Yann Seimbille | Erasmus University Rotterdam (original) (raw)
Papers by Yann Seimbille
EJNMMI Research, 2021
Background There is a growing body of nuclear contrast agents that are repurposed for fluorescenc... more Background There is a growing body of nuclear contrast agents that are repurposed for fluorescence-guided surgery. New contrast agents are obtained by substituting the radioactive tag with, or adding a fluorescent cyanine to the molecular structure of antibodies or peptides. This enables intra-operative fluorescent detection of cancerous tissue, leading to more complete tumor resection. However, these fluorescent cyanines can have a remarkable influence on pharmacokinetics and tumor uptake, especially when labeled to smaller targeting vectors such as peptides. Here we demonstrate the effect of cyanine-mediated dead cell-binding of Ac-Lys0(IRDye800CW)-Tyr3-octreotate (800CW-TATE) and how this can be used as an advantage for fluorescence-guided surgery. Results Binding of 800CW-TATE could be blocked with DOTA0-Tyr3-octreotate (DOTA-TATE) on cultured SSTR2-positive U2OS cells and was absent in SSTR2 negative U2OS cells. However, strong binding was observed to dead cells, which could no...
Radiotherapy and Oncology, 2012
Nuclear Medicine and Biology
Contrast Media & Molecular Imaging
Necrosis only occurs in pathological situations and is directly related to disease severity and, ... more Necrosis only occurs in pathological situations and is directly related to disease severity and, therefore, is an important biomarker. Tumor necrosis occurs in most solid tumors due to improperly functioning blood vessels that cannot keep up with the rapid growth, especially in aggressively growing tumors. The amount of necrosis per tumor volume is often correlated to rapid tumor proliferation and can be used as a diagnostic tool. Furthermore, efficient therapy against solid tumors will directly or indirectly lead to necrotic tumor cells, and detection of increased tumor necrosis can be an early marker for therapy efficacy. We propose the application of necrosis avid contrast agents to detect therapy-induced tumor necrosis. Herein, we advance gallium-68-labeled IRDye800CW, a near-infrared fluorescent dye that exhibits excellent necrosis avidity, as a potential PET tracer for in vivo imaging of tumor necrosis. We developed a reliable labeling procedure to prepare [68Ga]Ga-DOTA-PEG4-I...
International Journal of Molecular Sciences
Carbonic anhydrase IX (CAIX) is a tumor-specific and hypoxia-induced biomarker for the molecular ... more Carbonic anhydrase IX (CAIX) is a tumor-specific and hypoxia-induced biomarker for the molecular imaging of solid malignancies. The nuclear- and optical-imaging of CAIX-expressing tumors have received great attention due to their potential for clinical applications. Nuclear imaging is a powerful tool for the non-invasive diagnosis of primary and metastatic CAIX-positive tumors and for the assessment of responses to antineoplastic treatment. Intraoperative optical fluorescence imaging provides improved visualization for surgeons to increase the discrimination of tumor lesions, allowing for safer surgical treatment. Over the past decades, many CAIX-targeted molecular imaging probes, based on monoclonal antibodies, antibody fragments, peptides, and small molecules, have been reported. In this review, we outline the recent development of CAIX-targeted probes for single-photon emission computerized tomography (SPECT), positron emission tomography (PET), and near-infrared fluorescence ima...
Additional file 1. Supplementary data 1: controls in vitro dead/alive cell binding. Supplementary... more Additional file 1. Supplementary data 1: controls in vitro dead/alive cell binding. Supplementary data 2: microscopy. Supplementary data 3: ex vivo binding of 800CW-TATE and to NCI-H69 and CH-157MN tumor sections. Supplementary data 4: SSTR2 IF staining.
Cancers, 2022
Purpose: To assess our improved NACA for the detection of tumor necrosis. Methods: We increased t... more Purpose: To assess our improved NACA for the detection of tumor necrosis. Methods: We increased the blood circulation time of our NACA by adding an albumin-binding domain to the molecular structure. We tested the necrosis avidity on dead or alive cultured cells and performed SPECT and fluorescence imaging of both spontaneous and treatment-induced necrosis in murine breast cancer models. We simultaneously recorded [18F]FDG-PET and bioluminescence images for complementary detection of tumor viability. Results: We generated two albumin-binding IRDye800CW derivatives which were labeled with indium-111 with high radiochemical purity. Surprisingly, both albumin-binding NACAs had >10x higher in vitro binding towards dead cells. We selected [111In]3 for in vivo experiments which showed higher dead cell binding in vitro and in vivo stability. The doxorubicin-treated tumors showed increased [111In]3-uptake (1.74 ± 0.08%ID/g after saline treatment, 2.25 ± 0.16%ID/g after doxorubicin treatme...
endocannabinoid plasma levels are associated with coronary circulatory dysfunction in obesity
Statistical analyses of the biodistribution data of [18F]FPyPEGCBT-c(RGDfK) in nude mice bearing ... more Statistical analyses of the biodistribution data of [18F]FPyPEGCBT-c(RGDfK) in nude mice bearing U-87 MG or SKOV-3 subcutaneous tumours a . Figure S1. siRNA-mediated integrin depletions analysis by densitometry. αV, β1, β3 or β5 integrin subunits and indicated combinations were knocked-down by siRNA in U-87 MG and SKOV-3 and protein extracts were submitted to immunoblotting using specific antibodies. Expression levels of each integrin were then quantified with a Chemidoc MP. Data are mean fold expression changes in indicated samples as compared to untransfected cells (Unt) ± SD (n = 3). Figure S2. Uptake of [125I]echistatin in cells with selective siRNA-mediated integrin knocked down. U-87 MG and SKOV-3 cells knocked down for αV, β1, β3 or β5 integrin subunits and indicated combinations were incubated with 100 kBq/mL [18F]FPyPEGCBT-c(RGDfK) for 15 to 120 min at 37 °C. Depletions were verified by immunoblotting using specific antibodies as compared to untransfected cells (Unt) and to...
Organic & biomolecular chemistry, Jan 11, 2015
In a bid to find an efficient means to radiolabel biomolecules under mild conditions for PET imag... more In a bid to find an efficient means to radiolabel biomolecules under mild conditions for PET imaging, a bifunctional (18)F prosthetic molecule has been developed. The compound, dubbed [(18)F]FPyPEGCBT, consists of a 2-substituted pyridine moiety for [(18)F]F(-) incorporation and a 2-cyanobenzothiazole moiety for coupling to terminal cysteine residues. The two functionalities are separated by a mini-PEG chain. [(18)F]FPyPEGCBT could be prepared from its corresponding 2-trimethylammonium triflate precursor (100 °C, 15 min, MeCN) in preparative yields of 11% ± 2 (decay corrected, n = 3) after HPLC purification. However, because the primary radiochemical impurity of the fluorination reaction will not interact with 1,2-aminothiol functionalities, the (18)F prosthetic could be prepared for bioconjugation reactions by way of partial purification on a molecularly imprinted polymer solid-phase extraction cartridge. [(18)F]FPyPEGCBT was used to (18)F-label a cyclo-(RGDfK) analogue which was m...
Nuklearmedizin, 2010
Summary Purpose: To evaluate the mean effective radiation dose of 13N-ammonia PET/CT and ECGpulsi... more Summary Purpose: To evaluate the mean effective radiation dose of 13N-ammonia PET/CT and ECGpulsing CT angiography (CTA) in the evaluation of myocardial perfusion, myocardial blood flow (MBF) and coronary morphology for the identification of subclinical CAD. Patients, material, methods: Following rest-stress 13N-ammonia PET/CT perfusion imaging and MBF quantification, ECG-pulsing CTA at a pulse window of 70% of the R-R cycle was performed in ten healthy controls and in sixteen individuals with cardiovascular risk factors. Individual radiation dose exposure for ECG-pulsing CTA was estimated from the dose-length product. Results: PET demonstrated normal perfusion in all study individuals, while hyperemic MBFs during dipyridamole stimulation and the myocardial flow reserve (MFR) in cardiovascular risk individuals were significantly lower than in healthy controls (1.34 ± 0.26 vs. 2.28 ± 0.47 ml/g/min and 1.48 ± 0.39 vs. 3.24 ± 0.81, both p . 0.0001). Further, ECG-pulsing CTA identified ...
Journal of Nuclear Cardiology, 2010
Background. The aim of this study was to determine whether epicardial structural disease may affe... more Background. The aim of this study was to determine whether epicardial structural disease may affect the manifestation of a longitudinal decrease in myocardial blood flow (MBF) or MBF difference during hyperemia in cardiovascular risk individuals, and its dependency on the flow increase. Methods and Results. In 54 cardiovascular risk individuals (at risk) and in 26 healthy controls, MBF was measured with 13 N-ammonia and PET/CT in mL/g/min at rest and during dipyridamole stimulation. Computed tomography coronary angiography (CTA) was performed using a 64-slice CT of a PET/CT system. Absolute MBFs during dipyridamole stimulation were mildly lower in the mid-distal than in the mid-LV myocardium in controls (2.20 ± .51 vs 2.29 ± .51, P < .0001), while it was more pronounced in at risk with normal and abnormal CTA (1.56 ± .42 vs 1.91 ± .46 and 1.18 ± .34 vs 1.51 ± .40 mL/g/min, respectively, P < .0001), resulting in a longitudinal MBF difference that was highest in at risk with normal CTA, intermediate in at risk abnormal CTA, and lowest in controls (.35 ± .16 and .22 ± .09 vs .09 ± .04 mL/g/min, respectively, P < .0001). On multivariate analysis, log-CCS and mid-LV hyperemic MBF increase, indicative of microvascular function, were independent predictors of the observed longitudinal MBF difference (P £ .004 by ANOVA). Conclusions. Epicardial structural disease and microvascular function are important determinants of an abnormal longitudinal MBF difference as determined with PET/CT.
Journal of Nuclear Cardiology, 2012
Background. To define the relationship between regional coronary vasodilator capacity and myocard... more Background. To define the relationship between regional coronary vasodilator capacity and myocardial circumferential strain at rest in normal weight, overweight, and obese individuals with normal global left-ventricular function. Methods and Results. Myocardial blood flow at rest and during pharmacologic vasodilation was measured with 13 N-ammonia PET/CT in mL/g/minute in normal weight control (CON, n 5 12), overweight (OW, n 5 10), and obese individuals (OB, n 5 10). In addition, resting myocardial function was evaluated as circumferential strain (" c, %) by MRI. Global myocardial flow reserve (MFR) did not differ significantly between CON and OW (2.98 ± 0.96 vs 2.70 ± 0.66, P 5 .290), whereas it declined significantly in OB (1.98 ± 1.04, P 5 .030). Further, global " c (%) was comparable between CON, OW, and OB (20.24 ± 0.03, 20.23 ± 0.02, and 20.23 ± 0.04) but it was lowest in OB when normalized to the rate-pressure product (N " c: 20.31 ± 0.06, 20.32 ± 0.05, and 20.26 ± 0.08). When MFR of the three major coronary territories was correlated with corresponding " c, a positive association was observed in CON (r 5 0.36, P 5 .030), in OW (r 5 0.54, P 5 .002), and also in OB when relating N " c to coronary vascular resistance during pharmacologic vasodilation (r 5 20.46, P 5 .010). Conclusions. Higher coronary vasodilator capacity is related to corresponding regional circumferential strain at rest in non-obese individuals, while this is also observed for reduced MFR in obesity. (
![Research paper thumbnail of Evaluation of [18F]gefitinib as a molecular imaging probe for the assessment of the epidermal growth factor receptor status in malignant tumors](https://attachments.academia-assets.com/89862866/thumbnails/1.jpg)
](European Journal of Nuclear Medicine and Molecular Imaging, 2008
Purpose Gefitinib, an inhibitor of the epidermal growth factor receptor-tyrosine kinase (EGFR-TK)... more Purpose Gefitinib, an inhibitor of the epidermal growth factor receptor-tyrosine kinase (EGFR-TK), has shown potent effects in a subset of patients carrying specific EGFR-TK mutations in advanced non-small-cell lung cancer. In this study, we asked whether PET with [ 18 F]gefitinib may be used to study noninvasively the pharmacokinetics of gefitinib in vivo and to image the EGFR status of cancer cells. Materials and methods Synthesis of [ 18 F]gefitinib has been previously described. The biodistribution and metabolic stability of [ 18 F]gefitinib was assessed in mice and vervet monkeys for up to 2 h post injection by both micropositron emission tomography (PET)/computed tomography (CT) scans and postmortem ex vivo tissue harvesting. Uptake levels of radiolabeled gefitinib in EGFR-expressing human cancer cell lines with various levels of EGFR expression or mutation status were evaluated both in vivo and in vitro. Results MicroPET/CT scans in two species demonstrated a rapid and predominantly hepatobiliary clearance of [ 18 F]gefitinib in vivo. However, uptake levels of radiolabeled gefitinib, both in vivo and in vitro, did not correlate with EGFR expression levels or functional status. This unexpected observation was due to high nonspecific, nonsaturable cellular uptake of gefitinib. Conclusion The biodistribution of the drug analogue [ 18 F]gefitinib suggests that it may be used to assess noninvasively the pharmacokinetics of gefitinib in patients by PET imaging. This is of clinical relevance, as insufficient intratumoral drug concentrations are considered to be a factor for resistance to gefitinib therapy. However, the highly nonspecific cellular binding of [ 18 F]gefitinib may preclude the use of this imaging probe for noninvasive assessment of EGFR receptor status in patients.
European Heart Journal, 2011
Aim of this study was to evaluate a possible association between endocannabinoid (EC) plasma leve... more Aim of this study was to evaluate a possible association between endocannabinoid (EC) plasma levels, such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and coronary circulatory function in obesity. Methods and results Myocardial blood flow (MBF) responses to cold pressor test (CPT) and during pharmacological vasodilation with dipyridamole were measured with 13 N-ammonia PET/CT. Study participants (n ¼ 77) were divided into three groups based on their body mass index (BMI, kg/m 2): control group 20≤ BMI ,25 (n ¼ 21); overweight group, 25≤ BMI ,30 (n ¼ 26); and obese group, BMI ≥30 (n ¼ 30). Anandamide plasma levels, but not 2-AG plasma levels, were significantly elevated in obesity as compared with controls, respectively [0.68 (0.53, 0.78) vs. 0.56 (0.47, 0.66) ng/mL, P ¼ 0.020, and 2.2 (1.21, 4.59) vs. 2.0 (0.80, 5.90) ng/mL, P ¼ 0.806)]. The endothelium-related change in MBF during CPT from rest (DMBF) progressively declined in overweight and obese when compared with control group [0.21 (0.10, 0.27) and 0.09 (20.01, 0.15) vs. 0.26 (0.23, 0.39) mL/g/min; P ¼ 0.010 and P ¼ 0.0001, respectively). Compared with controls, hyperaemic MBFs were significantly lower in overweight and obese individuals [2.39 (1.97, 2.62) vs. 1.98 (1.69, 2.26) and 2.10 (1.76, 2.36); P ¼ 0.007 and P ¼ 0.042, respectively)]. In obese individuals, AEA and 2-AG plasma levels were inversely correlated with DMBF to CPT (r ¼ 20.37, P ¼ 0.046 and r ¼ 20.48, P ¼ 0.008) and hyperaemic MBFs (r ¼ 20.38, P ¼ 0.052 and r ¼ 20.45, P ¼ 0.017), respectively. Conclusions Increased EC plasma levels of AEA and 2-AG are associated with coronary circulatory dysfunction in obese individuals. This observation might suggest increases in EC plasma levels as a novel endogenous cardiovascular risk factor in obesity, but needing further investigations.
Diabetes & Metabolism, 2011
Pharmaceutics, 2022
Nuclear and optical dual-modality probes can be of great assistance in prostate cancer localizati... more Nuclear and optical dual-modality probes can be of great assistance in prostate cancer localization, providing the means for both preoperative nuclear imaging and intraoperative surgical guidance. We developed a series of probes based on the backbone of the established GRPR-targeting radiotracer NeoB. The inverse electron demand of the Diels–Alder reaction was used to integrate the sulfo-cyanine 5 dye. Indium-111 radiolabeling, stability studies and a competition binding assay were carried out. Pilot biodistribution and imaging studies were performed in PC-3 tumor-bearing mice, using the best two dual-labeled probes. The dual-modality probes were radiolabeled with a high yield (>92%), were proven to be hydrophilic and demonstrated high stability in mouse serum (>94% intact labeled ligand at 4 h). The binding affinity for the GRPR was in the nanomolar range (21.9–118.7 nM). SPECT/CT images at 2 h p.i. clearly visualized the tumor xenograft and biodistribution studies, after sca...
EJNMMI Research, 2021
Background There is a growing body of nuclear contrast agents that are repurposed for fluorescenc... more Background There is a growing body of nuclear contrast agents that are repurposed for fluorescence-guided surgery. New contrast agents are obtained by substituting the radioactive tag with, or adding a fluorescent cyanine to the molecular structure of antibodies or peptides. This enables intra-operative fluorescent detection of cancerous tissue, leading to more complete tumor resection. However, these fluorescent cyanines can have a remarkable influence on pharmacokinetics and tumor uptake, especially when labeled to smaller targeting vectors such as peptides. Here we demonstrate the effect of cyanine-mediated dead cell-binding of Ac-Lys0(IRDye800CW)-Tyr3-octreotate (800CW-TATE) and how this can be used as an advantage for fluorescence-guided surgery. Results Binding of 800CW-TATE could be blocked with DOTA0-Tyr3-octreotate (DOTA-TATE) on cultured SSTR2-positive U2OS cells and was absent in SSTR2 negative U2OS cells. However, strong binding was observed to dead cells, which could no...
Radiotherapy and Oncology, 2012
Nuclear Medicine and Biology
Contrast Media & Molecular Imaging
Necrosis only occurs in pathological situations and is directly related to disease severity and, ... more Necrosis only occurs in pathological situations and is directly related to disease severity and, therefore, is an important biomarker. Tumor necrosis occurs in most solid tumors due to improperly functioning blood vessels that cannot keep up with the rapid growth, especially in aggressively growing tumors. The amount of necrosis per tumor volume is often correlated to rapid tumor proliferation and can be used as a diagnostic tool. Furthermore, efficient therapy against solid tumors will directly or indirectly lead to necrotic tumor cells, and detection of increased tumor necrosis can be an early marker for therapy efficacy. We propose the application of necrosis avid contrast agents to detect therapy-induced tumor necrosis. Herein, we advance gallium-68-labeled IRDye800CW, a near-infrared fluorescent dye that exhibits excellent necrosis avidity, as a potential PET tracer for in vivo imaging of tumor necrosis. We developed a reliable labeling procedure to prepare [68Ga]Ga-DOTA-PEG4-I...
International Journal of Molecular Sciences
Carbonic anhydrase IX (CAIX) is a tumor-specific and hypoxia-induced biomarker for the molecular ... more Carbonic anhydrase IX (CAIX) is a tumor-specific and hypoxia-induced biomarker for the molecular imaging of solid malignancies. The nuclear- and optical-imaging of CAIX-expressing tumors have received great attention due to their potential for clinical applications. Nuclear imaging is a powerful tool for the non-invasive diagnosis of primary and metastatic CAIX-positive tumors and for the assessment of responses to antineoplastic treatment. Intraoperative optical fluorescence imaging provides improved visualization for surgeons to increase the discrimination of tumor lesions, allowing for safer surgical treatment. Over the past decades, many CAIX-targeted molecular imaging probes, based on monoclonal antibodies, antibody fragments, peptides, and small molecules, have been reported. In this review, we outline the recent development of CAIX-targeted probes for single-photon emission computerized tomography (SPECT), positron emission tomography (PET), and near-infrared fluorescence ima...
Additional file 1. Supplementary data 1: controls in vitro dead/alive cell binding. Supplementary... more Additional file 1. Supplementary data 1: controls in vitro dead/alive cell binding. Supplementary data 2: microscopy. Supplementary data 3: ex vivo binding of 800CW-TATE and to NCI-H69 and CH-157MN tumor sections. Supplementary data 4: SSTR2 IF staining.
Cancers, 2022
Purpose: To assess our improved NACA for the detection of tumor necrosis. Methods: We increased t... more Purpose: To assess our improved NACA for the detection of tumor necrosis. Methods: We increased the blood circulation time of our NACA by adding an albumin-binding domain to the molecular structure. We tested the necrosis avidity on dead or alive cultured cells and performed SPECT and fluorescence imaging of both spontaneous and treatment-induced necrosis in murine breast cancer models. We simultaneously recorded [18F]FDG-PET and bioluminescence images for complementary detection of tumor viability. Results: We generated two albumin-binding IRDye800CW derivatives which were labeled with indium-111 with high radiochemical purity. Surprisingly, both albumin-binding NACAs had >10x higher in vitro binding towards dead cells. We selected [111In]3 for in vivo experiments which showed higher dead cell binding in vitro and in vivo stability. The doxorubicin-treated tumors showed increased [111In]3-uptake (1.74 ± 0.08%ID/g after saline treatment, 2.25 ± 0.16%ID/g after doxorubicin treatme...
endocannabinoid plasma levels are associated with coronary circulatory dysfunction in obesity
Statistical analyses of the biodistribution data of [18F]FPyPEGCBT-c(RGDfK) in nude mice bearing ... more Statistical analyses of the biodistribution data of [18F]FPyPEGCBT-c(RGDfK) in nude mice bearing U-87 MG or SKOV-3 subcutaneous tumours a . Figure S1. siRNA-mediated integrin depletions analysis by densitometry. αV, β1, β3 or β5 integrin subunits and indicated combinations were knocked-down by siRNA in U-87 MG and SKOV-3 and protein extracts were submitted to immunoblotting using specific antibodies. Expression levels of each integrin were then quantified with a Chemidoc MP. Data are mean fold expression changes in indicated samples as compared to untransfected cells (Unt) ± SD (n = 3). Figure S2. Uptake of [125I]echistatin in cells with selective siRNA-mediated integrin knocked down. U-87 MG and SKOV-3 cells knocked down for αV, β1, β3 or β5 integrin subunits and indicated combinations were incubated with 100 kBq/mL [18F]FPyPEGCBT-c(RGDfK) for 15 to 120 min at 37 °C. Depletions were verified by immunoblotting using specific antibodies as compared to untransfected cells (Unt) and to...
Organic & biomolecular chemistry, Jan 11, 2015
In a bid to find an efficient means to radiolabel biomolecules under mild conditions for PET imag... more In a bid to find an efficient means to radiolabel biomolecules under mild conditions for PET imaging, a bifunctional (18)F prosthetic molecule has been developed. The compound, dubbed [(18)F]FPyPEGCBT, consists of a 2-substituted pyridine moiety for [(18)F]F(-) incorporation and a 2-cyanobenzothiazole moiety for coupling to terminal cysteine residues. The two functionalities are separated by a mini-PEG chain. [(18)F]FPyPEGCBT could be prepared from its corresponding 2-trimethylammonium triflate precursor (100 °C, 15 min, MeCN) in preparative yields of 11% ± 2 (decay corrected, n = 3) after HPLC purification. However, because the primary radiochemical impurity of the fluorination reaction will not interact with 1,2-aminothiol functionalities, the (18)F prosthetic could be prepared for bioconjugation reactions by way of partial purification on a molecularly imprinted polymer solid-phase extraction cartridge. [(18)F]FPyPEGCBT was used to (18)F-label a cyclo-(RGDfK) analogue which was m...
Nuklearmedizin, 2010
Summary Purpose: To evaluate the mean effective radiation dose of 13N-ammonia PET/CT and ECGpulsi... more Summary Purpose: To evaluate the mean effective radiation dose of 13N-ammonia PET/CT and ECGpulsing CT angiography (CTA) in the evaluation of myocardial perfusion, myocardial blood flow (MBF) and coronary morphology for the identification of subclinical CAD. Patients, material, methods: Following rest-stress 13N-ammonia PET/CT perfusion imaging and MBF quantification, ECG-pulsing CTA at a pulse window of 70% of the R-R cycle was performed in ten healthy controls and in sixteen individuals with cardiovascular risk factors. Individual radiation dose exposure for ECG-pulsing CTA was estimated from the dose-length product. Results: PET demonstrated normal perfusion in all study individuals, while hyperemic MBFs during dipyridamole stimulation and the myocardial flow reserve (MFR) in cardiovascular risk individuals were significantly lower than in healthy controls (1.34 ± 0.26 vs. 2.28 ± 0.47 ml/g/min and 1.48 ± 0.39 vs. 3.24 ± 0.81, both p . 0.0001). Further, ECG-pulsing CTA identified ...
Journal of Nuclear Cardiology, 2010
Background. The aim of this study was to determine whether epicardial structural disease may affe... more Background. The aim of this study was to determine whether epicardial structural disease may affect the manifestation of a longitudinal decrease in myocardial blood flow (MBF) or MBF difference during hyperemia in cardiovascular risk individuals, and its dependency on the flow increase. Methods and Results. In 54 cardiovascular risk individuals (at risk) and in 26 healthy controls, MBF was measured with 13 N-ammonia and PET/CT in mL/g/min at rest and during dipyridamole stimulation. Computed tomography coronary angiography (CTA) was performed using a 64-slice CT of a PET/CT system. Absolute MBFs during dipyridamole stimulation were mildly lower in the mid-distal than in the mid-LV myocardium in controls (2.20 ± .51 vs 2.29 ± .51, P < .0001), while it was more pronounced in at risk with normal and abnormal CTA (1.56 ± .42 vs 1.91 ± .46 and 1.18 ± .34 vs 1.51 ± .40 mL/g/min, respectively, P < .0001), resulting in a longitudinal MBF difference that was highest in at risk with normal CTA, intermediate in at risk abnormal CTA, and lowest in controls (.35 ± .16 and .22 ± .09 vs .09 ± .04 mL/g/min, respectively, P < .0001). On multivariate analysis, log-CCS and mid-LV hyperemic MBF increase, indicative of microvascular function, were independent predictors of the observed longitudinal MBF difference (P £ .004 by ANOVA). Conclusions. Epicardial structural disease and microvascular function are important determinants of an abnormal longitudinal MBF difference as determined with PET/CT.
Journal of Nuclear Cardiology, 2012
Background. To define the relationship between regional coronary vasodilator capacity and myocard... more Background. To define the relationship between regional coronary vasodilator capacity and myocardial circumferential strain at rest in normal weight, overweight, and obese individuals with normal global left-ventricular function. Methods and Results. Myocardial blood flow at rest and during pharmacologic vasodilation was measured with 13 N-ammonia PET/CT in mL/g/minute in normal weight control (CON, n 5 12), overweight (OW, n 5 10), and obese individuals (OB, n 5 10). In addition, resting myocardial function was evaluated as circumferential strain (" c, %) by MRI. Global myocardial flow reserve (MFR) did not differ significantly between CON and OW (2.98 ± 0.96 vs 2.70 ± 0.66, P 5 .290), whereas it declined significantly in OB (1.98 ± 1.04, P 5 .030). Further, global " c (%) was comparable between CON, OW, and OB (20.24 ± 0.03, 20.23 ± 0.02, and 20.23 ± 0.04) but it was lowest in OB when normalized to the rate-pressure product (N " c: 20.31 ± 0.06, 20.32 ± 0.05, and 20.26 ± 0.08). When MFR of the three major coronary territories was correlated with corresponding " c, a positive association was observed in CON (r 5 0.36, P 5 .030), in OW (r 5 0.54, P 5 .002), and also in OB when relating N " c to coronary vascular resistance during pharmacologic vasodilation (r 5 20.46, P 5 .010). Conclusions. Higher coronary vasodilator capacity is related to corresponding regional circumferential strain at rest in non-obese individuals, while this is also observed for reduced MFR in obesity. (
European Journal of Nuclear Medicine and Molecular Imaging, 2008
Purpose Gefitinib, an inhibitor of the epidermal growth factor receptor-tyrosine kinase (EGFR-TK)... more Purpose Gefitinib, an inhibitor of the epidermal growth factor receptor-tyrosine kinase (EGFR-TK), has shown potent effects in a subset of patients carrying specific EGFR-TK mutations in advanced non-small-cell lung cancer. In this study, we asked whether PET with [ 18 F]gefitinib may be used to study noninvasively the pharmacokinetics of gefitinib in vivo and to image the EGFR status of cancer cells. Materials and methods Synthesis of [ 18 F]gefitinib has been previously described. The biodistribution and metabolic stability of [ 18 F]gefitinib was assessed in mice and vervet monkeys for up to 2 h post injection by both micropositron emission tomography (PET)/computed tomography (CT) scans and postmortem ex vivo tissue harvesting. Uptake levels of radiolabeled gefitinib in EGFR-expressing human cancer cell lines with various levels of EGFR expression or mutation status were evaluated both in vivo and in vitro. Results MicroPET/CT scans in two species demonstrated a rapid and predominantly hepatobiliary clearance of [ 18 F]gefitinib in vivo. However, uptake levels of radiolabeled gefitinib, both in vivo and in vitro, did not correlate with EGFR expression levels or functional status. This unexpected observation was due to high nonspecific, nonsaturable cellular uptake of gefitinib. Conclusion The biodistribution of the drug analogue [ 18 F]gefitinib suggests that it may be used to assess noninvasively the pharmacokinetics of gefitinib in patients by PET imaging. This is of clinical relevance, as insufficient intratumoral drug concentrations are considered to be a factor for resistance to gefitinib therapy. However, the highly nonspecific cellular binding of [ 18 F]gefitinib may preclude the use of this imaging probe for noninvasive assessment of EGFR receptor status in patients.
European Heart Journal, 2011
Aim of this study was to evaluate a possible association between endocannabinoid (EC) plasma leve... more Aim of this study was to evaluate a possible association between endocannabinoid (EC) plasma levels, such as anandamide (AEA) and 2-arachidonoylglycerol (2-AG), and coronary circulatory function in obesity. Methods and results Myocardial blood flow (MBF) responses to cold pressor test (CPT) and during pharmacological vasodilation with dipyridamole were measured with 13 N-ammonia PET/CT. Study participants (n ¼ 77) were divided into three groups based on their body mass index (BMI, kg/m 2): control group 20≤ BMI ,25 (n ¼ 21); overweight group, 25≤ BMI ,30 (n ¼ 26); and obese group, BMI ≥30 (n ¼ 30). Anandamide plasma levels, but not 2-AG plasma levels, were significantly elevated in obesity as compared with controls, respectively [0.68 (0.53, 0.78) vs. 0.56 (0.47, 0.66) ng/mL, P ¼ 0.020, and 2.2 (1.21, 4.59) vs. 2.0 (0.80, 5.90) ng/mL, P ¼ 0.806)]. The endothelium-related change in MBF during CPT from rest (DMBF) progressively declined in overweight and obese when compared with control group [0.21 (0.10, 0.27) and 0.09 (20.01, 0.15) vs. 0.26 (0.23, 0.39) mL/g/min; P ¼ 0.010 and P ¼ 0.0001, respectively). Compared with controls, hyperaemic MBFs were significantly lower in overweight and obese individuals [2.39 (1.97, 2.62) vs. 1.98 (1.69, 2.26) and 2.10 (1.76, 2.36); P ¼ 0.007 and P ¼ 0.042, respectively)]. In obese individuals, AEA and 2-AG plasma levels were inversely correlated with DMBF to CPT (r ¼ 20.37, P ¼ 0.046 and r ¼ 20.48, P ¼ 0.008) and hyperaemic MBFs (r ¼ 20.38, P ¼ 0.052 and r ¼ 20.45, P ¼ 0.017), respectively. Conclusions Increased EC plasma levels of AEA and 2-AG are associated with coronary circulatory dysfunction in obese individuals. This observation might suggest increases in EC plasma levels as a novel endogenous cardiovascular risk factor in obesity, but needing further investigations.
Diabetes & Metabolism, 2011
Pharmaceutics, 2022
Nuclear and optical dual-modality probes can be of great assistance in prostate cancer localizati... more Nuclear and optical dual-modality probes can be of great assistance in prostate cancer localization, providing the means for both preoperative nuclear imaging and intraoperative surgical guidance. We developed a series of probes based on the backbone of the established GRPR-targeting radiotracer NeoB. The inverse electron demand of the Diels–Alder reaction was used to integrate the sulfo-cyanine 5 dye. Indium-111 radiolabeling, stability studies and a competition binding assay were carried out. Pilot biodistribution and imaging studies were performed in PC-3 tumor-bearing mice, using the best two dual-labeled probes. The dual-modality probes were radiolabeled with a high yield (>92%), were proven to be hydrophilic and demonstrated high stability in mouse serum (>94% intact labeled ligand at 4 h). The binding affinity for the GRPR was in the nanomolar range (21.9–118.7 nM). SPECT/CT images at 2 h p.i. clearly visualized the tumor xenograft and biodistribution studies, after sca...