with α-synuclein related disorders, 11 with other neurodegenerative disorders and eight controls. In vivo [18F]ACI-12589 demonstrates clear binding in the cerebellar white matter and middle cerebellar peduncles of MSA patients, regions known to be highly affected by α-synuclein pathology, but shows limited binding in PD. The binding statistically separates MSA patients from healthy controls and subjects with other neurodegenerative disorders, including other synucleinopathies. Our results indicate that α-synuclein pathology in MSA can be identified using [18F]ACI-12589 PET imaging, potentially improving the diagnostic work-up of MSA and allowing for detection of drug target engagement in vivo of novel α-synuclein targeting therapies.

Evaluation of an Image-Derived Input Function for Kinetic Modeling of Nicotinic Acetylcholine Receptor-Binding PET Ligands in Mice.

Positron emission tomography (PET) radioligands that bind with high-affinity to α4β2-type nicotinic receptors (α4β2Rs) allow for in vivo investigations of the mechanisms underlying nicotine addiction and smoking cessation. Here, we investigate the use of an image-derived arterial input function and the cerebellum for kinetic analysis of radioligand binding in mice. Two radioligands were explored: 2-[18F]FA85380 (2-FA), displaying similar pKa and binding affinity to the smoking cessation drug varenicline (Chantix), and [18F]Nifene, displaying similar pKa and binding affinity to nicotine. Time-activity curves of the left ventricle of the heart displayed similar distribution across wild type mice, mice lacking the β2-subunit for ligand binding, and acute nicotine-treated mice, whereas reference tissue binding displayed high variation between groups. Binding potential estimated from a two-tissue compartment model fit of the data with the image-derived input function were higher than estimates from reference tissue-based estimations. Rate constants of radioligand dissociation were very slow for 2-FA and very fast for Nifene. We conclude that using an image-derived input function for kinetic modeling of nicotinic PET ligands provides suitable results compared to reference tissue-based methods and that the chemical properties of 2-FA and Nifene are suitable to study receptor response to nicotine addiction and smoking cessation therapies.

Synthesis and evaluation of a novel PET ligand, a GSK’963 analog, aiming at autoradiography and imaging of the receptor interacting protein kinase 1 in the brain

BackgroundReceptor interacting protein kinase 1 (RIPK1) is a serine/threonine kinase, which regulates programmed cell death and inflammation. Recently, the involvement of RIPK1 in the pathophysiology of Alzheimer’s disease (AD) has been reported; RIPK1 is involved in microglia’s phenotypic transition to their dysfunctional states, and it is highly expressed in the neurons and microglia in the postmortem brains in AD patients. They prompt neurodegeneration leading to accumulations of pathological proteins in AD. Therefore, regulation of RIPK1 could be a potential therapeutic target for the treatment of AD, and in vivo imaging of RIPK1 may become a useful modality in studies of drug discovery and pathophysiology of AD. The purpose of this study was to develop a suitable radioligand for positron emission tomography (PET) imaging of RIPK1.Results(S)-2,2-dimethyl-1-(5-phenyl-4,5-dihydro-1H-pyrazol-1-yl)propan-1-one (GSK’963) has a high affinity, selectivity for RIPK1, and favorable physiochemical properties based on its chemical structure. In this study, since 11C-labeling (half-life: 20.4 min) GSK’963 retaining its structure requiring the Grignard reaction of tert-butylmagnesium halides and [11C]carbon dioxide was anticipated to give a low yield, we decided instead to 11C-label a GSK’963 analog ((S)-2,2-dimethyl-1-(5-(m-tolyl)-4,5-dihydro-1H-pyrazol-1-yl)propan-1-one, GG502), which has a high RIPK1 inhibitory activity equivalent to that of the original compound GSK’963. Thus, we successfully 11C-labeled GG502 using a Pd-mediated cross-coupling reaction in favorable yields (3.6 ± 1.9%) and radiochemical purities (> 96%), and molar activity (47–115 GBq/μmol). On autoradiography, radioactivity accumulation was observed for [11C]GG502 and decreased by non-radioactive GG502 in the mouse spleen and human brain, indicating the possibility of specific binding of this ligand to RIPK1. On brain PET imaging in a rhesus monkey, [11C]GG502 showed a good brain permeability (peak standardized uptake value (SUV) ~3.0), although there was no clear evidence of specific binding of [11C]GG502. On brain PET imaging in acute inflammation model rats, [11C]GG502 also showed a good brain permeability, and no significant increased uptake was observed in the lipopolysaccharide-treated side of striatum. On metabolite analysis in rats at 30 min after administration of [11C]GG502, ~55% and ~10% of radioactivity was from unmetabolized [11C]GG502 in the brain and the plasma, respectively.ConclusionsWe synthesized and evaluated a 11C-labeled PET ligand based on the methylated analog of GSK’963 for imaging of RIPK1 in the brain. Although in autoradiography of the resulting [11C]GG502 indicated the possibility of specific binding, the actual PET imaging failed to detect any evidence of specific binding to RIPK1 despite its good brain permeability. Further development of radioligands with a higher binding affinity for RIPK1 in vivo and more stable metabolite profiles compared with the current compound may be required.

Recent Advances of S-18F Radiochemistry for Positron Emission Tomography.

The click chemistry of sulfur(VI) fluoride exchange (SuFEx) has facilitated the widespread application of sulfur-fluoride compounds such as sulfonyl fluorides, fluorosulfates, and sulfamoyl fluorides in various fields, especially in the development of 18F ligands for PET (positron emission tomography) imaging. In recent years, the prominent progress of sulfur-[18F]fluoride compounds has been achieved through the combination of 18F and sulfur-fluoride chemistry. These compounds serve as potential 18F tracers, 18F synthons, and reagents for 18F-fluorination, thereby complementing the range of 18F ligands, typically C-18F structures, used in PET studies. This review aims to provide an overview of S-18F labeling reactions through examples of relevant 18F compounds and highlight the advancements and breakthroughs achieved in the past decade.

Development of Novel 11C-Labeled Selective Orexin-2 Receptor Radioligands for Positron Emission Tomography Imaging.

Orexin 2 receptors (OX2R) represent a vital subtype of orexin receptors intricately involved in the regulation of wakefulness, arousal, and sleep-wake cycles. Despite their importance, there are currently no positron emission tomography (PET) tracers available for imaging the OX2R in vivo. Herein, we report [11C]1 ([11C]OX2-2201) and [11C]2 ([11C]OX2-2202) as novel PET ligands. Both compounds 1 (Ki = 3.6 nM) and 2 (Ki = 2.2 nM) have excellent binding affinity activities toward OX2R and target selectivity (OX2/OX1 > 600 folds). In vitro autoradiography in the rat brain suggested good to excellent in vitro binding specificity for [11C]1 and [11C]2. PET imaging in rat brains indicated that the low brain uptake of [11C]2 may be due to P-glycoprotein and/or breast cancer resistance protein efflux interaction and/or low passive permeability. Continuous effort in medicinal chemistry optimization is necessary to improve the brain permeability of this scaffold.

Mild Motor Signs in Healthy Aging Are Associated with Lower Synaptic Density in the Brain.

To investigate whether mild motor signs (MMS) in old age correlate with synaptic density in the brain. Normal aging is associated with a decline in movement quality and quantity, commonly termed "mild parkinsonian signs" or more recently MMS. Whether MMS stem from global brain aging or pathology within motor circuits remains unresolved. The synaptic vesicle glycoprotein 2A positron emission tomography (PET) ligand 11 C-UCB-J allows the investigation of brain-motor associations at the synaptic level in vivo. Fifty-eight healthy older adults (≥50 years) were included from two monocentric control cohorts. Brain magnetic resonance imaging and 11 C-UCB-J PET data were available in 54 participants. 11 C-UCB-J PET binding was quantified by standardized uptake value ratio (SUVR) values in grey matter (GM) volumes of interest (VOIs): caudate, putamen, globus pallidus, substantia nigra, thalamus, cerebellum, and the frontal, parietal, temporal, and occipital cortex. Multiple linear regression analyses were performed with Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III score measuring MMS as the dependent variable and mean SUVR values in each VOI as the independent variable with age, Fazekas score (white matter lesion [WML] load), VOI and cohort as covariates. Participants (68 ± 7.5 years; 52% female) had an average MDS-UPDRS part III score of 3.3 ± 2.8. The MDS-UPDRS part III score was inversely associated with synaptic density, independently of WML load or GM volume, in the caudate, substantia nigra, thalamus, cerebellum, and parietal, occipital, temporal cortex. Cohen's f2 showed moderate effect sizes for subcortical (range, 0.30-0.35), cortical (0.28-0.35) and cerebellar VOIs (0.31). MMS in healthy aging are associated with lower synaptic density throughout the brain. © 2023 International Parkinson and Movement Disorder Society.

Synaptic density in aging mice measured by [18F]SynVesT-1 PET

Synaptic alterations in certain brain structures are related to cognitive decline in neurodegeneration and in aging. Synaptic loss in many neurodegenerative diseases can be visualized by positron emission tomography (PET) imaging of synaptic vesicle glycoprotein 2A (SV2A). However, the use of SV2A PET for studying synaptic changes during aging is not particularly explored. Thus, in the present study, PET ligand [18F]SynVesT-1, which binds to SV2A, was used to investigate synaptic density at different ages in healthy mice.Wild type C57BL/6 mice divided into three age groups (4–5 months (n = 7), 12–14 months (n = 11), 17–19 months (n = 7)) were PET scanned with [18F]SynVesT-1. Brain retention of [18F]SynVesT-1 expressed as the volume of distribution (VIDIF) was calculated using an image-derived input function. Estimates of VIDIF were derived using either a one-tissue compartment model (1TCM), a two-tissue compartment model (2TCM), or the Logan plot with blood input to find the best-fit model for [18F]SynVesT-1. After the PET scans, tissue sections were immunostained for the detection of SV2A and neuronal markers.We found that [18F]SynVesT-1 data acquired 60 min post intravenously injection and analyzed with 1TCM described the brain pharmacokinetics of the radioligand in mice well. [18F]SynVesT-1 brain retention was lower in the oldest group of mice, indicating a decrease in synaptic density in this age group. However, no gradual age-dependent decrease in synaptic density at a region-specific level was observed. Immunostaining indicated that SV2A expression and neuron numbers were similar across all three age groups. In general, these data obtained in healthy aging mice are consistent with previous findings in humans where synaptic density appeared stable during aging up to a certain age, after which a small decrease is observed.

First GPR119 PET Imaging Ligand: Synthesis, Radiochemistry, and Preliminary Evaluations.

G-protein-coupled receptor 119 (GPR119) has emerged as a promising target for treating type 2 diabetes mellitus. Activating GPR119 improves glucose homeostasis, while suppressing appetite and weight gain. Measuring GPR119 levels in vivo could significantly advance GPR119-based drug development strategies including target engagement, occupancy, and distribution studies. To date, no positron emission tomography (PET) ligands are available to image GPR119. In this paper, we report the synthesis, radiolabeling, and preliminary biological evaluations of a novel PET radiotracer [18F]KSS3 to image GPR119. PET imaging will provide information on GPR119 changes with diabetic glycemic loads and the efficacy of GPR119 agonists as antidiabetic drugs. Our results demonstrate [18F]KSS3's high radiochemical purity, specific activity, cellular uptake, and in vivo and ex vivo uptake in pancreas, liver, and gut regions, with high GPR119 expression. Cell pretreatment with nonradioactive KSS3, rodent PET imaging, biodistribution, and autoradiography studies showed significant blocking in the pancreas showing [18F]KSS3's high specificity.

Prostate-specific membrane antigen ligand positron emission tomography (PSMA-PET) disease extent and overall survival (OS) in patients (pts) with high-risk nonmetastatic castration-resistant prostate cancer (nmCRPC): An international multicenter retrospective study.

5010 Background: PSMA-PET was positive for distant metastases (39% distant nodes, 24% bone, 6% visceral organ) in &gt;50% of nmCRPC pts who were nonmetastatic by conventional imaging (Fendler et al. CCR 2019). However, the prognostic impact of PSMA-PET disease extent and its association with oncologic outcomes is unknown. We assessed the prognostic utility of PSMA-PET disease extent in nmCRPC pts defined by conventional imaging for OS and new metastases-free survival (nMFS). Methods: 200 pts (6 centers) with nmCRPC by conventional imaging and prostate-specific antigen doubling time (PSADT) ≤10 mo and/or ISUP grade group ≥4 underwent PSMA-PET. Clinical course and treatment management after PSMA-PET imaging were recorded for 4-9 y. Pt characteristics and PSMA-PET disease extent were analyzed retrospectively. OS and PSMA-PET nMFS (time from primary PSMA-PET to appearance of new distant metastases by PSMA-PET or death) were analyzed for pt subgroups based on disease extent by univariate Cox regression. Results: Median OS was 74 mo, similar to the SPARTAN study of nmCRPC pts (74 mo; Smith et al. Eur Urol 2021). Polymetastatic disease (≥5 distant lesions by PSMA-PET) was associated with shorter OS (median 61 mo vs not reached [NR]) and shorter PSMA-PET nMFS (HR 1.8, 95% CI 1.1-2.9; median 38 vs 60 mo; p=0.021). Any metastatic disease by PSMA-PET and whole-body PSMA tumor volume were not prognostic for OS and PSMA-PET nMFS (all p&gt;0.05). Initial pN1 status was associated with shorter OS (median 55 mo vs NR), but not with PSMA-PET nMFS (p&gt;0.05). Baseline age, baseline Gleason grade ≥8, prior radiotherapy (RT), and PSA and PSADT at time of primary PSMA-PET were not associated with outcomes (all p&gt;0.05). Management after PSMA-PET imaging was mostly local/targeted therapy in pts with no visible/locoregional disease (40/30%) and androgen receptor signaling inhibition therapy in pts with nodal/bone distant metastases (35/43%). Conclusions: Polymetastases (&gt;5) by PSMA-PET and initial pN1 status were significantly associated with worse OS. PSMA-PET disease extent provides a potential novel additional risk stratification for pts with nmCRPC without distant metastasis based on conventional imaging. Further validation is needed to prove its independent prognostic value. Clinical trial information: NCT01946204 . [Table: see text]