Development and validation of an immuno-PET tracer for patient stratification and therapy monitoring of antibody-drug conjugate therapy.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 11006-11006
Author(s):  
Ohad Ilovich ◽  
Arutselvan Natarajan ◽  
Ataya Sathirachinda ◽  
Richard Kimura ◽  
Ananth Srinivasan ◽  
...  
Keyword(s):  
Therapy Monitoring ◽  
Small Animal Pet ◽  
Patient Stratification ◽  
Phase I Clinical Trials ◽  
Serum Stability ◽  
Pet Tracer ◽  
Biodistribution Studies ◽  
Companion Diagnostic ◽  
Antibody Drug

11006 Background: SAR566658 is an antibody-drug immunoconjugate consisting of a humanized monoclonal antibody (huDS6) against the tumor-associated MUC1-sialoglycotope, CA6, conjugated to a cytotoxic maytansinoid (DM4). SAR566658 is currently undergoing phase I clinical trials in patients with CA6-positive solid tumors. A companion diagnostic based on huDS6 may facilitate patient stratification and early evaluation of therapeutic efficacy. The present study describes the development and preclinical evaluation of three novel Copper-64 (t½= 12.7h) labeled antibody fragments (two Fabs and a diabody) derived from the huDS6 antibody. One fragment was chosen based on imaging figures of merit for further specificity evaluations. Methods: The affinity of all fragments and their DOTA conjugates to CA6 was validated using flow cytometry. The DOTA conjugates were labeled with Copper-64 and evaluated in human serum stability studies, in vivo small animal PET imaging and 24-hour biodistribution studies in nude mice bearing either CA6 positive (WISH) or CA6 negative (A2780) subcutaneous tumors. The specificity of the lead tracer was evaluated in vivo via blocking studies and isotype controls. Results: All fragments and their DOTA conjugates had high affinity (Kd = 4-20 nM) for WISH cells. 64Cu-DOTA-B-Fab gave superior results in radio-synthesis (RCY - 60%, SA - 55 GBq/µmole, >99% purity), serum stability (94±5%, n=3) and biodistribution profile. Its two isotype controls gave statistically significant (P<0.05) uptake values in WISH but not A2780 tumors (see table). Blocking with B-Fab or huDS6 prior to tracer administration afforded a 23% (p<0.05, n=8) and 26% (p<0.05, n=7) decrease in WISH tumor uptake, respectively. Conclusions: These preclinical studies suggest that 64Cu-DOTA-B-Fab may be a suitable companion diagnostic for SAR566658 in cancer patients and requires further investigation.[Table: see text]

scholarly journals New 55Co-labeled Albumin-Binding Folate Derivatives as Potential PET Agents for Folate Receptor Imaging

2019 ◽  
Vol 12 (4) ◽  
pp. 166 ◽  
Author(s):  
Lauren L. Radford ◽  
Solana Fernandez ◽  
Rebecca Beacham ◽  
Retta El Sayed ◽  
Renata Farkas ◽  
...  
Keyword(s):  
Folate Receptor ◽  
Small Animal ◽  
Small Animal Pet ◽  
Receptor Imaging ◽  
Albumin Binding ◽  
Liver Uptake ◽  
Biodistribution Studies ◽  
Positron Emission

Overexpression of folate receptors (FRs) on different tumor types (e.g., ovarian, lung) make FRs attractive in vivo targets for directed diagnostic/therapeutic agents. Currently, no diagnostic agent suitable for positron emission tomography (PET) has been adopted for clinical FR imaging. In this work, two 55Co-labeled albumin-binding folate derivatives-[55Co]Co-cm10 and [55Co]Co-rf42-with characteristics suitable for PET imaging have been developed and evaluated. High radiochemical yields (≥95%) and in vitro stabilities (≥93%) were achieved for both compounds, and cell assays demonstrated FR-mediated uptake. Both 55Co-labeled folate conjugates demonstrated high tumor uptake of 17% injected activity per gram of tissue (IA/g) at 4 h in biodistribution studies performed in KB tumor-bearing mice. Renal uptake was similar to other albumin-binding folate derivatives, and liver uptake was lower than that of previously reported [64Cu]Cu-rf42. Small animal PET/CT images confirmed the biodistribution results and showed the clear delineation of FR-expressing tumors.

scholarly journals Development and Validation of an Immuno-PET Tracer as a Companion Diagnostic Agent for Antibody-Drug Conjugate Therapy to Target the CA6 Epitope

Radiology ◽  
2015 ◽  
Vol 276 (1) ◽  
pp. 191-198 ◽  
Author(s):  
Ohad Ilovich ◽  
Arutselvan Natarajan ◽  
Sharon Hori ◽  
Ataya Sathirachinda ◽  
Richard Kimura ◽  
...  
Keyword(s):  
Antibody Drug Conjugate ◽  
Drug Conjugate ◽  
Pet Tracer ◽  
Companion Diagnostic ◽  
Diagnostic Agent ◽  
Development And Validation ◽  
Antibody Drug

scholarly journals In vivo Imaging of Cannabinoid Type 2 Receptors: Functional and Structural Alterations in Mouse Model of Cerebral Ischemia by PET and MRI

2021 ◽  
Author(s):  
Ruiqing Ni ◽  
Adrienne Müller Herde ◽  
Ahmed Haider ◽  
Claudia Keller ◽  
Georgios Louloudis ◽  
...  
Keyword(s):  
Inflammatory Markers ◽  
Temporal Dynamics ◽  
Ex Vivo ◽  
Receptor Expression ◽  
Neuronal Marker ◽  
Subacute Stage ◽  
Pet Tracer ◽  
Biodistribution Studies

Abstract Purpose Stroke is one of the most prevalent vascular diseases. Non-invasive molecular imaging methods have the potential to provide critical insights into the temporal dynamics and follow alterations of receptor expression and metabolism in ischemic stroke. The aim of this study was to assess the cannabinoid type 2 receptor (CB2R) levels in transient middle cerebral artery occlusion (tMCAO) mouse models at subacute stage using positron emission tomography (PET) with our novel tracer [18F]RoSMA-18-d6 and structural imaging by magnetic resonance imaging (MRI). Procedures Our recently developed CB2R PET tracer [18F]RoSMA-18-d6 was used for imaging neuroinflammation at 24 h after reperfusion in tMCAO mice. The RNA expression levels of CB2R and other inflammatory markers were analyzed by quantitative real-time polymerase chain reaction using brain tissues from tMCAO (1 h occlusion) and sham-operated mice. [18F]fluorodeoxyglucose (FDG) was included for evaluation of the cerebral metabolic rate of glucose (CMRglc). In addition, diffusion-weighted imaging and T2-weighted imaging were performed for anatomical reference and delineating the lesion in tMCAO mice. Results mRNA expressions of inflammatory markers TNF-α, Iba1, MMP9 and GFAP, CNR2 were increased to 1.3–2.5 fold at 24 h after reperfusion in the ipsilateral compared to contralateral hemisphere of tMCAO mice, while mRNA expression of the neuronal marker MAP-2 was markedly reduced to ca. 50 %. Reduced [18F]FDG uptake was observed in the ischemic striatum of tMCAO mouse brain at 24 h after reperfusion. Although higher activity of [18F]RoSMA-18-d6 in ex vivo biodistribution studies and higher standard uptake value ratio (SUVR) were detected in the ischemic ipsilateral compared to contralateral striatum in tMCAO mice, the in vivo specificity of [18F]RoSMA-18-d6 was confirmed only in the CB2R-rich spleen. Conclusions This study revealed an increased [18F]RoSMA-18-d6 measure of CB2R and a reduced [18F]FDG measure of CMRglc in the ischemic striatum of tMCAO mice at subacute stage. [18F]RoSMA-18-d6 might be a promising PET tracer for detecting CB2R alterations in animal models of neuroinflammation without neuronal loss.

scholarly journals In Vivo Imaging of Cannabinoid Type 2 Receptors, Functional and Structural Alterations in Mouse Model of Cerebral Ischemia by PET and MRI

2021 ◽  
Author(s):  
Ruiqing Ni ◽  
Adrienne Müller Herde ◽  
Ahmed Haider ◽  
Claudia Keller ◽  
Georgios Louloudis ◽  
...  
Keyword(s):  
Inflammatory Markers ◽  
Temporal Dynamics ◽  
Ex Vivo ◽  
Receptor Expression ◽  
Neuronal Marker ◽  
Subacute Stage ◽  
Pet Tracer ◽  
Biodistribution Studies

Abstract Background and purposeBrain ischemia is one of the most important pathologies of the central nervous system. Non-invasive molecular imaging methods have the potential to provide critical insights into the temporal dynamics and follow alterations of receptor expression and metabolism in ischemic stroke. The aim of this study was to assess the cannabinoid type 2 receptors (CB2R) levels in transient middle cerebral artery occlusion (tMCAO) mouse models at subacute stage using positron emission tomography (PET) with our novel tracer [18F]RoSMA-18-d6, and structural imaging by magnetic resonance imaging (MRI). MethodsOur recently developed CB2R PET tracer [18F]RoSMA-18-d6 was used for imaging the neuroinflammation at 24 h after reperfusion in tMCAO mice. The RNA expression levels of CB2R and other inflammatory markers were analyzed by quantitative real-time polymerase chain reaction using brain tissues from tMCAO (1 h occlusion) and sham-operated mice. [18F]fluorodeoxyglucose (FDG) was included for evaluation of the cerebral metabolic rate of glucose (CMRglc). In addition, diffusion-weighted imaging and T2-weighted imaging were performed for anatomical reference and delineating the lesion in tMCAO mice. ResultsmRNA expressions of inflammatory markers TNF-a, Iba1, MMP9 and GFAP, CNR2 were increased at 24 h after reperfusion in the ipsilateral compared to contralateral hemisphere of tMCAO mice, while mRNA expression of the neuronal marker MAP-2 was markedly reduced. Reduced [18F]FDG uptake was observed in the ischemic striatum of tMCAO mouse brain at 24 h after reperfusion. Although higher activity of [18F]RoSMA-18-d6 in ex-vivo biodistribution studies and higher standard uptake value ratio (SUVR) were detected in the ischemic ipsilateral compared to contralateral striatum in tMCAO mice, the in-vivo specificity of [18F]RoSMA-18-d6 was confirmed only in the CB2R-rich spleen. ConclusionsThis study revealed an increased [18F]RoSMA-18-d6 measure of CB2R and a reduced [18F]FDG measure of CMRglc in ischemic striatum of tMCAO mice at subacute stage. [18F]RoSMA-18-d6 might be a promising PET tracer for detecting CB2R alterations in animal models of neuroinflammation without neuronal loss.

scholarly journals Radiosynthesis and Preliminary Biological Evaluation of 18F-Fluoropropionyl-Chlorotoxin as a Potential PET Tracer for Glioma Imaging

2018 ◽  
Vol 2018 ◽  
pp. 1-9 ◽  
Author(s):  
Jing Zhao ◽  
Yu-liang Wang ◽  
Xin-bei Li ◽  
Si-yuan Gao ◽  
Shao-yu Liu ◽  
...  
Keyword(s):  
Pet Imaging ◽  
Biological Evaluation ◽  
Brain Parenchyma ◽  
C6 Glioma ◽  
Small Animal Pet ◽  
Matrix Metalloproteinase 2 ◽  
Normal Brain ◽  
High Accumulation ◽  
Pet Tracer

Purposes. Chlorotoxin can specifically bind to matrix metalloproteinase 2 (MMP-2), which are overexpressed in the glioma. In this work, radiosynthesis of [18F]-fluoropropionyl-chlorotoxin ([18F]-FP-chlorotoxin) as a novel PET tracer was investigated, and biodistribution in vivo and PET imaging were performed in the C6 glioma model. Procedures. [18F]-FP-chlorotoxin was prepared from the reaction of chlorotoxin with [18F]-NFB (4-nitrophenyl 2-[18F]-fluoropropionate), which was synthesized from multistep reactions. Biodistribution was determined in 20 normal Kunming mice. Small-animal PET imaging with [18F]-FP-chlorotoxin was performed on the same rats bearing orthotopic C6 glioma at different time points (60 min, 90 min, and 120 min) after injection and compared with 2-deoxy-2-[18F] fluoro-D-glucose ([18F]-FDG). Results. [18F]-FP-Chlorotoxin was successfully synthesized in the radiochemical yield of 41% and the radiochemical purity of more than 98%. Among all the organs, the brain had the lowest and stable uptake of [18F]-FP-chlorotoxin, while the kidney showed the highest uptake. Compared with [18F]-FDG, a low uptake of [18F]-FP-chlorotoxin was detected in normal brain parenchyma and a high accumulation of [18F]-FP-chlorotoxin was found in the gliomas tissue. The glioma to normal brain uptake ratio of [18F]-FP-chlorotoxin was higher than that of [18F]-FDG. Furthermore, the uptake of [18F]-FP-chlorotoxin at 90 min after injection was better than that at 60 min after injection. Conclusions. Compared with [18F]-FDG, [18F]-FP-chlorotoxin has a low and stable uptake in normal brain parenchyma. [18F]-FP-Chlorotoxin seems to be a potential PET tracer with a good performance in diagnosis of the glioma.

scholarly journals Advances in the In Vivo Molecular Imaging of Invasive Aspergillosis

2020 ◽  
Vol 6 (4) ◽  
pp. 338
Author(s):  
Matthias Gunzer ◽  
Christopher R. Thornton ◽  
Nicolas Beziere
Keyword(s):  
Molecular Imaging ◽  
Therapy Monitoring ◽  
Invasive Pulmonary Aspergillosis ◽  
Invasive Approach ◽  
Magnetic Imaging ◽  
Pet Tracer ◽  
Positron Emission ◽  
Humanized Monoclonal Antibody ◽  
Risk Patients

Invasive pulmonary aspergillosis (IPA) is a life-threatening infection of immunocompromised patients with Aspergillus fumigatus, a ubiquitous environmental mould. While there are numerous functioning antifungal therapies, their high cost, substantial side effects and fear of overt resistance development preclude permanent prophylactic medication of risk-patients. Hence, a fast and definitive diagnosis of IPA is desirable, to quickly identify those patients that really require aggressive antimycotic treatment and to follow the course of the therapeutic intervention. However, despite decades of research into this issue, such a diagnostic procedure is still not available. Here, we discuss the array of currently available methods for IPA detection and their limits. We then show that molecular imaging using positron emission tomography (PET) combined with morphological computed tomography or magnetic imaging is highly promising to become a future non-invasive approach for IPA diagnosis and therapy monitoring, albeit still requiring thorough validation and relying on further acceptance and dissemination of the approach. Thereby, our approach using the A. fumigatus-specific humanized monoclonal antibody hJF5 labelled with 64Cu as PET-tracer has proven highly effective in pre-clinical models and hence bears high potential for human application.

scholarly journals One-Pot Radiosynthesis and Biological Evaluation of a Caspase-3 Selective 5-[123,125I]iodo-1,2,3-triazole derived Isatin SPECT Tracer

2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Matthias Glaser ◽  
Vineeth Rajkumar ◽  
Seckou Diocou ◽  
Thibault Gendron ◽  
Ran Yan ◽  
...  
Keyword(s):  
Caspase 3 ◽  
Clinical Decision Making ◽  
Cycloaddition Reaction ◽  
Xenograft Model ◽  
Biological Evaluation ◽  
One Pot ◽  
Tumour Uptake ◽  
Pet Tracer ◽  
Biodistribution Studies

AbstractInduction of apoptosis is often necessary for successful cancer therapy, and the non-invasive monitoring of apoptosis post-therapy could assist in clinical decision making. Isatins are a class of compounds that target activated caspase-3 during apoptosis. Here we report the synthesis of the 5-iodo-1,2,3-triazole (FITI) analog of the PET tracer [18F]ICMT11 as a candidate tracer for imaging of apoptosis with SPECT, as well as PET. Labelling with radioiodine (123,125I) was achieved in 55 ± 12% radiochemical yield through a chelator-accelerated one-pot cycloaddition reaction mediated by copper(I) catalysis. The caspase-3 binding affinity and selectivity of FITI compares favourably to that of [18F]ICMT11 (Ki = 6.1 ± 0.9 nM and 12.4 ± 4.7 nM, respectively). In biodistribution studies, etoposide-induced cell death in a SW1222 xenograft model resulted in a 2-fold increase in tumour uptake of the tracer. However, the tumour uptake was too low to allow in vivo imaging of apoptosis with SPECT.

scholarly journals In vivo imaging of cannabinoid type 2 receptors, functional and structural alterations in mouse model of cerebral ischemia by PET and MRI

2021 ◽  
Author(s):  
Ruiqing Ni ◽  
Adrienne Muller Herde ◽  
Ahmed Haider ◽  
Claudia Keller ◽  
Georgios Louloudis ◽  
...  
Keyword(s):  
Inflammatory Markers ◽  
Temporal Dynamics ◽  
Receptor Expression ◽  
Neuronal Marker ◽  
Subacute Stage ◽  
Pet Tracer ◽  
Biodistribution Studies ◽  
18F Fdg

Background and purpose: Brain ischemia is one of the most important pathologies of the central nervous system. Non-invasive molecular imaging methods have the potential to provide critical insights into the temporal dynamics and follow alterations of receptor expression and metabolism in ischemic stroke. The aim of this study was to assess the cannabinoid type 2 receptors (CB2R) levels in transient middle cerebral artery occlusion (tMCAO) mouse models at subacute stage using positron emission tomography (PET) with our novel tracer [18F]RoSMA-18-d6, and structural imaging by magnetic resonance imaging (MRI). Methods: Our recently developed CB2R PET tracer [18F]RoSMA-18-d6 was used for imaging the neuroinflammation at 24 h after reperfusion in tMCAO mice. The RNA expression levels of CB2R and other inflammatory markers were analyzed by quantitative real-time polymerase chain reaction using brain tissues from tMCAO (1 h occlusion) and sham-operated mice. [18F]fluorodeoxyglucose (FDG) was included for evaluation of the cerebral metabolic rate of glucose (CMRglc). In addition, diffusion-weighted imaging an T2- weighted imaging were performed for anatomical reference and for delineating the lesion in tMCAO mice. Results: mRNA expressions of inflammatory markers TNF-a, Iba1, MMP9 and GFAP, CNR2 were increased at 24 h after reperfusion in the ipsilateral compared to contralateral hemisphere of tMCAO mice, while mRNA expression of the neuronal marker MAP-2 was markedly reduced. Reduced [18F]FDG uptake was observed in the ischemic striatum of tMCAO mouse brain at 24 h after reperfusion. Although higher activity of [18F]RoSMA-18-d6 in ex-vivo biodistribution studies and higher standard uptake value ratio (SUVR) were detected in the ischemic ipsilateral compared to contralateral striatum in tMCAO mice, the in-vivo specificity of [18F]RoSMA-18-d6 was confirmed only in the CB2R-rich spleen. Conclusions: This study revealed an increased [18F]RoSMA-18-d6 measure of CB2R and a reduced [18F]FDG measure of CMRglc in ischemic striatum of tMCAO mice at subacute stage. [18F]RoSMA-18-d6 might be a promising PET tracer for detecting CB2R alterations in animal models of neuroinflammation without neuronal loss.

scholarly journals Synthesis of [18F]F-γ-T-3, a Redox-Silent γ-Tocotrienol (γ-T-3) Vitamin E Analogue for Image-Based In Vivo Studies of Vitamin E Biodistribution and Dynamics

Molecules ◽  
2020 ◽  
Vol 25 (23) ◽  
pp. 5700
Author(s):  
Peter Roselt ◽  
Carleen Cullinane ◽  
Wayne Noonan ◽  
Hassan Elsaidi ◽  
Peter Eu ◽  
...  
Keyword(s):  
Vitamin E ◽  
Small Animal ◽  
Tumor Model ◽  
Radiochemical Yield ◽  
Small Animal Pet ◽  
Molecular Probe ◽  
In Vivo Studies ◽  
Pet Tracer ◽  
Low Concentrations

Vitamin E, a natural antioxidant, is of interest to scientists, health care pundits and faddists; its nutritional and biomedical attributes may be validated, anecdotal or fantasy. Vitamin E is a mixture of tocopherols (TPs) and tocotrienols (T-3s), each class having four substitutional isomers (α-, β-, γ-, δ-). Vitamin E analogues attain only low concentrations in most tissues, necessitating exacting invasive techniques for analytical research. Quantitative positron emission tomography (PET) with an F-18-labeled molecular probe would expedite access to Vitamin E’s biodistributions and pharmacokinetics via non-invasive temporal imaging. (R)-6-(3-[18F]Fluoropropoxy)-2,7,8-trimethyl-2-(4,8,12-trimethyltrideca-3,7,11-trien-1-yl)-chromane ([18F]F-γ-T-3) was prepared for this purpose. [18F]F-γ-T-3 was synthesized from γ-T-3 in two steps: (i) 1,3-di-O-tosylpropane was introduced at C6-O to form TsO-γ-T-3, and (ii) reaction of this tosylate with [18F]fluoride in DMF/K222. Non-radioactive F-γ-T-3 was synthesized by reaction of γ-T-3 with 3-fluoropropyl methanesulfonate. [18F]F-γ-T-3 biodistribution in a murine tumor model was imaged using a small-animal PET scanner. F-γ-T-3 was prepared in 61% chemical yield. [18F]F-γ-T-3 was synthesized in acceptable radiochemical yield (RCY 12%) with high radiochemical purity (>99% RCP) in 45 min. Preliminary F-18 PET images in mice showed upper abdominal accumulation with evidence of renal clearance, only low concentrations in the thorax (lung/heart) and head, and rapid clearance from blood. [18F]F-γ-T-3 shows promise as an F-18 PET tracer for detailed in vivo studies of Vitamin E. The labeling procedure provides acceptable RCY, high RCP and pertinence to all eight Vitamin E analogues.

Evaluation of A Novel GLP-1R Ligand for PET Imaging of Prostate Cancer

2019 ◽  
Vol 19 (4) ◽  
pp. 509-514 ◽  
Author(s):  
Yuanyuan Yue ◽  
Yuping Xu ◽  
Lirong Huang ◽  
Donghui Pan ◽  
Zhicheng Bai ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Pet Imaging ◽  
Ex Vivo ◽  
Xenograft Model ◽  
Small Animal ◽  
Small Animal Pet ◽  
Great Promise ◽  
Western Blots ◽  
Biodistribution Studies

Background:Glucagon-like peptide 1 receptor (GLP-1R) is an important biomarker for diagnosis and therapy of the endocrine cancers due to overexpression. Recently, in human prostate cancer cell lines the receptor was also observed, therefore it may be a potential target for the disease. 18F-Al-NOTA-MAL-Cys39- exendin-4 holds great promise for GLP-1R. Therefore, the feasibility of the 18F-labeled exendin-4 analog for prostate cancer imaging was investigated.Methods:New probe 18F-Al-NOTA-MAL-Cys39-exendin-4 was made through one-step fluorination. Prostate cancer PC3 cell xenograft model mice were established to primarily evaluate the imaging properties of the tracer via small animal PET studies in vivo. Pathological studies and Western Blots were also performed.Results:PC-3 prostate xenografts were clearly imaged under baseline conditions. At 30 and 60 min postinjection, the tumor uptakes were 2.90±0.41%ID/g and 2.26±0.32 %ID/g respectively. The presence of cys39-exendin-4 significantly reduced the tumor uptake to 0.82±0.10 %ID/g at 60 min p.i. Findings of ex vivo biodistribution studies were similar to those of in vivo PET imaging. The tumors to blood and muscles were significantly improved with the increase of time due to rapid clearance of the tracer from normal organs. Low levels of radioactivity were also detected in the GLP-1R positive tumor and normal organs after coinjection with excessive unlabeled peptides. Immunohistochemistry and Western Blots results confirmed that GLP-1R was widely expressed in PC-3 prostate cancers.Conclusion:18F-Al labeled exendin-4 analog might be a promising tracer for in vivo detecting GLP-1R positive prostate cancer with the advantage of facile synthesis and favorable pharmacokinetics. It may be useful in differential diagnosis, molecularly targeted therapy and prognosis of the cancers.

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