scholarly journals Amyloid β-binding Bifunctional Chelators with Favorable Lipophilicity for 64Cu PET Imaging in Alzheimer’s Disease

2021 ◽  
Author(s):  
Yujue Wang ◽  
Truc T. Huynh ◽  
Hong-Jun Cho ◽  
Wang Yung-Ching ◽  
Buck E. Rogers ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Pet Imaging ◽  
Ex Vivo ◽  
Amyloid Β ◽  
Specific Staining ◽  
Bifunctional Chelators ◽  
Biodistribution Studies ◽  
Positron Emission ◽  
D Values ◽  
Radiolabeled Compounds

Herein we report a new series of bifunctional chelators (BFCs) with high affinity for amyloid aggregates, strong binding affinity towards Cu(II) and favorable lipophilicity for potential blood-brain barrier (BBB) penetration. The alkyl carboxylate pendant arms offer up to three orders of magnitude higher binding affinity towards Cu(II) vs. the parent chelating fragment, and can generate fairly stable Cu complexes, including <sup>64</sup>Cu-radiolabeled compounds. Among the five compounds tested, the <sup>64</sup>Cu-YW-7 and <sup>64</sup>Cu-YW-10 complexes exhibit strong and specific staining of amyloid plaques in <i>ex vivo</i> autoradiography studies. Importantly, these compounds have promising partition coefficient (Log D) values of 0.91-1.26 and show moderate brain uptake in biodistribution studies using CD-1 mice. Overall, these BFCs could serve as lead compounds for the development of positron emission tomography (PET) imaging agents for AD diagnosis.

scholarly journals Amyloid β-binding Bifunctional Chelators with Favorable Lipophilicity for 64Cu PET Imaging in Alzheimer’s Disease

2021 ◽  
Author(s):  
Yujue Wang ◽  
Truc T. Huynh ◽  
Hong-Jun Cho ◽  
Wang Yung-Ching ◽  
Buck E. Rogers ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Pet Imaging ◽  
Ex Vivo ◽  
Amyloid Β ◽  
Specific Staining ◽  
Bifunctional Chelators ◽  
Biodistribution Studies ◽  
Positron Emission ◽  
D Values ◽  
Radiolabeled Compounds

Herein we report a new series of bifunctional chelators (BFCs) with high affinity for amyloid aggregates, strong binding affinity towards Cu(II) and favorable lipophilicity for potential blood-brain barrier (BBB) penetration. The alkyl carboxylate pendant arms offer up to three orders of magnitude higher binding affinity towards Cu(II) vs. the parent chelating fragment, and can generate fairly stable Cu complexes, including <sup>64</sup>Cu-radiolabeled compounds. Among the five compounds tested, the <sup>64</sup>Cu-YW-7 and <sup>64</sup>Cu-YW-10 complexes exhibit strong and specific staining of amyloid plaques in <i>ex vivo</i> autoradiography studies. Importantly, these compounds have promising partition coefficient (Log D) values of 0.91-1.26 and show moderate brain uptake in biodistribution studies using CD-1 mice. Overall, these BFCs could serve as lead compounds for the development of positron emission tomography (PET) imaging agents for AD diagnosis.

scholarly journals Benzothiazole Carboxylate Diester Bifunctional Chelators for 64Cu PET Imaging in Alzheimer’s Disease

2021 ◽  
Author(s):  
Yujue Wang ◽  
Truc T. Huynh ◽  
Nilantha Bandara ◽  
Hong-Jun Cho ◽  
Buck E. Rogers ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Pet Imaging ◽  
Ex Vivo ◽  
Amyloid Β ◽  
Amyloid Plaques ◽  
Bifunctional Chelators ◽  
High Affinity ◽  
D Values ◽  
Pendant Arms ◽  
High Binding Affinity

Herein we report a new series of bifunctional chelators (BFCs) with high affinity for amyloid β aggregates, strong binding affinity towards Cu(II), and favorable lipophilicity for potential blood-brain barrier (BBB) penetration. The alkyl carboxylate ester pendant arms enable high binding affinity towards Cu(II). The BFCs form stable <sup>64</sup>Cu-radiolabeled complexes and exhibit favorable partition coefficient (log D) values of 0.75-0.95. Among the five compounds tested, the <b><sup>64</sup>Cu-YW-1</b> and <b><sup>64</sup>Cu-YW-13</b> complexes exhibit significant staining of amyloid plaques in <i>ex vivo</i> autoradiography studies.

scholarly journals Benzothiazole Carboxylate Diester Bifunctional Chelators for 64Cu PET Imaging in Alzheimer’s Disease

2021 ◽  
Author(s):  
Yujue Wang ◽  
Truc T. Huynh ◽  
Nilantha Bandara ◽  
Hong-Jun Cho ◽  
Buck E. Rogers ◽  
...  
Keyword(s):  
Binding Affinity ◽  
Pet Imaging ◽  
Ex Vivo ◽  
Amyloid Β ◽  
Amyloid Plaques ◽  
Bifunctional Chelators ◽  
High Affinity ◽  
D Values ◽  
Pendant Arms ◽  
High Binding Affinity

Herein we report a new series of bifunctional chelators (BFCs) with high affinity for amyloid β aggregates, strong binding affinity towards Cu(II), and favorable lipophilicity for potential blood-brain barrier (BBB) penetration. The alkyl carboxylate ester pendant arms enable high binding affinity towards Cu(II). The BFCs form stable <sup>64</sup>Cu-radiolabeled complexes and exhibit favorable partition coefficient (log D) values of 0.75-0.95. Among the five compounds tested, the <b><sup>64</sup>Cu-YW-1</b> and <b><sup>64</sup>Cu-YW-13</b> complexes exhibit significant staining of amyloid plaques in <i>ex vivo</i> autoradiography studies.

2-(4-Hydroxyphenyl)benzothiazole Dicarboxylate Ester TACN Chelators for 64Cu PET imaging in Alzheimer’s Disease

2022 ◽  
Author(s):  
Yujue Wang ◽  
Truc T. Huynh ◽  
Nilantha Bandara ◽  
Hong-Jun Cho ◽  
Buck E. Rogers ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Binding Affinity ◽  
Blood Brain Barrier ◽  
Pet Imaging ◽  
Amyloid Β ◽  
Brain Barrier ◽  
Bifunctional Chelators ◽  
High Affinity ◽  
Strong Binding ◽  
Blood Brain

Herein we report a new series of bifunctional chelators (BFCs) with high affinity for amyloid β aggregates, strong binding affinity towards Cu(II), and favorable lipophilicity for potential blood-brain barrier (BBB)...

scholarly journals Effect of ethanol and cocaine on [11C]MPC-6827 uptake in SH-SY5Y cells

2021 ◽  
Author(s):  
Naresh Damuka ◽  
Miranda Orr ◽  
Paul W. Czoty ◽  
Jeffrey L. Weiner ◽  
Thomas J. Martin ◽  
...  
Keyword(s):  
Mechanism Of Action ◽  
Ex Vivo ◽  
Neuroblastoma Cells ◽  
Proper Function ◽  
Brain Functions ◽  
Biodistribution Studies ◽  
Positron Emission ◽  
Vitro Binding

AbstractMicrotubules (MTs) are structural units in the cytoskeleton. In brain cells they are responsible for axonal transport, information processing, and signaling mechanisms. Proper function of these processes is critical for healthy brain functions. Alcohol and substance use disorders (AUD/SUDs) affects the function and organization of MTs in the brain, making them a potential neuroimaging marker to study the resulting impairment of overall neurobehavioral and cognitive processes. Our lab reported the first brain-penetrant MT-tracking Positron Emission Tomography (PET) ligand [11C]MPC-6827 and demonstrated its in vivo utility in rodents and non-human primates. To further explore the in vivo imaging potential of [11C]MPC-6827, we need to investigate its mechanism of action. Here, we report preliminary in vitro binding results in SH-SY5Y neuroblastoma cells exposed to ethanol (EtOH) or cocaine in combination with multiple agents that alter MT stability. EtOH and cocaine treatments increased MT stability and decreased free tubulin monomers. Our initial cell-binding assay demonstrated that [11C]MPC-6827 may have high affinity to free/unbound tubulin units. Consistent with this mechanism of action, we observed lower [11C]MPC-6827 uptake in SH-SY5Y cells after EtOH and cocaine treatments (e.g., fewer free tubulin units). We are currently performing in vivo PET imaging and ex vivo biodistribution studies in rodent and nonhuman primate models of AUD and SUDs and Alzheimer's disease.

The Transition of Mild Cognitive Impairment Over Time: An AV45- and FDG-PET Study of Reversion and Conversion Phenomena

2021 ◽  
Vol 18 ◽  
Author(s):  
Amir Ashraf-Ganjouei ◽  
Kamyar Moradi ◽  
Shahriar Faghani ◽  
AmirHussein Abdolalizadeh ◽  
Mohammadreza Khomeijani-Farahani ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Mild Cognitive Impairment ◽  
Glucose Metabolism ◽  
Pet Imaging ◽  
Fdg Pet ◽  
Amyloid Β ◽  
Positron Emission ◽  
One Year ◽  
T Tau ◽  
Over Time

Background: Mild cognitive impairment (MCI) is a state between normal cognition and dementia. However, MCI diagnosis does not necessarily guarantee the progression to dementia. Since no previous study investigated brain positron emission tomography (PET) imaging of MCI-- to-normal reversion, we provided PET imaging of MCI-to-normal reversion using the Alzheimer's Disease Neuroimaging Initiative (ADNI) database. Methods: We applied comprehensive neuropsychological criteria (NP criteria), consisting of mem- ory, language, and attention/executive function domains, to include patients with a baseline diagno- sis of MCI (n=613). According to the criteria, the year 1 status of the patients was categorized into three groups (reversion: n=105, stable MCI: n=422, conversion: n=86). Demographic, neuropsycho- logical, genetic, CSF, and cognition biomarker variables were compared between the groups. Addi- tionally, after adjustment for confounding variables, the deposition pattern of amyloid-β and cere- bral glucose metabolism were compared between three groups via AV45- and FDG-PET modali- ties, respectively. Results: MCI reversion rate was 17.1% during one year of follow-up. The reversion group had the lowest frequency of APOE ε4+ subjects, the highest CSF level of amyloid-β, and the lowest CSF levels of t-tau and p-tau. Neuropsychological assessments were also suggestive of better cognitive performance in the reversion group. Patients with reversion to normal state had higher glucose metabolism in bilateral angular and left middle/inferior temporal gyri, when compared to those with stable MCI state. Meanwhile, lower amyloid-β deposition at baseline was observed in the fron- tal and parietal regions of the reverted subjects. On the other hand, the conversion group showed lower cerebral glucose metabolism in bilateral angular and bilateral middle/inferior temporal gyri compared to the stable MCI group, whereas the amyloid-β accumulation was similar between the groups. Conclusions: This longitudinal study provides novel insight regarding the application of PET imag- ing in predicting MCI transition over time.

scholarly journals A Novel PET Imaging Using64Cu-Labeled Monoclonal Antibody against Mesothelin Commonly Expressed on Cancer Cells

2015 ◽  
Vol 2015 ◽  
pp. 1-15 ◽  
Author(s):  
Kazuko Kobayashi ◽  
Takanori Sasaki ◽  
Fumiaki Takenaka ◽  
Hiromasa Yakushiji ◽  
Yoshihiro Fujii ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Cancer Cells ◽  
Pet Imaging ◽  
Ex Vivo ◽  
Chelating Agent ◽  
Pancreatic Cancer Cells ◽  
Positron Emission ◽  
Wide Range

Mesothelin (MSLN) is a 40-kDa cell differentiation-associated glycoprotein appearing with carcinogenesis and is highly expressed in many human cancers, including the majority of pancreatic adenocarcinomas, ovarian cancers, and mesotheliomas, while its expression in normal tissue is limited to mesothelial cells lining the pleura, pericardium, and peritoneum. Clone 11-25 is a murine hybridoma secreting monoclonal antibody (mAb) against human MSLN. In this study, we applied the 11-25 mAb toin vivoimaging to detect MSLN-expressing tumors. Inin vitroandex vivoimmunochemical studies, we demonstrated specificity of 11-25 mAb to membranous MSLN expressed on several pancreatic cancer cells. We showed the accumulation of Alexa Fluor 750-labeled 11-25 mAb in MSLN-expressing tumor xenografts in athymic nude mice. Then, 11-25 mAb was labeled with64Cu via a chelating agent DOTA and was used in bothin vitrocell binding assay andin vivopositron emission tomography (PET) imaging in the tumor-bearing mice. We confirmed that64Cu-labeled 11-25 mAb highly accumulated in MSLN-expressing tumors as compared to MSLN-negative ones. The64Cu-labeled 11-25 mAb is potentially useful as a PET probe capable of being used for wide range of tumors, rather than18F-FDG that occasionally provides nonspecific accumulation into the inflammatory lesions.

Dose Escalation Biodistribution, Positron Emission Tomography/Computed Tomography Imaging and Dosimetry of a Highly Specific Radionuclide-labeled Non-blocking Nanobody

2021 ◽  
Author(s):  
Yang yanling ◽  
Feng Zhao ◽  
Daquan Chen ◽  
Chao Wang ◽  
Yan Sun ◽  
...  
Keyword(s):  
Positron Emission Tomography ◽  
Nude Mice ◽  
Ex Vivo ◽  
Dose Range ◽  
Emission Tomography ◽  
Humanized Mice ◽  
Biodistribution Studies ◽  
Positron Emission ◽  
Pet Ct ◽  
Ex Vivo Biodistribution

Abstract Backgroud: Immunotherapy is a valuable option for the treatment of cancers, and the curative effect anti-PD-1/PD-L1 therapy correlates closely with PD-L1 expression levels. Positron emission tomography (PET) imaging of PD-L1 expression is feasible using 68Ga-NOTA-Nb109 nanobodies. 68Ga-NOTA-Nb109 was generated by radionuclide (68Ga) labeling of Nb109 using a NOTA chelator. To facilitate clinical trials, We explored the optimal dose range of 68Ga-NOTA-Nb109 in BALB/c A375-hPD-L1 tumor-burdened nude mice and C57-hPD-L1 transgenic MC38-hPD-L1 tumor-burdened mice by intravenous of a single intravenous dose of 68Ga-NOTA-Nb109 and confirmed the dose in cynomolgus monkeys. The biodistribution data of cynomolgus monkey PET images were extrapolated to estimate the radiation dose for the adult male using OLINDA2.1 software.Results: 68Ga-NOTA-Nb109 was stable in physiologic media and human serum. Ex vivo biodistribution studies showed rapid and specific uptake in A375-hPDL1 or MC38-hPDL1 tumors. The estimated ED50 was approximately 5.4 µg in humanized mice. The injected mass (0.3–100 µg in nude mice and approximately 1–100 µg in humanized mice) greatly influenced the general biodistribution, with a better tumor-to-background ratio acquired at lower doses of Nb109 (0.3–10 µg in nude mice and approximately 1 µg in humanized mice), indicating maximum uptake in tumors at administered mass doses below the estimated ED50. Therefore, a single 15 μg/kg dose was adopted for the PET/CT imaging in cynomolgus monkey. The highest specific and persistent uptake of the tracer was detected in the spleen, with the exception of the levels in the kidney and urine bladder, which was related to metabolism and excretion. The spleen-to-muscle ratio of the tracer exceeded 10 from immediately to 4 h after administration, indicating that the dose was appropriate. The estimated effective dose was calculated to yield a radiation dose of 4.1 mSv to a patient after injection of 185 MBq of 68Ga-NOTA-Nb109.Conclusion: 68Ga-NOTA-Nb109 showed specific accumulation in hPD-L1 xenografts in ex vivo biodistribution studies and monkey PET/CT imaging. The dose escalation distribution data provided a recommended dose range for further use, and the safety of the tracer was confirmed in dosimetry studies.

scholarly journals No Influence of Age-Related Hearing Loss on Brain Amyloid-β

2021 ◽  
pp. 1-9
Author(s):  
Julia Z. Sarant ◽  
David C. Harris ◽  
Peter A. Busby ◽  
Christopher Fowler ◽  
Jurgen Fripp ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Pet Imaging ◽  
Clinical Sample ◽  
Amyloid Β ◽  
Carrier Status ◽  
Cognitive Assessments ◽  
Age Related ◽  
Positron Emission ◽  
Study Results ◽  
Study Participants

Background: Hearing loss is independently associated with a faster rate of cognitive decline in older adults and has been identified as a modifiable risk factor for dementia. The mechanism for this association is unknown, and there has been limited exploration of potential casual pathology. Objective: Our objective was to investigate whether there was an association between degree of audiometrically measured hearing loss (HL) and brain amyloid-β (Aβ) in a pre-clinical sample. Methods: Participants of the Australian Imaging and Biomarker Longitudinal Study (AIBL; n = 143) underwent positron emission tomography (PET) imaging and objective measurement of hearing thresholds within 5 years of imaging, as well as cognitive assessment within 2 years of imaging in this observational cohort study. Results: With one exception, study participants who had cognitive assessments within 2 years of their PET imaging (n = 113) were classified as having normal cognition. There was no association between cognitive scores and degree of hearing loss, or between cognitive scores and Aβ load. No association between HL and Aβ load was found once age was controlled for. As previously reported, positive Apolipoprotein E4 (APOE4) carrier status increased the risk of being Aβ positive (p = 0.002). Conclusion: Degree of HL was not associated with positive Aβ status.

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