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BACKGROUND: This study aimed to evaluate the biodistribution of 64Cu-DOTA-rituximab and its diagnostic feasibility for lymphoma using CD20-targeted 64Cu-DOTA-rituximab PET/computed tomography (PET/CT). METHODS: A prospective study involving six patients diagnosed with lymphoma was conducted between January 2022 and January 2023. These patients underwent 18F-fluorodeoxyglucose (18F-FDG) and 64Cu-DOTA-rituximab PET/CT scans. 64Cu-DOTA-rituximab PET/CT images were acquired at 1, 24, and 48 h after administering 64Cu-DOTA-rituximab to assess the biodistribution and dosimetry over time. The observed lymph nodes were categorized into specific regions, including cervical and supraclavicular, axillary and infraclavicular, mediastinal, hilar, abdominal paraaortic and retroperitoneal, iliac, mesenteric, and inguinal regions, to compare the diagnostic ability of 18F-FDG and 64Cu-DOTA-rituximab PET/CT in detecting lymphoma lesions. Furthermore, the tumor-to-background ratio was calculated and compared with the maximum standardized uptake (SUVmax) of the tumors and the mean standardized uptake (SUVmean) of normal organs. Internal radiation dosimetry was determined using the OLINDA/EXM software. RESULTS: 64Cu-DOTA-rituximab uptake in lymph nodes associated with lymphoma progressively increased from 1 to 48 h after injection. In contrast, 64Cu-DOTA-rituximab uptake in normal organs, such as blood, lung, kidney, bladder, muscle, bone, and brain, decreased over time, whereas it increased in the liver and spleen. When it comes to the comparison between 64Cu-DOTA-rituximab and 18F-FDG, the SUVmax of tumors was higher on 64Cu-DOTA-rituximab PET/CT (18.1â ±â 8.3) than on 18F-FDG PET/CT (5.2â ±â 1.5). Additionally, the tumor-to-background ratio, measured using the SUVmean of normal muscles, was higher on 64Cu-DOTA-rituximab PET/CT (55.7â ±â 31.0) than on 18F-FDG PET/CT (8.6â ±â 2.8). No adverse events related to 64Cu-DOTA-rituximab injection were reported. CONCLUSION: The results of this study demonstrate the feasibility of using 64Cu-DOTA-rituximab PET/CT to evaluate the CD20 expression. The increased 64Cu-DOTA-rituximab uptake in lymph nodes associated with tumors, higher SUVmax, and tumor-to-muscle ratios observed with 64Cu-DOTA-rituximab PET/CT compared with 18F-FDG PET/CT, highlight the diagnostic potential of this imaging modality.
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The study introduces a novel maleamate-based prosthetic group specifically designed for efficient, site-specific radioiodination of biomolecules that contain or are modified with cysteine residues. This strategy is a compelling alternative to the conventional maleimide-based approach, demonstrating outstanding attributes such as high radiochemical yield, rapid reaction kinetics, applicability in aqueous media at neutral pH, and exceptional stability under a competitive environment.
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Among clinically used radiopharmaceuticals, iodine-123 labeled metaiodobenzylguanidine ([123I]mIBG) serves for diagnosing neuroendocrine tumors and obtaining images of myocardial sympathetic innervation. mIBG, a structural analogue of norepinephrine (NE), a neurotransmitter acting in peripheral and central nerves, follows a pathway similar to NE, transmitting signals through the NE transporter (NET) located at synaptic terminals. It moves through the body without decomposing, enabling noninvasive image evaluation. In this study, we aimed to quantify [123I]mIBG uptake in the adrenal glands using small animal single-photon emission computed tomography/computed tomography (SPECT/CT) images post [123I]mIBG administration. We investigated the possibility of assessing the effectiveness of ß-adrenergic receptor blockers by quantifying SPECT/CT images and biodistribution results to determine the degree of [123I]mIBG uptake in the adrenal glands treated with labetalol, a known ß-adrenergic receptor blocker. Upon intravenous administration of [123I]mIBG to mice, SPECT/CT images were acquired over time to confirm the in vivo distribution pattern, revealing a clear uptake in the adrenal glands. Labetalol inhibited the uptake of [123I]mIBG in cell lines expressing NET. A decrease in [123I]mIBG uptake in the adrenal glands was observed in the labetalol-treated group compared with the normal group through SPECT/CT imaging and biodistribution studies. These results demonstrate that SPECT/CT imaging with [123I]mIBG could be applicable for evaluating the preclinical efficacy of new antihypertensive drug candidates such as labetalol, a ß-adrenergic receptor blocker.
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3-Iodobenzilguanidina , Antagonistas Adrenérgicos beta , Radioisótopos do Iodo , Labetalol , Animais , Humanos , Masculino , Camundongos , Glândulas Suprarrenais/diagnóstico por imagem , Glândulas Suprarrenais/efeitos dos fármacos , Glândulas Suprarrenais/metabolismo , Antagonistas Adrenérgicos beta/farmacologia , Antagonistas Adrenérgicos beta/farmacocinética , Linhagem Celular Tumoral , Estudos de Viabilidade , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/metabolismo , Proteínas da Membrana Plasmática de Transporte de Norepinefrina/antagonistas & inibidores , Compostos Radiofarmacêuticos/farmacocinética , Tomografia Computadorizada com Tomografia Computadorizada de Emissão de Fóton Único , Distribuição TecidualRESUMO
Radiolabeling of biomolecules and cells with radiolabeled prosthetic groups has significant implications for nuclear medicine, imaging, and radiotherapy. Achieving site-specific and controlled incorporation of radiolabeled prostheses under mild reaction conditions is crucial for minimizing the impact on the bioactivity of the radiolabeled compounds. The targeting of natural and abundant amino acids during radiolabeling of biomolecules often results in nonspecific and uncontrolled modifications. Cysteine is distinguished by its low natural abundance and unique nucleophilicity. It is therefore an optimal target for site-selective and site-specific radiolabeling of biomolecules under controlled parameters. This review extensively discusses thiol-specific radiolabeled prosthetic groups and provides a critical analysis and comprehensive study of the synthesis of these groups, their in vitro and in vivo stability profiles, reaction kinetics, stability of resulting adducts, and overall impact on the targeting ability of radiolabeled biomolecules. The insights presented here aim to facilitate the development of highly efficient radiopharmaceuticals, initially in preclinical settings and ultimately in clinical applications.
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Compostos Radiofarmacêuticos , Compostos de Sulfidrila , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/síntese química , Humanos , Compostos de Sulfidrila/química , Animais , Cisteína/químicaRESUMO
The burgeoning interest in developing boron neutron capture therapy (BNCT) tracers and their accompanying diagnostics for the treatment of recalcitrant tumors has prompted this investigation. Our study aims to devise a tumor treatment strategy utilizing BNCT to target the αvß3 integrin. To this end, we propose a pioneering boron-infused cyclic Arg-Gly-Asp (RGD) peptide, cRGD(d-BPA)K, designed as an efficacious BNCT tracer. Additionally, we introduce its diagnostic complement, DOTA-cRGD(d-BPA)K, tailored for positron emission tomography (PET) to visualize αvß3 expressed tumors. Radiolabeling [64Cu]Cu-DOTA-cRGD(d-BPA)K (64Cu-1) resulted in a high radiochemical yield and purity. The radiotracer exhibited exceptional in vitro stability and demonstrated significant uptake in U87MG tumors via PET imaging. Biodistribution analysis using compound 2 showed a 7.0 ppm accumulation of boron in the U87MG tumor 1 h post-intravenous injection. Furthermore, compound 2 displayed superior tumor/blood (2.41) and tumor/muscle (2.46) ratios compared to the clinically approved l-BPA-fructose. Both compound 2 and its diagnostic counterpart 64Cu-1 hold potential for BNCT and cancer diagnosis, respectively, via molecular imaging.
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BACKGROUND: Immunotherapy with clodronate-encapsulated liposomes, which induce macrophage depletion, has been studied extensively. However, previously reported liposomal formulation-based drugs (Clodrosome® and m-Clodrosome®) are limited by their inconsistent size and therapeutic efficacy. Thus, we aimed to achieve consistent therapeutic effects by effectively depleting macrophages with uniform-sized liposomes. RESULTS: We developed four types of click chemistry-based liposome nanoplatforms that were uniformly sized and encapsulated with clodronate, for effective macrophage depletion, followed by conjugation with Man-N3 and radiolabeling. Functionalization with Man-N3 improves the specific targeting of M2 macrophages, and radioisotope labeling enables in vivo imaging of the liposome nanoplatforms. The functionalized liposome nanoplatforms are stable under physiological conditions. The difference in the biodistribution of the four liposome nanoplatforms in vivo were recorded using positron emission tomography imaging. Among the four platforms, the clodronate-encapsulated mannosylated liposome effectively depleted M2 macrophages in the normal liver and tumor microenvironment ex vivo compared to that by Clodrosome® and m-Clodrosome®. CONCLUSION: The newly-developed liposome nanoplatform, with finely tuned size control, high in vivo stability, and excellent ex vivo M2 macrophage targeting and depletion effects, is a promising macrophage-depleting agent.
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Ácido Clodrônico , Lipossomos , Masculino , Humanos , Lipossomos/farmacologia , Ácido Clodrônico/farmacologia , Distribuição Tecidual , MacrófagosRESUMO
Positron emission tomography (PET) and single photon emission computed tomography (SPECT) are potent technologies for non-invasive imaging of pharmacological and biochemical processes in both preclinical and advanced clinical research settings. In the field of radiation therapy, boron neutron capture therapy (BNCT) stands out because it harnesses biological mechanisms to precisely target tumor cells while preserving the neighboring healthy tissues. To achieve the most favorable therapeutic outcomes, the delivery of boron-enriched tracers to tumors must be selective and efficient, with a substantial concentration of boron atoms meticulously arranged in and around the tumor cells. Although several BNCT tracers have been developed to facilitate the targeted and efficient delivery of boron to tumors, only a few have been labeled with PET or SPECT radionuclides. Such radiolabeling enables comprehensive in vivo examination, encompassing crucial aspects such as pharmacodynamics, pharmacokinetics, tumor selectivity, and accumulation and retention of the tracer within the tumor. This review provides a comprehensive summary of the essential aspects of BNCT tracers, focusing on their radiolabeling with PET or SPECT radioisotopes. This leads to more effective and targeted treatment approaches which ultimately enhance the quality of patient care with respect to cancer treatment.
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Terapia por Captura de Nêutron de Boro , Neoplasias , Humanos , Terapia por Captura de Nêutron de Boro/métodos , Boro , Tomografia por Emissão de Pósitrons/métodos , Neoplasias/diagnóstico por imagem , Neoplasias/radioterapia , Compostos de BoroRESUMO
Introduction: Traumatic events in early life have a deleterious effect on the development of normal brain developments, which may be a cause of various psychiatric disorders in adulthood. Most prior studies focused on molecular biological aspects, and research on functional changes in neural circuits is still limited. We aimed to elucidate the effect of early life stress on in vivo excitation-inhibition and serotonergic neurotransmission in the adulthood using non-invasive functional molecular imaging (positron emission tomography, PET). Methods: To compare the effect of stress intensity, early life stress animal models were divided into single trauma (MS) and double trauma groups (MRS). MS was derived from maternal separation, whereas MRS was derived from maternal separation and restraint stress after birth. And to evaluate the stress vulnerability on the sex, we used male and female rats. Results: The MRS group showed greater weight loss and more severe depressive/anxiety-like behaviors than the MS and control groups. Corticosterone levels in MRS showed a greater extent of decline than in the MS group; however, there was no significant difference in the change of T3 and T4 between MS and MRS. In the PET, the stress exposure groups showed lower brain uptake for GABAergic, glutamatergic, and serotonergic systems compared with the control group. The excitatory/inhibitory balance, which was derived by dividing glutamate brain uptake into GABAergic uptake, increased as stress intensity increased. Neuronal degeneration in the stress exposure groups was confirmed by immunohistochemistry. In the sex comparison, female showed the greater changes of body weight, corticosterone level, depressive/anxiety-like behavior, and neurotransmission systems than those in male. Conclusion: Taken together, we demonstrated that developmental stress induces dysfunction of neurotransmission in vivo, and that females are more vulnerable to stress than males.
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We have compared the similarity of the in vivo distribution of the prostate-specific membrane antigen (PSMA)-targeted positron emission tomography (PET) imaging agents [18F]DCFPyL, [68Ga]galdotadipep, and [68Ga]PSMA-11. This study is designed for a further selection of a PSMA-targeted PET imaging agent for the therapeutic evaluation of [177Lu]ludotadipep, our previously developed prostate-specific membrane antigen (PSMA)-targeted prostate cancer therapeutic radiopharmaceutical. In vitro cell uptake was performed to evaluate the affinity to PSMA using PSMA + PC3-PIP, and PSMA- PC3-flu was used for the study. MicroPET/CT 60 min dynamic imaging and biodistribution were performed at 1, 2, and 4 h after injection. Autoradiography and immunohistochemistry were performed to evaluate the PSMA + tumor target efficiency. In the microPET/CT image, [68Ga]PSMA-11 showed the highest uptake in the kidney among all three compounds. [18F]DCFPyL and [68Ga]PSMA-11 showed similar patterns of in vivo biodistribution and high tumor targeting efficiency, similar to those of[68Ga]galdotadipep. All three agents showed high uptake in tumor tissue on autoradiography, and PSMA expression was confirmed by immunohistochemistry. Thus, [18F]DCFPyL or [68Ga]PSMA-11 can be used as a PET imaging agent to monitor [177Lu]ludotadipep therapy in prostate cancer patients.
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Radioisótopos de Gálio , Neoplasias da Próstata , Humanos , Masculino , Detecção Precoce de Câncer , Tomografia por Emissão de Pósitrons/métodos , Neoplasias da Próstata/patologia , Compostos Radiofarmacêuticos , Distribuição Tecidual , Antígeno Prostático Específico/metabolismoRESUMO
Over the last decade, 64Cu-labeling of monoclonal antibody (mAb) via inverse electron demand Diels-Alder click chemistry (IEDDA) have received much attention. Despite the tetrazine-transcyclooctene (Tz-TCO) click chemistry's convenience and efficiency in mAb labeling, there is limited information about the ideal parameters in the development of click chemistry mediated (radio)immunoconjugates. This encourages us to conduct a systematic optimization while concurrently determining the physiochemical characteristics of the model mAb, trastuzumab, and TCO conjugates. To accomplish this, we investigated a few critical parameters, first, we determined the degree of conjugations with varying molar equivalents (eq.) of TCO (3, 5, 10, and 15 eq.). Through analytical techniques like size exclusion chromatography, dynamic light scattering, and zeta potential, qualitative analysis were performed to determine the purity, degree of aggregation and net charge of the conjugates. We found that as the degree of conjugation increased the purity of intact mAb fraction is compromised and net charge of conjugates became less positive. Next, all trastuzumab-PEG4-TCO conjugates with varying molar ratio and quantity (30, 50, 100, 200, 250 µg) were radiolabeled with 64Cu-NOTA-PEG4-Tz via IEDDA click chemistry and radiochemical yields were determined by radio-thin layer chromatography. The radiochemical yields of trastuzumab conjugates improved with increased amount and molar ratio. Next, we investigated the effect of the radioprotectant ascorbic acid (AA) of varied concentrations (0.25, 0.5, 0.75, 1 mM) on radiochemical yields and subsequent pharmacokinetics. A concentration of 0.25 mM of AA was found to be optimal for click reaction and in vivo biodistribution. Finally, we investigated the indirect influence of bioconjugation buffers on radiochemical yields and biodistribution in NIH3T6.7 tumor models that resulted approximately â¼11 %ID/g tumor uptake.
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Radioisótopos de Cobre , Neoplasias , Humanos , Trastuzumab , Química Click/métodos , Distribuição Tecidual , Anticorpos Monoclonais , Compostos Radiofarmacêuticos/farmacocinética , Linhagem Celular TumoralRESUMO
Early diagnosis of radiation-induced pulmonary fibrosis (RIPF) in lung cancer patients after radiation therapy is important. A gastrin-releasing peptide receptor (GRPR) mediates the inflammation and fibrosis after irradiation in mice lungs. Previously, our group synthesized a GRPR-targeted positron emission tomography (PET) imaging probe, [64Cu]Cu-NODAGA-galacto-bombesin (BBN), an analogue peptide of GRP. In this study, we evaluated the usefulness of [64Cu]Cu-NODAGA-galacto-BBN for the early prediction of RIPF. We prepared RIPF mice and acquired PET/CT images of [18F]F-FDG and [64Cu]Cu-NODAGA-galacto-BBN at 0, 2, 5, and 11 weeks after irradiation (n = 3-10). We confirmed that [64Cu]Cu-NODAGA-galacto-BBN targets GRPR in irradiated RAW 264.7 cells. In addition, we examined whether [64Cu]Cu-NODAGA-galacto-BBN monitors the therapeutic efficacy in RIPF mice (n = 4). As a result, the lung uptake ratio (irradiated-to-normal) of [64Cu]Cu-NODAGA-galacto-BBN was the highest at 2 weeks, followed by its decrease at 5 and 11 weeks after irradiation, which matched with the expression of GRPR and was more accurately predicted than [18F]F-FDG. These uptake results were also confirmed by the cell uptake assay. Furthermore, [64Cu]Cu-NODAGA-galacto-BBN could monitor the therapeutic efficacy of pirfenidone in RIPF mice. We conclude that [64Cu]Cu-NODAGA-galacto-BBN is a novel PET imaging probe for the early prediction of RIPF-targeting GRPR expressed during the inflammatory response.
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Fibrose Pulmonar , Receptores da Bombesina , Animais , Camundongos , Receptores da Bombesina/metabolismo , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Fibrose Pulmonar/diagnóstico por imagem , Fibrose Pulmonar/etiologia , Fluordesoxiglucose F18 , Tomografia por Emissão de Pósitrons/métodos , Bombesina/metabolismo , Pulmão/diagnóstico por imagem , Pulmão/metabolismo , Linhagem Celular TumoralRESUMO
ABSTRACT: 64 Cu-DOTA-rituximab PET/CT was performed on a 62-year-old and a 71-year-old men diagnosed with B-cell non-Hodgkin lymphoma. Compared with 18 F-FDG PET/CT, lesions could be detected more sensitively, and it was confirmed that there was no discernible 64 Cu-DOTA-rituximab uptake in the tumor other than lymphoma. 64 Cu-DOTA-rituximab PET/CT could be a powerful tool for the diagnosis and monitoring treatment response of lymphoma because of imaging the CD20 expression.
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Linfoma não Hodgkin , Linfoma , Masculino , Humanos , Pessoa de Meia-Idade , Idoso , Rituximab/uso terapêutico , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Anticorpos Monoclonais Murinos , Compostos Radiofarmacêuticos , Linfoma não Hodgkin/diagnóstico por imagem , Linfoma não Hodgkin/patologia , Fluordesoxiglucose F18RESUMO
[This corrects the article DOI: 10.3389/fnins.2022.930613.].
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Boron neutron capture therapy (BNCT) is a precision treatment technology that ideally damages only boron-accumulating cells. The effectiveness of BNCT depends on the amount of boron in the tumor cells and the concentration ratio between normal and tumor tissues. Therefore, for successful brain-tumor treatment using BNCT, it is essential to develop a drug with high blood-brain barrier (BBB) permeability and high tumor accumulation. The benzothiazole-based boron complex 4-(benzo[d]thiazol-2-yl)phenylboronic acid (BTPB) is a hydrophobic, low-molecular-weight compound that has shown high BBB permeability and brain accumulation. The highest boron concentration of BTPB is 36.11 ± 2.73 µg/g (at 1 h post-injection) in the brain, and the highest brain/blood ratio is 3.94 ± 0.46 (at 2 h post-injection), which is sufficient for the BNCT drug condition. In addition, BTPB showed good tumor-targeting ability in vivo in a U87MG glioma tumor model. In this study, we conducted a biological evaluation of BTPB compared to boronophenylalanine as a novel drug for BNCT.
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Photodynamic therapy (PDT) is an effective cancer treatment option, but it suffers from penetration limit of light, making it available only for superficial and endoscopically accessible cancers. Recently, there have been reports that Cerenkov luminescence originated from radioisotopes can be utilized as an excitation source for PDT without external light illumination. Here, cancer-selective agents, i.e., (1) clinically available 5-aminolevulinic acid (5-ALA), which promotes cancer metabolism-specific accumulation of protoporphyrin IX (PpIX), and (2) 64Cu-DOTA-trastuzumab, which has HER2-expressing cancer selective uptake, are separately applied as a photosensitizer and an in situ radiator, respectively, to potentiate tumor-specific Cerenkov luminescence energy transfer (CLET) from 64Cu to PpIX for high-precision PDT of cancer. It is shown that the combinational administration and tumor colocalization of 5-ALA and 64Cu-DOTA-trastuzumab exert significant in vitro cytotoxicity (cell viability <9%) as well as in vivo antitumor effects (tumor volume ratio of 0.50 on 14 days post-injection) on HER2-expressing breast and gastric cancer models. This study proves that high-precision treatment regimen using dual-targeted CLET-based PDT is feasible for HER2-expressing cancers. Furthermore, the results offer great potential for clinical translation to the dual-targeted CLET-based PDT because the treatment regimen uses components, 5-ALA and 64Cu-DOTA-trastuzumab, which are already in clinical uses.
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Neoplasias , Fotoquimioterapia , Humanos , Ácido Aminolevulínico , Protoporfirinas , Fármacos Fotossensibilizantes/uso terapêutico , Fotoquimioterapia/métodos , Neoplasias/tratamento farmacológico , Trastuzumab , Linhagem Celular TumoralRESUMO
Triple-negative breast cancer (TNBC) does not express estrogen receptor, progesterone receptor, and human epidermal growth factor receptor 2. Because TNBC lacks the expression of commonly targeted receptors, it is challenging to develop a new imaging agent for this cancer subtype. Heterogeneous nuclear ribonucleoproteins (hnRNPs) are RNA-protein complexes that have been linked to tumor development and progression. Considering the high expression of hnRNPA2B1, an hnRNP subtype, in TNBC MDA-MB-231 cells, this study aimed to develop a novel hnRNPA2B1 antibody-based nuclear imaging agent. The hnRNPA2B1-specific antibody was radiolabeled with 64Cu and evaluated in vitro and in vivo. The trans-cyclooctene (TCO) was functionalized on the antibody to obtain hnRNP-PEG4-TCO and reactive tetrazine (Tz) on the ultrastable bifunctional chelator PCB-TE2A-alkyne to yield PCB-TE2A-Tz for the inverse electron demand Diels-Alder reaction. The 64Cu-radiolabeled antibody was administered and imaged at 1-18 h time points for conventional imaging. Alternatively, the unlabeled antibody conjugate was administered, and 48 h later radiolabeled 64Cu-PCB-TE2A-Tz was administered to the same mice for the pretargeting strategy and imaged at the same time intervals for direct comparison. The tumor was successfully visualized in both strategies, and comparatively, pretargeting showed superior results. The 64Cu-PCB-TE2A-Tz was successfully clicked at the tumor site with hnRNP-PEG4-TCO and the non-clicked were concurrently eliminated. This led to increase the tumor uptake with extremely high tumor-to-background ratio manifested by positron emission tomography (PET) imaging and biodistribution studies.
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This study aimed to investigate how amyloid pathology affects the functional aspects of neurotransmitter systems in Alzheimer's disease. APPswe/PS2 mice (21 months of age) and wild-type (WT) mice underwent positron emission tomography (PET) and magnetic resonance spectroscopy (MRS). First, we obtained 18F-FDG and 18F-florbetaben PET scans to evaluate neuronal integrity and amyloid pathology. Second, 18F-FPEB and 18F-FMZ PET data were acquired to assess the excitatory-inhibitory neurotransmission. Third, to monitor the dopamine system, 18F-fallypride PET was performed. Amyloid PET imaging revealed that radioactivity was higher in the AD group than that in the WT group, which was validated by immunohistochemistry. In the cortical and limbic areas, the AD group showed a 25-27% decrease and 14-35% increase in the glutamatergic and GABAergic systems, respectively. The dopaminergic system in the AD group exhibited a 29% decrease in brain uptake compared with that in the WT group. A reduction in glutamate, N-acetylaspartate, and taurine levels was observed in the AD group using MRS. Our results suggest that dysfunction of the neurotransmitter system is associated with AD pathology. Among the systems, the GABAergic system was prominent, implying that the inhibitory neurotransmission system may be the most vulnerable to AD pathology.
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PURPOSE: Hydrogen sulfide (H2S) plays important roles in brain pathophysiology. However, nuclear imaging probes for the in vivo detection of brain H2S in living animals have not been developed. Here, we report the first nuclear imaging probe that enables in vivo imaging of endogenous H2S in the brain of live mice. METHODS: Utilizing a bis(thiosemicarbazone) backbone, a fluorescent ATSM-FITC conjugate was synthesized. Its copper complex, Cu(ATSM-FITC) was thoroughly tested as a biosensor for H2S. The same ATSM-FITC ligand was quantitatively labeled with [64Cu]CuCl2 to obtain a radioactive [64Cu][Cu(ATSM-FITC)] imaging probe. Biodistribution and positron emission tomography (PET) imaging studies were performed in healthy mice and neuroinflammation models. RESULTS: The Cu(ATSM-FITC) complex reacts instantly with H2S to release CuS and becomes fluorescent. It showed excellent reactivity, sensitivity, and selectivity to H2S. Endogenous H2S levels in living cells were successfully detected by fluorescence microscopy. Exceptionally high brain uptake of [64Cu][Cu(ATSM-FITC)] (> 9% ID/g) was observed in biodistribution and PET imaging studies. Subtle changes in brain H2S concentrations in live mice were accurately detected by quantitative PET imaging. Due to its dual modality feature, increased H2S levels in neuroinflammation models were characterized at the subcellular level by fluorescence imaging and at the whole-body scale by PET imaging. CONCLUSION: Our biosensor can be readily utilized to study brain H2S function in live animal models and shows great potential as a novel imaging agent for diagnosing brain diseases.
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Complexos de Coordenação , Sulfeto de Hidrogênio , Compostos Organometálicos , Tiossemicarbazonas , Animais , Encéfalo/diagnóstico por imagem , Cobre , Fluoresceína-5-Isotiocianato , Corantes Fluorescentes , Ligantes , Camundongos , Doenças Neuroinflamatórias , Distribuição TecidualRESUMO
A number of researchers in Korea have tried to set-up the production of radionuclides and develop new radiopharmaceuticals for several decades. Thanks to their 60-year endeavor to advance the field of radiopharmaceutical sciences, now we have a lot of research units and facilities in Korea. Still, there are huge number of issues to be solved in radiopharmaceutical sciences; however, our efforts will be continued to develop new radiopharmaceuticals and to apply the new radiopharmaceuticals into nuclear medicine field.
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The aim of this work was to evaluate Gd-FC705, a prostate-specific membrane antigen (PSMA)-targeted MRI contrast agent. The r1 and r2 relaxivities of Gd-FC705 are 5.94 mM-1s-1 and 17.77 mM-1s-1, respectively, in HSA solution (0.67 mM) at 3 T, which are higher than those of Gd-DOTA. Specific targeting efficacy was found with a 3-fold enhancement between PSMA-negative (PSMA-) and PSMA-positive (PSMA+) cells. The in vivo targeting and bio-distribution of Gd-FC705 were further confirmed using nude mice bearing PC3 human prostate cancer xenografts, which showed a 2-fold increase in the contrast-to-noise ratio (CNR) for PSMA+ tumors compared to PSMA- tumors 1 h post injection and a longer circulation time than Gd-DOTA. These results demonstrate that Gd-FC705 has great potential as a diagnostic agent for prostate cancer.