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Development and <i>in vivo</i> evaluation of a novel kappa opioid receptor agonist as PET radiotracer with superior imaging characteristics
摘要： Studies have shown kappa opioid receptor (KOR) abnormalities in addictive disorders, other central nervous system diseases and Alzheimer’s disease. We have developed the first set of agonist 11C-GR103545 and antagonist 11C-LY2795050 radiotracers for positron emission tomography imaging of KOR in human. Nonetheless, 11C-GR103545 displays protracted uptake kinetics and is not an optimal radiotracer. Here we report the development and evaluation of 11C-EKAP and its comparison with 11C-GR103545. Methods: EKAP was synthesized and assayed for in vitro binding affinities, then radiolabeled with 11C-CH3OTf. PET studies were carried out in rhesus monkeys. Blocking studies were performed with naloxone and the selective KOR antagonists LY2795050 and LY2456302. Arterial input functions were generated for use in kinetic modeling. Brain time-activity curves were analyzed with the multilinear analysis 1 (MA1) method to derive binding parameters. Results: EKAP has high KOR affinity (Ki = 0.28 nM) and good selectivity in vitro. 11C-EKAP was prepared in good radiochemical purity. 11C-EKAP rapidly metabolized in plasma, and displayed fast and reversible kinetics in brain with peak uptake at < 20 min post-injection. Pre-blocking with naloxone (1 mg/kg) or LY2795050 (0.2 mg/kg) produced 84-89% receptor occupancy, while LY2456302 (0.05 & 0.3 mg/kg) dose-dependently reduced 11C-EKAP specific binding, thus demonstrating its binding specificity and selectivity in vivo. Mean MA1-derived BPND values were 1.74, 1.79, 1.46, 0.80 and 0.77 for cingulate cortex, globus pallidus, insula, striatum and frontal cortex, consistent with the known KOR distribution in primate brains. Conclusions: We have successfully developed 11C-EKAP as a novel KOR agonist tracer with dual attractive imaging properties of fast uptake kinetics and high specific binding in vivo.
关键词： 11C-EKAP,PET radiotracer,agonist,non-human primates,kappa opioid receptor
更新于2025-09-23 15:22:29
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PET-Liganden für die Diagnostik der Alzheimer-Demenz: Amyloid und Tau
摘要： Over the last 15 years diagnostic imaging of amyloid and tau deposits with PET has gained increasing importance especially in the context of diagnosis of dementia such as Alzheimer's disease. First radiotracers that were developed aimed at the detection of amyloid plaques in the brain. In the meantime the contribution of hyperphosphorylated proteins (TAU) that lead to another type of protein deposits is getting more and more in the focus of current research on the origin of this disease. While a number of 18F-labelled ligands for amyloid imaging have recently been granted marketing authorization and therefore are commercially available and can be used by licensed nuclear medicine physicians throughout Europe and the US, this is not true for radiotracers for TAU-protein imaging. Therefore their use is restricted to clinical trials or to the application of in house manufactured substances. This article should give an overview on characteristics, development and availability of PET tracers for amyloid and tau imaging and in addition to that exemplify the challenges associated with a GMP compliant manufacturing of these short lived radiotracers.
关键词： Alzheimer,18F,Amyloid,11C,PET,Tau
更新于2025-09-23 15:22:29
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Modeling clustered activity increase in amyloid-beta positron emission tomographic images with statistical descriptors
摘要： Background: Amyloid-beta (Aβ) imaging with positron emission tomography (PET) holds promise for detecting the presence of Aβ plaques in the cortical gray matter. Many image analyses focus on regional average measurements of tracer activity distribution; however, considerable additional information is available in the images. Metrics that describe the statistical properties of images, such as the two-point correlation function (S2), have found wide applications in astronomy and materials science. S2 provides a detailed characterization of spatial patterns in images typically referred to as clustering or flocculence. The objective of this study was to translate the two-point correlation method into Aβ-PET of the human brain using 11C-Pittsburgh compound B (11C-PiB) to characterize longitudinal changes in the tracer distribution that may reflect changes in Aβ plaque accumulation. Methods: We modified the conventional S2 metric, which is primarily used for binary images and formulated a weighted two-point correlation function (wS2) to describe nonbinary, real-valued PET images with a single statistical function. Using serial 11C-PiB scans, we calculated wS2 functions from two-dimensional PET images of different cortical regions as well as three-dimensional data from the whole brain. The area under the wS2 functions was calculated and compared with the mean/median of the standardized uptake value ratio (SUVR). For three-dimensional data, we compared the area under the wS2 curves with the subjects’ cerebrospinal fluid measures. Results: Overall, the longitudinal changes in wS2 correlated with the increase in mean SUVR but showed lower variance. The whole brain results showed a higher inverse correlation between the cerebrospinal Aβ and wS2 than between the cerebrospinal Aβ and SUVR mean/median. We did not observe any confounding of wS2 by region size or injected dose. Conclusion: The wS2 detects subtle changes and provides additional information about the binding characteristics of radiotracers and Aβ accumulation that are difficult to verify with mean SUVR alone.
关键词： positron emission tomography,statistical descriptors,two-point correlation function,amyloid-beta plaques,11C-Pittsburgh compound B
更新于2025-09-04 15:30:14
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Metabolic Volumetric Parameters in <sup>11</sup> C-Choline PET/MR Are Superior PET Imaging Biomarkers for Primary High-Risk Prostate Cancer
摘要： Purpose. Positron emission tomography/magnetic resonance imaging (PET/MRI) can facilitate the use of noninvasive imaging biomarkers in clinical prostate cancer staging. Although multiparametric MRI is a widely used technique, the clinical value of simultaneous PET imaging remains unclear. This study aimed at investigating this issue. Methods. Between January 2015 and December 2016, 31 high-risk prostate cancer patients underwent 11C-choline PET/MRI for staging purposes. Clinical characteristics and imaging parameters, including the standardized uptake value (SUV) and metabolic volumetric parameters from PET imaging; apparent diffusion coefficient (ADC) values from diffusion-weighted imaging; and volume transfer rate constant (Ktrans), reflux rate constant (Kep), and initial area under curve (iAUC) in 60 seconds from dynamic contrast-enhanced (DCE) MRI were analyzed. Results. 11C-Choline PET imaging parameters were significantly correlated with prostate-specific antigen (PSA) levels, and metabolic volumetric parameters, including metabolic tumor volume (MTV) and uptake volume product (UVP), showed significant correlations with other MRI parameters. In our cohort analysis, the PET/MRI parameters UVP/minimal ADC value (ADCmin) and kurtosis of Kep (Kepkur)/ADCmin were significant predictors for progression-free survival (PFS) (HR = 1.01, 95% CI: 1.00–1.02, p = 0.031 and HR = 1.09, 95% CI: 1.02–1.16, p = 0.009, respectively) in multivariate Cox regression analysis. High UVP/ADCmin and Kepkur/ADCmin values were significantly associated with shorter PFS. Conclusions. Metabolic volumetric parameters such as MTV and UVP can be routinely used as PET imaging biomarkers to add prognostic value and show better correlations in combination with MR imaging parameters in high-risk prostate cancer patients undergoing 11C-choline PET/MRI.
关键词： 11C-choline,metabolic volumetric parameters,imaging biomarkers,PET/MRI,prostate cancer
更新于2025-09-04 15:30:14