68Ga-Labeled Benzothiazole Derivatives for Imaging Aβ Plaques in Cerebral Amyloid Angiopathy
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ABSTRACT:
SUBMITTER: Huynh T
PROVIDER: S-EPMC9202065 | biostudies-literature | 2022 Jun
REPOSITORIES: biostudies-literature
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Project description:Objective: We aimed to investigate the distribution of [68Ga]Ga-p14-032, a novel PET ligand that binds to vascular amyloid, in patients diagnosed clinically with probable cerebral amyloid angiopathy (CAA) compared with patients with Alzheimer's disease (AD) and normal controls (NC). Methods: This longitudinal cohort study was composed of 10 subjects (three probable CAA patients, two AD patients, five NC subjects), recruited from a clinic in China. CAA patients had a history of lobar intracerebral hemorrhage (ICH) and met modified Boston criteria for probable CAA. All participants were aged at least 55 years and underwent [68Ga] Ga-p14-032 PET/CT or/and PET/MRI, and the Montreal Cognitive Assessment on initial assessment. Demographics were measured at baseline (diabetes, hypertension, hypercholesterolemia, ischemic stroke, and ICH). Two PET imaging experts reviewed the PET images with cortical standardized uptake value ratio (SUVr) displayed on a color scale and visually classified the images as positive or negative. The mean of SUVr was calculated using the pons as reference. Results: In CAA patients, PET scans were positive in regions with higher numbers of CMBs. No significant signal was seen in AD subjects or controls. The relative [68Ga]Ga-p14-032 retention in the cortex was stronger in patients with CAA than AD and NC (median SUVr 2.68 ± 1.53 vs. 1.77 ± 0.08 and 0.83 ± 0.24). Conclusions: Our results provide early evidence that the [68Ga] Ga-p14-032 PET probe binds preferentially to vascular amyloid and may be a useful tracer for diagnosing CAA.
| S-EPMC8580011 | biostudies-literature
Project description:In this study, we synthesized four novel Al18/19F-labeled 2-phenylbenzothiazole derivatives conjugated to 1,4,7-triazacyclononane-1,4-diacetic acid via alkyl linkers and evaluated them as imaging agent targets to amyloid-β (Aβ) plaques deposited in the blood vessels of cerebral amyloid angiopathy (CAA) brain. The four ligands exhibited moderate-to-high binding ability to Aβ1-42 aggregates, of which complex 17 possessing the most potent affinity (K i = 11.3 nM) was selected for further biological evaluations. In vitro fluorescent staining and in vitro autoradiography studies on brain sections from CAA patients proved that this ligand could label Aβ deposits in blood vessels selectively. In biodistribution study, [18F]17 can hardly penetrate the blood-brain barrier (brain2 min = 0.3% ID/g) and displayed a rapid blood washout rate (blood2 min/blood60 min = 25.2), which is favorable as CAA imaging agents. In conclusion, this Al18F-labeled 2-phenylbenzothiazole complex was developed and proved to be a promising CAA positron emission tomography agent.
| S-EPMC6217595 | biostudies-literature
Project description:Cerebral amyloid angiopathy (CAA) corresponds to the deposition of amyloid material in the cerebral vasculature, leading to structural modifications of blood vessel walls. The most frequent form of sporadic CAA involves fibrillar β-amyloid peptide (Aβ) deposits, mainly the 40 amino acid form (Aβ1-40), which are commonly found in the elderly with or without Alzheimer's disease. Sporadic CAA usually remains clinically silent. However, in some cases, acute complications either hemorrhagic or inflammatory can occur. Similar complications occurred after active or passive immunization against Aβ in experimental animal models exhibiting CAA, and in subjects with Alzheimer's disease during clinical trials. The triggering of these adverse events by active immunization and monoclonal antibody administration in CAA-bearing individuals suggests that analogous mechanisms could be involved during spontaneous CAA complications, drawing particular attention to the role of anti-Aβ antibodies. However, antibodies that react with several monomeric and aggregated forms of Aβ spontaneously occur in virtually all human individuals, hence being part of the "natural antibody" repertoire. Natural antibodies are usually described as having low-affinity and high cross-reactivity toward microbial components and autoantigens. Although frequently of the IgM class, they also belong to IgG and IgA isotypes. They likely display homeostatic functions and protective roles in aging. Until recently, the peculiar properties of these natural antibodies have hindered proper analysis of the Aβ-reactive antibody repertoire and the study of their implication in CAA complications. Herein, we review and comment the evidences of an auto-immune nature of spontaneous CAA complications, and discuss implications for forthcoming research and clinical practice.
| S-EPMC6620823 | biostudies-literature
Project description:The ε4 allele of the apolipoprotein E (APOE) gene is the strongest genetic risk factor for late-onset Alzheimer's disease (AD) and greatly influences the development of amyloid-β (Aβ) pathology. Our current study investigated the potential therapeutic effects of the anti-human APOE antibody HAE-4, which selectively recognizes human APOE that is co-deposited with Aβ in cerebral amyloid angiopathy (CAA) and parenchymal amyloid pathology. In addition, we tested whether HAE-4 provoked brain hemorrhages, a component of amyloid-related imaging abnormalities (ARIA). ARIA is an adverse effect secondary to treatment with anti-Aβ antibodies that can occur in blood vessels with CAA. We used 5XFAD mice expressing human APOE4+/+ (5XE4) that have prominent CAA and parenchymal plaque pathology to assess the efficacy of HAE-4 compared to an Aβ antibody that removes parenchymal Aβ but increases ARIA in humans. In chronically treated 5XE4 mice, HAE-4 reduced Aβ deposition including CAA compared to a control antibody, whereas the anti-Aβ antibody had no effect on CAA. Furthermore, the anti-Aβ antibody exacerbated microhemorrhage severity, which highly correlated with reactive astrocytes surrounding CAA. In contrast, HAE-4 did not stimulate microhemorrhages and instead rescued CAA-induced cerebrovascular dysfunction in leptomeningeal arteries in vivo. HAE-4 not only reduced amyloid but also dampened reactive microglial, astrocytic, and proinflammatory-associated genes in the cortex. These results suggest that targeting APOE in the core of both CAA and plaques could ameliorate amyloid pathology while protecting cerebrovascular integrity and function.
| S-EPMC8128342 | biostudies-literature
Project description:The development of a 99mTc-radiotracer for imaging of β-amyloid (Aβ) plaques with single photon emission computed tomography (SPECT) is strongly anticipated to provide a low cost and broadly accessible diagnostic tool for Alzheimer's disease (AD). Within this framework, 2-(4'-aminophenyl)benzothiazole, known to display affinity and specificity for Aβ plaques, has been joined to the tricarbonyl fac-[M(CO)3]+ (M = Re(I), 99mTc(I)) core through the cyclopentadienyl moiety to yield stable, neutral, and lipophilic complexes (Re-1 and 99mTc-1, respectively). The Re-1 complex was completely characterized with spectroscopic methods and was shown to selectively stain Aβ plaques on sections of human AD brain tissue. The 99mTc-1 complex displayed satisfactory initial brain uptake (0.53% ID/g at 2 min) and in vivo stability in healthy mice, while in transgenic 5xFAD mice, models for AD, a notable retention in the brain was noted (1.94% ID/g at 90 min). The results are encouraging and contribute to the effort of developing a SPECT amyloid imaging agent.
| S-EPMC5641965 | biostudies-literature
Project description:AimThe aim of this study was to evaluate and correct for partial-volume-effects (PVE) on [68Ga]Ga-Pentixafor uptake in atherosclerotic plaques of the carotid arteries, and the impact of ignoring bone in MR-based attenuation correction (MR-AC).MethodsTwenty [68Ga]Ga-pentixafor PET/MR examinations including a high-resolution T2-TSE MR of the neck were included in this study. Carotid plaques located at the carotid bifurcation were delineated and the anatomical information was used for partial-volume-correction (PVC). Mean and max tissue-to-background ratios (TBR) of the [68Ga]Ga-Pentixafor uptake were compared for standard and PVC-PET images. A potential influence of ignoring bone in MR-AC was assessed in a subset of the data reconstructed after incorporating bone into MR-AC and a subsequent comparison of standardized-uptake values (SUV).ResultsIn total, 34 atherosclerotic plaques were identified. Following PVC, mean and max TBR increased by 77 and 95%, respectively, when averaged across lesions. When accounting for bone in the MR-AC, SUV of plaque changed by 0.5%.ConclusionQuantitative readings of [68Ga]Ga-pentixafor uptake in plaques are strongly affected by PVE, which can be reduced by PVC. Including bone information into the MR-AC yielded no clinically relevant effect on tracer quantification.
| S-EPMC8993720 | biostudies-literature
Project description:Accumulating data suggest that cerebrovascular disease contributes to Alzheimer's disease pathophysiology and progression toward dementia. Cerebral amyloid angiopathy is a form of cerebrovascular pathology that results from the build-up of β-amyloid in the vessel walls. Cerebral amyloid angiopathy commonly co-occurs with Alzheimer's disease pathology in the ageing brain and increases the risk of Alzheimer's disease dementia. In the present study, we examined whether cerebral amyloid angiopathy influences tau deposition and cognitive decline independently or synergistically with parenchymal β-amyloid burden. Secondly, we examined whether tau burden mediates the association between cerebral amyloid angiopathy and cognitive decline. We included data from autopsied subjects recruited from one of three longitudinal clinical-pathological cohort studies: the Rush Memory and Aging Project, the Religious Orders Study and the Minority Aging Research Study. Participants completed annual clinical and cognitive evaluations and underwent brain autopsy. Cerebral amyloid angiopathy pathology was rated as none, mild, moderate or severe. Bielschowsky silver stain was used to visualize neuritic β-amyloid plaques and neurofibrillary tangles. We used linear regression and linear mixed models to test independent versus interactive associations of cerebral amyloid angiopathy and neuritic plaque burden with tau burden and longitudinal cognitive decline, respectively. We used causal mediation models to examine whether tau mediates the association between cerebral amyloid angiopathy and cognitive decline. The study sample included 1722 autopsied subjects (age at baseline = 80.2 ± 7.1 years; age at death = 89.5 ± 6.7 years; 68% females). Cerebral amyloid angiopathy interacted with neuritic plaques to accelerate tau burden and cognitive decline. Specifically, those with more severe cerebral amyloid angiopathy pathology and higher levels of neuritic plaque burden had greater tau burden and faster cognitive decline. We also found that tau mediated the association between cerebral amyloid angiopathy and cognitive decline among participants with higher neuritic plaque burden. In summary, more severe levels of cerebral amyloid angiopathy and higher parenchymal β-amyloid burden interacted to promote cognitive decline indirectly via tau deposition. These results highlight the dynamic interplay between cerebral amyloid angiopathy and Alzheimer's disease pathology in accelerating progression toward dementia. These findings have implications for Alzheimer's disease clinical trials and therapeutic development.
| S-EPMC9420012 | biostudies-literature
Project description:BackgroundSomatostatin receptor (SSTR)-targeted positron emission tomography/computed tomography (PET/CT) imaging has risen to the forefront for neuroendocrine tumor (NET) detection and management, yet the variability of significant uptake variability (SUV) as a semiquantitative measure of disease detection and tumor response to treatment has not been fully explored.MethodsWe assess the reproducibility and interscan variability of SUV metrics of normal tissue and NET in serial 68Ga-DOTA-NOC and 68Ga-DOTA-TATE PET imaging to clinically monitor disease state. Eighty-one patients were enrolled in this retrospective study.ResultsBoth primary and metastatic hepatic lesions demonstrated SUV (SUVmean 16.5±8.0). The median SUVmean was 16 for the spleen, 9.7 for the pituitary, 12.6 for the adrenal glands, and 4.8 for the liver. The normal pituitary gland demonstrates focal homogenous uptake with SUVmax range of 4.5-23. The adrenal gland showed uptake with SUVmax range of 4.1-29.4, which is more than two times greater than liver uptake (SUVmean range, 2.3-12.4). Highest physiological uptake seen in the spleen (average SUVmean of 17.3, range of 5.4-34.4).ConclusionsThe highly variable nature of regional SUVmean and SUVmax in both physiologic tissue and lesions suggests the need for incorporation of more reliable quantitative measures for clinical decision making.
| S-EPMC9577978 | biostudies-literature
Project description:68Ga-radiolabeled small molecules that specifically target prostate-specific membrane antigen (PSMA) have been extensively investigated, and some of these tracers have been used in the diagnosis of prostate cancer via 68Ga-positron emission tomography (68Ga-PET). Nevertheless, current 68Ga-labeled radiotracers show only fair detection rates for metastatic prostate cancer lesions, especially those with lower levels of prostate specific antigen (PSA), which often occurs in the biochemical recurrence of prostate cancer. The goal of this study was to design and synthesize a new PSMA-targeted radiotracer, 68Ga-SC691, with high affinity for prostate cancer cells and excellent pharmacokinetics. To this end, structural optimization was carried out on the bifunctional group, target motif, and linker while the high affinity targeting scaffold remained. To explore its potential in the clinic, a comparative study was further performed in vitro and in vivo between 68Ga-SC691 and 68Ga-PSMA-11, a clinically approved tracer for PSMA-positive prostate cancer. SC691 was radiolabeled to provide 68Ga-SC691 in 99% radiolabeling yield under mild conditions. High uptake and a high internalization ratio into LNCaP cells were observed in in vitro studies. In vivo studies showed that 68Ga-SC691 had favorable biodistribution properties and could specifically accumulate on PSMA-positive LNCaP xenografts visualized by micro-PET/CT. This radiotracer showed excellent PET imaging quality and comparable, if not higher, uptake in LNCaP xenografts than 68Ga-PSMA-11.
| S-EPMC8476564 | biostudies-literature
Project description:Radiolabeled erythrocytes have multiple applications in nuclear medicine, including blood pool imaging. Historically they have been labeled with SPECT radionuclides. A PET blood pool imaging agent is highly desirable as it would improve clinical applications with better image quality and resolution, higher sensitivity, and dynamic scanning capabilities. With the coming of age of modern 68Ge/68Ga generator systems, gallium-68 is now widely accessible. In this paper we describe an updated method for the preparation of 68Ga-labeled erythrocytes and their preliminary use in rodent blood pool imaging. A novel automated synthesis of [68Ga]oxine using a 68Ga/68Ge generator and automated synthesis module is reported. [68Ga]Oxine was synthesized in 50 ± 5% (n = 3) non-decay corrected radiochemical yield and >99% radiochemical purity. Rat and human erythrocytes were successfully labeled with the complex in 42% RCY, and the 68Ga-labeled erythrocytes have been shown to clearly image the blood pool in a healthy rat. Human erythrocytes labelled with [68Ga]oxine were shown to be viable up to 2 hours post-labelling, and washout of the radiolabel was minimal up to 1 hour post-labelling. Further optimization of the labeling method to translate for use in human cardiac and oncologic blood pool PET imaging studies, is underway.
| S-EPMC6071839 | biostudies-literature