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The aim of this guideline is to provide recommendations for the implementation of an effective and efficient quality control (QC) programme for SPECT and PET systems in a preclinical imaging lab. These recommendations aim to strengthen the translational power of preclinical imaging results obtained using preclinical SPECT and PET. As for clinical imaging, reliability, reproducibility, and repeatability are essential when groups of animals are used in a longitudinal imaging experiment. The larger the variability of the imaging endpoint, the more animals are needed to be able to observe statistically significant differences between groups. Therefore, preclinical imaging requires quality control procedures to maintain reliability, reproducibility, and repeatability of imaging procedures, and to ensure the accuracy and precision of SPECT and PET quantification. While the Physics Committee of the European Association of Nuclear Medicine (EANM) has already published excellent procedure guidelines for Routine Quality Control Recommendations for Nuclear Medicine Instrumentation that also includes procedures for small animal PET systems, and important steps have already been made concerning preclinical quality control aspects, this new guideline provides a review and update of these previous guidelines such that guidelines are also adapted to new technological developments.
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Since the discovery of cisplatin's antitumoral activity and its approval as an anticancer drug, significant efforts have been made to enhance its physiological stability and anticancer efficacy and to reduce its side effects. With the rapid development of targeted and personalized therapies, and the promising theranostic approach, platinum drugs have found new opportunities in more sophisticated systems. Theranostic agents combine diagnostic and therapeutic moieties in one scaffold, enabling simultaneous disease monitoring, therapy delivery, response tracking, and treatment efficacy evaluation. In these systems, the platinum core serves as the therapeutic agent, while the functionalized ligand provides diagnostic tools using various imaging techniques. This review aims to highlight the significant role of platinum-based complexes in theranostic applications, and, to the best of our knowledge, this is the first focused contribution on this type of platinum compounds. This review presents a brief introduction to the development of platinum chemotherapeutic drugs, their limitations, and resistance mechanisms. It then describes recent advancements in integrating platinum complexes with diagnostic agents for both tumor treatment and monitoring. The main body is organized into three categories based on imaging techniques: fluorescence, positron emission tomography (PET), single-photon emission computed tomography (SPECT), and magnetic resonance imaging (MRI). Finally, this review outlines promising strategies and future perspectives in this evolving field.
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Antineoplásicos , Neoplasias , Nanomedicina Teranóstica , Humanos , Antineoplásicos/uso terapêutico , Antineoplásicos/farmacologia , Antineoplásicos/química , Neoplasias/tratamento farmacológico , Neoplasias/diagnóstico por imagem , Animais , Tomografia por Emissão de Pósitrons/métodos , Imageamento por Ressonância Magnética , Compostos de Platina/química , Compostos de Platina/uso terapêutico , Compostos de Platina/farmacologia , Medicina de Precisão/métodosRESUMO
Transporter-mediated drug-drug interactions (DDIs) are of concern in antimicrobial drug development, as they can have serious safety consequences. We used positron emission tomography (PET) imaging-based pharmacokinetic (PK) analysis to assess the effect of different drugs, which may cause transporter-mediated DDIs, on the tissue distribution and excretion of [18F]ciprofloxacin as a radiolabeled model antimicrobial drug. Mice underwent PET scans after intravenous injection of [18F]ciprofloxacin, without and with pretreatment with either probenecid (150 mg/kg), cimetidine (50 mg/kg), or pyrimethamine (5 mg/kg). A 3-compartment kidney PK model was used to assess the involvement of renal transporters in the examined DDIs. Pretreatment with probenecid and cimetidine significantly decreased the renal clearance (CLrenal) of [18F]ciprofloxacin. The effect of cimetidine (-86%) was greater than that of probenecid (-63%), which contrasted with previously published clinical data. The kidney PK model revealed that the decrease in CLrenal was caused by inhibition of basal uptake transporters and apical efflux transporters in kidney proximal tubule cells. Changes in the urinary excretion of [18F]ciprofloxacin after pretreatment with probenecid and cimetidine resulted in increased blood and organ exposure to [18F]ciprofloxacin. Our results suggest that multiple membrane transporters mediate the tubular secretion of ciprofloxacin, with possible species differences between mice and humans. Concomitant medication inhibiting renal transporters may precipitate DDIs, leading to decreased urinary excretion and increased blood and organ exposure to ciprofloxacin, potentially exacerbating adverse effects. Our study highlights the strength of PET imaging-based PK analysis to assess transporter-mediated DDIs at a whole-body level.
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Anti-Infecciosos , Probenecid , Humanos , Camundongos , Animais , Probenecid/farmacologia , Cimetidina/farmacologia , Rim/diagnóstico por imagem , Proteínas de Membrana Transportadoras , Interações Medicamentosas , Tomografia por Emissão de Pósitrons , Ciprofloxacina/farmacocinéticaRESUMO
Multidrug resistance-associated protein 1 (MRP1, encoded by the ABCC1 gene) may contribute to the clearance of amyloid-beta (Aß) peptides from the brain into the blood and stimulation of MRP1 transport activity may be a therapeutic approach to enhance brain Aß clearance. In this study, we assessed the effect of thiethylperazine, an antiemetic drug which was shown to stimulate MRP1 activity in vitro and to decrease Aß load in a rapid ß-amyloidosis mouse model (APP/PS1-21), on MRP1 transport activity by means of positron emission tomography (PET) imaging with the MRP1 tracer 6-bromo-7-[11C]methylpurine. Groups of wild-type, APP/PS1-21 and Abcc1(-/-) mice underwent PET scans before and after a 5-day oral treatment period with thiethylperazine (15 mg/kg, once daily). The elimination rate constant of radioactivity (kelim) was calculated from time-activity curves in the brain and the lungs as a measure of tissue MRP1 activity. Treatment with thiethylperazine had no significant effect on MRP1 activity in the brain and the lungs of wild-type and APP/PS1-21 mice. This may either be related to a lack of an MRP1-stimulating effect of thiethylperazine in vivo or to other factors, such as substrate-dependent MRP1 stimulation, insufficient target tissue exposure to thiethylperazine or limited sensitivity of the PET tracer to measure MRP1 stimulation.
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Doença de Alzheimer , Tietilperazina , Doença de Alzheimer/diagnóstico por imagem , Doença de Alzheimer/tratamento farmacológico , Doença de Alzheimer/genética , Peptídeos beta-Amiloides/metabolismo , Precursor de Proteína beta-Amiloide/genética , Precursor de Proteína beta-Amiloide/metabolismo , Animais , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Modelos Animais de Doenças , Camundongos , Camundongos Transgênicos , Proteínas Associadas à Resistência a Múltiplos Medicamentos/genética , Proteínas Associadas à Resistência a Múltiplos Medicamentos/metabolismo , Tomografia por Emissão de Pósitrons/métodos , Presenilina-1/genética , Tietilperazina/metabolismoRESUMO
In recent years, radiofluorinated alkyl azides have been reported for click radiolabeling and pretargeted PET imaging, but only little is known about the biodistribution and metabolism of these compounds. In this work, we present a significantly improved procedure for the synthesis of [18F]fluoroethyl azide and reinvestigated this radiolabeled probe in detail showing poor stability and very restricted suitability for in vivo application. Therefore, modified low-molecular-weight [18F]fluoroalkyl azides were developed. Propargyl-tagged endomorphin-1 (as model compound) was successfully radiolabeled in high yield and short reaction time making these probes useful and efficient bioorthogonal tools for rapid radiolabeling. Biodistribution, pharmacokinetics and in vivo stability were studied by preclinical PET/MR scanning and metabolite analysis. The results of this study revealed only limited applicability of [18F]fluoroalkyl azides for in vivo application.
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A low-molecular-weight tetrazine labeled with the short-lived positron emitter carbon-11 was developed as a bioorthogonal PET probe for pretargeted imaging. A method for efficient and fast synthesis of this imaging agent is presented using radiolabeling of a readily available precursor. High reactivity with trans-cyclooctenes was observed and in vivo investigations including PET/MR scanning showed homogeneous biodistribution, good metabolic stability, and rapid excretion in naive mice. These properties are key to the success of bioorthogonal (11)C-PET imaging, which has been shown in a simple pretargeting experiment using TCO-modified mesoporous silica nanoparticles. Overall, this (11)C-labeled tetrazine represents a highly versatile and advantageous chemical tool for bioorthogonal PET imaging and enables pretargeting approaches using carbon-11 for the first time.
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Radioisótopos de Carbono , Desenho de Fármacos , Tomografia por Emissão de Pósitrons/métodos , Tetrazóis/química , Tetrazóis/síntese química , Animais , Técnicas de Química Sintética , Química Click , Feminino , Marcação por Isótopo , Camundongos , Peso Molecular , Tetrazóis/metabolismo , Tetrazóis/farmacocinética , Distribuição TecidualRESUMO
Positron emission tomography (PET) using fluorine-18 (18F)-labeled 2-nitroimidazole radiotracers has proven useful for assessment of tumor oxygenation. However, the passive diffusion-driven cellular uptake of currently available radiotracers results in slow kinetics and low tumor-to-background ratios. With the aim to develop a compound that is actively transported into cells, 1-(6'-deoxy-6'-[18F]fluoro-ß-d-allofuranosyl)-2-nitroimidazole (ß-[18F]1), a putative nucleoside transporter substrate, was synthetized by nucleophilic [18F]fluoride substitution of an acetyl protected labeling precursor with a tosylate leaving group (ß-6) in a final radiochemical yield of 12±8% (n=10, based on [18F]fluoride starting activity) in a total synthesis time of 60min with a specific activity at end of synthesis of 218±58GBq/µmol (n=10). Both radiolabeling precursor ß-6 and unlabeled reference compound ß-1 were prepared in multistep syntheses starting from 1,2:5,6-di-O-isopropylidene-α-d-allofuranose. In vitro experiments demonstrated an interaction of ß-1 with SLC29A1 and SLC28A1/2/3 nucleoside transporter as well as hypoxia specific retention of ß-[18F]1 in tumor cell lines. In biodistribution studies in healthy mice ß-[18F]1 showed homogenous tissue distribution and excellent metabolic stability, which was unaffected by tissue oxygenation. PET studies in tumor bearing mice showed tumor-to-muscle ratios of 2.13±0.22 (n=4) at 2h after administration of ß-[18F]1. In ex vivo autoradiography experiments ß-[18F]1 distribution closely matched staining with the hypoxia marker pimonidazole. In conclusion, ß-[18F]1 shows potential as PET hypoxia radiotracer which merits further investigation.
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Hipóxia/diagnóstico por imagem , Imidazóis/análise , Imidazóis/química , Monossacarídeos/análise , Monossacarídeos/química , Neoplasias/diagnóstico por imagem , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/análise , Compostos Radiofarmacêuticos/síntese química , Animais , Linhagem Celular Tumoral , Relação Dose-Resposta a Droga , Humanos , Hipóxia/patologia , Imidazóis/síntese química , Imidazóis/farmacocinética , Camundongos , Estrutura Molecular , Monossacarídeos/síntese química , Monossacarídeos/farmacocinética , Neoplasias/patologia , Compostos Radiofarmacêuticos/química , Compostos Radiofarmacêuticos/farmacocinética , Relação Estrutura-Atividade , Distribuição TecidualRESUMO
PURPOSE: The adenosine A3 receptor (A3R) is involved in cardiovascular, neurological and tumour-related pathologies and serves as an exceptional pharmaceutical target in the clinical setting. A3R antagonists are considered antiinflammatory, antiallergic and anticancer agents, and to have potential for the treatment of asthma, COPD, glaucoma and stroke. Hence, an appropriate A3R PET tracer would be highly beneficial for the diagnosis and therapy monitoring of these diseases. Therefore, in this preclinical in vivo study we evaluated the potential as a PET tracer of the A3R antagonist [(18)F]FE@SUPPY. METHODS: Rats were injected with [(18)F]FE@SUPPY for baseline scans and blocking scans (A3R with MRS1523 or FE@SUPPY, P-gp with tariquidar; three animals each). Additionally, metabolism was studied in plasma and brain. In a preliminary experiment in a mouse xenograft model (mice injected with cells expressing the human A3R; three animals), the animals received [(18)F]FE@SUPPY and [(18)F]FDG. Dynamic PET imaging was performed (60 min in rats, 90 min in xenografted mice). In vitro stability of [(18)F]FE@SUPPY in human and rat plasma was also evaluated. RESULTS: [(18)F]FE@SUPPY showed high uptake in fat-rich regions and low uptake in the brain. Pretreatment with MRS1523 led to a decrease in [(18)F]FE@SUPPY uptake (p = 0.03), and pretreatment with the P-gp inhibitor tariquidar led to a 1.24-fold increase in [(18)F]FE@SUPPY uptake (p = 0.09) in rat brain. There was no significant difference in metabolites in plasma and brain in the treatment groups. However, plasma concentrations of [(18)F]FE@SUPPY were reduced to levels similar to those in rat brain after blocking. In contrast to [(18)F]FDG uptake (p = 0.12), the xenograft model showed significantly increased uptake of [(18)F]FE@SUPPY in the tissue masses from CHO cells expressing the human A3R (p = 0.03). [(18)F]FE@SUPPY was stable in human plasma. CONCLUSION: Selective and significant tracer uptake of [(18)F]FE@SUPPY was found in xenografted mice injected with cells expressing human A3R. This finding supports the strategy of evaluating [(18)F]FE@SUPPY in "humanized animal models". In conclusion, preclinical evaluation points to the suitability of [(18)F]FE@SUPPY as an A3R PET tracer in humans.
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Ácidos Nicotínicos/farmacocinética , Tomografia por Emissão de Pósitrons , Compostos Radiofarmacêuticos/farmacocinética , Receptor A3 de Adenosina/metabolismo , Animais , Células CHO , Cricetinae , Cricetulus , Humanos , Masculino , Camundongos , Neoplasias Experimentais/diagnóstico por imagem , Ligação Proteica , Compostos Radiofarmacêuticos/síntese química , Ratos , Ratos Sprague-Dawley , Distribuição TecidualRESUMO
The adenosine triphosphate-binding cassette transporter P-glycoprotein (ABCB1/Abcb1a) restricts at the blood-brain barrier (BBB) brain distribution of many drugs. ABCB1 may be involved in drug-drug interactions (DDIs) at the BBB, which may lead to changes in brain distribution and central nervous system side effects of drugs. Positron emission tomography (PET) with the ABCB1 substrates (R)-[(11)C]verapamil and [(11)C]-N-desmethyl-loperamide and the ABCB1 inhibitor tariquidar has allowed direct comparison of ABCB1-mediated DDIs at the rodent and human BBB. In this work we evaluated different factors which could influence the magnitude of the interaction between tariquidar and (R)-[(11)C]verapamil or [(11)C]-N-desmethyl-loperamide at the BBB and thereby contribute to previously observed species differences between rodents and humans. We performed in vitro transport experiments with [(3)H]verapamil and [(3)H]-N-desmethyl-loperamide in ABCB1 and Abcb1a overexpressing cell lines. Moreover we conducted in vivo PET experiments and biodistribution studies with (R)-[(11)C]verapamil and [(11)C]-N-desmethyl-loperamide in wild-type mice without and with tariquidar pretreatment and in homozygous Abcb1a/1b((-/-)) and heterozygous Abcb1a/1b((+/-)) mice. We found no differences for in vitro transport of [(3)H]verapamil and [(3)H]-N-desmethyl-loperamide by ABCB1 and Abcb1a and its inhibition by tariquidar. [(3)H]-N-Desmethyl-loperamide was transported with a 5 to 9 times higher transport ratio than [(3)H]verapamil in ABCB1- and Abcb1a-transfected cells. In vivo, brain radioactivity concentrations were lower for [(11)C]-N-desmethyl-loperamide than for (R)-[(11)C]verapamil. Both radiotracers showed tariquidar dose dependent increases in brain distribution with tariquidar half-maximum inhibitory concentrations (IC50) of 1052 nM (95% confidence interval CI: 930-1189) for (R)-[(11)C]verapamil and 1329 nM (95% CI: 980-1801) for [(11)C]-N-desmethyl-loperamide. In homozygous Abcb1a/1b((-/-)) mice brain radioactivity distribution was increased by 3.9- and 2.8-fold and in heterozygous Abcb1a/1b((+/-)) mice by 1.5- and 1.1-fold, for (R)-[(11)C]verapamil and [(11)C]-N-desmethyl-loperamide, respectively, as compared with wild-type mice. For both radiotracers radiolabeled metabolites were detected in plasma and brain. When brain and plasma radioactivity concentrations were corrected for radiolabeled metabolites, brain distribution of (R)-[(11)C]verapamil and [(11)C]-N-desmethyl-loperamide was increased in tariquidar (15 mg/kg) treated animals by 14.1- and 18.3-fold, respectively, as compared with vehicle group. Isoflurane anesthesia altered [(11)C]-N-desmethyl-loperamide but not (R)-[(11)C]verapamil metabolism, and this had a direct effect on the magnitude of the increase in brain distribution following ABCB1 inhibition. Our data furthermore suggest that in the absence of ABCB1 function brain distribution of [(11)C]-N-desmethyl-loperamide but not (R)-[(11)C]verapamil may depend on cerebral blood flow. In conclusion, we have identified a number of important factors, i.e., substrate affinity to ABCB1, brain uptake of radiolabeled metabolites, anesthesia, and cerebral blood flow, which can directly influence the magnitude of ABCB1-mediated DDIs at the BBB and should therefore be taken into consideration when interpreting PET results.
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Transportadores de Cassetes de Ligação de ATP/metabolismo , Barreira Hematoencefálica/metabolismo , Encéfalo/metabolismo , Loperamida/análogos & derivados , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/metabolismo , Verapamil/metabolismo , Subfamília B de Transportador de Cassetes de Ligação de ATP/metabolismo , Animais , Transporte Biológico/efeitos dos fármacos , Barreira Hematoencefálica/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Bloqueadores dos Canais de Cálcio/metabolismo , Radioisótopos de Carbono/metabolismo , Interações Medicamentosas , Feminino , Humanos , Loperamida/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos KnockoutRESUMO
A low-molecular-weight (18) F-labeled tetrazine derivative was developed as a highly versatile tool for bioorthogonal PET imaging. Prosthetic groups and undesired carrying of (18) F through additional steps were evaded by direct (18) F-fluorination of an appropriate tetrazine precursor. Reaction kinetics of the cycloaddition with trans-cyclooctenes were investigated by applying quantum chemical calculations and stopped-flow measurements in human plasma; the results indicated that the labeled tetrazine is suitable as a bioorthogonal probe for the imaging of dienophile-tagged (bio)molecules. In vitro and in vivo investigations revealed high stability and PET/MRI in mice showed fast homogeneous biodistribution of the (18) F-labeled tetrazine that also passes the blood-brain barrier. An in vivo click experiment confirmed the bioorthogonal behavior of this novel tetrazine probe. Due to favorable chemical and pharmacokinetic properties this bioorthogonal agent should find application in bioimaging and biomedical research.
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Radioisótopos de Flúor/farmacocinética , Compostos Heterocíclicos/química , Compostos Heterocíclicos/farmacocinética , Tomografia por Emissão de Pósitrons/métodos , Compostos Radiofarmacêuticos/farmacocinética , Animais , Compostos Bicíclicos com Pontes/síntese química , Reação de Cicloadição , Feminino , Humanos , Marcação por Isótopo , Imageamento por Ressonância Magnética , Camundongos , Camundongos Endogâmicos BALB C , Distribuição TecidualRESUMO
Additive manufacturing and 3D printing allow for the design and rapid production of radiographic phantoms for X-ray imaging, including CT. These are used for numerous purposes, such as patient simulation, optimization of imaging procedures and dose levels, system evaluation and quality assurance. However, standard 3D printing polymers do not mimic X-ray attenuation properties of tissues like soft, adipose, lung or bone tissue, and standard materials like liquid water. The mass density of printing polymers-especially important in CT-is often inappropriate, i.e., mostly too high. Different methods can be applied to reduce mass density. This work examines reducing density by controlled underfilling either realized by using 3D printing materials expanded through foaming during heating in the printing process, or reducing polymer flow to introduce microscopic air-filled voids. The achievable density reduction depends on the base polymer used. When using foaming materials, density is controlled by the extrusion temperature, and ranges from 33 to 47% of the base polymer used, corresponding to a range of -650 to -394 HU in CT with 120 kV. Standard filaments (Nylon, modified PLA and modified ABS) allowed density reductions by 20 to 25%, covering HU values in CT from -260 to 77 (Nylon), -230 to -20 (ABS) and -81 to 143 (PLA). A standard chalk-filled PLA filament allowed reproduction of bone tissue in a wide range of bone mineral content resulting in CT numbers from 57 to 460 HU. Controlled underfilling allowed the production of radiographic phantom materials with continuously adjustable attenuation in a limited but appropriate range, allowing for the reproduction of X-ray attenuation properties of water, adipose, soft, lung, and bone tissue in an accurate, predictable and reproducible manner.
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Nanodiamonds (NDs) are emerging as a novel nanoparticle class with growing interest in medical applications. The surface coating of NDs can be modified by attaching binding ligands or imaging probes, turning them into multi-modal targeting agents. In this investigation, we assessed the targeting efficacy of octreotide-functionalized 68Ga-radiolabelled NDs for cancer imaging and compared it with the tumor uptake using [68Ga]Ga-DOTA-TOC. In vivo studies in mice bearing AR42J tumors demonstrated the highest accumulation of the radiolabeled functionalized NDs in the liver and spleen, with relatively low tumor uptake compared to [68Ga]Ga-DOTA-TOC. Our findings suggest that, within the scope of this study, functionalization did not enhance the tumor-targeting capabilities of NDs.
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Cholangiocarcinoma (CCA) is a type of primary liver cancer originating from the biliary tract epithelium, characterized by limited treatment options for advanced cases and low survival rates. This study aimed to establish an orthotopic mouse model for CCA and monitor tumor growth using PET/MR imaging. Murine CCA cells were implanted into the liver lobe of male C57BL/6J mice. The imaging groups included contrast-enhanced (CE) MR, CE-MR with static [18F]FDG-PET, and dynamic [18F]FDG-PET. Tumor volume and FDG uptake were measured weekly over four weeks. Early tumor formation was visible in CE-MR images, with a gradual increase in volume over time. Dynamic FDG-PET revealed an increase in the metabolic glucose rate (MRGlu) over time. Blood analysis showed pathological changes in liver-related parameters. Lung metastases were observed in nearly all animals after four weeks. The study concludes that PET-MR imaging effectively monitors tumor progression in the CCA mouse model, providing insights into CCA development and potential treatment strategies.
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PURPOSE: Preclinical imaging, with translational potential, lacks a standardized method for defining volumes of interest (VOIs), impacting data reproducibility. The aim of this study was to determine the interobserver variability of VOI sizes and standard uptake values (SUVmean and SUVmax) of different organs using the same [18F]FDG-PET and PET/CT datasets analyzed by multiple observers. In addition, the effect of a standardized analysis approach was evaluated. PROCEDURES: In total, 12 observers (4 beginners and 8 experts) analyzed identical preclinical [18F]FDG-PET-only and PET/CT datasets according to their local default image analysis protocols for multiple organs. Furthermore, a standardized protocol was defined, including detailed information on the respective VOI size and position for multiple organs, and all observers reanalyzed the PET/CT datasets following this protocol. RESULTS: Without standardization, significant differences in the SUVmean and SUVmax were found among the observers. Coregistering CT images with PET images improved the comparability to a limited extent. The introduction of a standardized protocol that details the VOI size and position for multiple organs reduced interobserver variability and enhanced comparability. CONCLUSIONS: The protocol offered clear guidelines and was particularly beneficial for beginners, resulting in improved comparability of SUVmean and SUVmax values for various organs. The study suggested that incorporating an additional VOI template could further enhance the comparability of the findings in preclinical imaging analyses.
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Fluordesoxiglucose F18 , Variações Dependentes do Observador , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada , Fluordesoxiglucose F18/química , Fluordesoxiglucose F18/farmacocinética , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/normas , Tomografia por Emissão de Pósitrons combinada à Tomografia Computadorizada/métodos , Humanos , Padrões de Referência , Animais , Processamento de Imagem Assistida por Computador/métodos , Reprodutibilidade dos TestesRESUMO
Preclinical molecular imaging is a rapidly growing field, where new imaging systems, methods, and biological findings are constantly being developed or discovered. Imaging systems and the associated software usually have multiple options for generating data, which is often overlooked but is essential when reporting the methods used to create and analyze data. Similarly, the ways in which animals are housed, handled, and treated to create physiologically based data must be well described in order that the findings be relevant, useful, and reproducible. There are frequently new developments for metabolic imaging methods. Thus, specific reporting requirements are difficult to establish; however, it remains essential to adequately report how the data have been collected, processed, and analyzed. To assist with future manuscript submissions, this article aims to provide guidelines of what details to report for several of the most common imaging modalities. Examples are provided in an attempt to give comprehensive, succinct descriptions of the essential items to report about the experimental process.
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Diagnóstico por Imagem , Imagem Molecular , Editoração , Projetos de Pesquisa , Animais , Processamento de Imagem Assistida por Computador , Imageamento por Ressonância Magnética , Camundongos , Camundongos Nus , Imagem Molecular/métodos , Revisão da Pesquisa por Pares , Cintilografia , Ratos , Tomografia Computadorizada por Raios X , UltrassonografiaRESUMO
Elacridar (ELC) and tariquidar (TQD) are generally thought to be nontransported inhibitors of P-glycoprotein (Pgp) and breast cancer resistance protein (BCRP), but recent data indicate that they may also be substrates of these multidrug transporters (MDTs). The present study was designed to investigate potential transport of ELC and TQD by MDTs at the blood-brain barrier at tracer doses as used in positron emission tomography (PET) studies. We performed PET scans with carbon-11-labeled ELC and TQD before and after MDT inhibition in wild-type and transporter-knockout mice as well as in in vitro transport assays in MDT-overexpressing cells. Brain entrance of [(11)C]ELC and [(11)C]TQD administered in nanomolar tracer doses was found to be limited by Pgp- and Bcrp1-mediated efflux at the mouse blood-brain barrier. At higher, MDT-inhibitory doses, i.e., 15 mg/kg for TQD and 5 mg/kg for ELC, brain activity uptake of [(11)C]ELC at 25 minutes after tracer injection was 5.8 ± 0.3, 2.1 ± 0.2, and 7.5 ± 1.0-fold higher in wild-type, Mdr1a/b((-/-),()) and Bcrp1((-/-)) mice, respectively, but remained unchanged in Mdr1a/b((-/-))Bcrp1((-/-)) mice. Activity uptake of [(11)C]TQD was 2.8 ± 0.2 and 6.8 ± 0.4-fold higher in wild-type and Bcrp1((-/-)) mice, but remained unchanged in Mdr1a/b((-/-)) and Mdr1a/b((-/-))Bcrp1((-/-)) mice. Consistent with the in vivo findings, in vitro uptake assays in Pgp- and Bcrp1-overexpressing cell lines confirmed low intracellular accumulation of ELC and TQD at nanomolar concentrations and increased uptake at micromolar concentrations. As this study shows that microdoses can behave pharmacokinetically differently from MDT-inhibitory doses if a compound interacts with MDTs, conclusions from microdose studies should be drawn carefully.
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Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Transportadores de Cassetes de Ligação de ATP/metabolismo , Acridinas/farmacocinética , Barreira Hematoencefálica/metabolismo , Quinolinas/farmacocinética , Tetra-Hidroisoquinolinas/farmacocinética , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/genética , Membro 2 da Subfamília G de Transportadores de Cassetes de Ligação de ATP , Transportadores de Cassetes de Ligação de ATP/antagonistas & inibidores , Transportadores de Cassetes de Ligação de ATP/genética , Animais , Transporte Biológico/genética , Barreira Hematoencefálica/diagnóstico por imagem , Encéfalo/diagnóstico por imagem , Encéfalo/metabolismo , Radioisótopos de Carbono , Linhagem Celular Transformada , Relação Dose-Resposta a Droga , Inibidores Enzimáticos/farmacocinética , Feminino , Neuroimagem Funcional , Camundongos , Camundongos Knockout , CintilografiaRESUMO
PURPOSE: Nanodiamonds (NDs) represent a new class of nanoparticles and have gained increasing interest in medical applications. Modifying the surface coating by attaching binding ligands or imaging probes can transform NDs into multi-modal targeting probes. This study evaluated the biokinetics and biodistribution of 68Ga-radiolabelled NDs in a xenograft model. PROCEDURES: NDs were coated with an albumin-derived copolymer modified with desferrioxamine to provide a chelator for radiolabeling. In vivo studies were conducted in AR42J tumor-bearing CD1 mice to evaluate biodistribution and tumor accumulation of the NDs. RESULTS: Coated NDs were successfully radiolabeled using 68Ga at room temperature with radiolabeling efficiencies up to 91.8 ± 3.2 % as assessed by radio-TLC. In vivo studies revealed the highest accumulation in the liver and spleen, whereas tumor radioactivity concentration was low. CONCLUSIONS: Radiolabeling of coated NDs could be achieved. However, the obtained results indicate these coated NDs' limitations in their biodistribution within the conducted studies.
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Nanodiamantes , Neoplasias , Humanos , Camundongos , Animais , Radioisótopos de Gálio , Distribuição Tecidual , PolímerosRESUMO
PURPOSE: To support acquisition of accurate, reproducible and high-quality preclinical imaging data, various standardisation resources have been developed over the years. However, it is unclear the impact of those efforts in current preclinical imaging practices. To better understand the status quo in the field of preclinical imaging standardisation, the STANDARD group of the European Society of Molecular Imaging (ESMI) put together a community survey and a forum for discussion at the European Molecular Imaging Meeting (EMIM) 2022. This paper reports on the results from the STANDARD survey and the forum discussions that took place at EMIM2022. PROCEDURES: The survey was delivered to the community by the ESMI office and was promoted through the Society channels, email lists and webpages. The survey contained seven sections organised as generic questions and imaging modality-specific questions. The generic questions focused on issues regarding data acquisition, data processing, data storage, publishing and community awareness of international guidelines for animal research. Specific questions on practices in optical imaging, PET, CT, SPECT, MRI and ultrasound were further included. RESULTS: Data from the STANDARD survey showed that 47% of survey participants do not have or do not know if they have QC/QA guidelines at their institutes. Additionally, a large variability exists in the ways data are acquired, processed and reported regarding general aspects as well as modality-specific aspects. Moreover, there is limited awareness of the existence of international guidelines on preclinical (imaging) research practices. CONCLUSIONS: Standardisation of preclinical imaging techniques remains a challenge and hinders the transformative potential of preclinical imaging to augment biomedical research pipelines by serving as an easy vehicle for translation of research findings to the clinic. Data collected in this project show that there is a need to promote and disseminate already available tools to standardise preclinical imaging practices.
Assuntos
Pesquisa Biomédica , Animais , Inquéritos e Questionários , Padrões de Referência , Imageamento por Ressonância Magnética , UltrassonografiaRESUMO
Approximately one-third of epilepsy patients are pharmacoresistant. Overexpression of P-glycoprotein and other multidrug transporters at the blood-brain barrier is thought to play an important role in drug-refractory epilepsy. Thus, quantification of regionally different P-glycoprotein activity in the brain in vivo is essential to identify P-glycoprotein overactivity as the relevant mechanism for drug resistance in an individual patient. Using the radiolabeled P-glycoprotein substrate (R)-[(11)C]verapamil and different doses of coadministered tariquidar, which is an inhibitor of P-glycoprotein, we evaluated whether small-animal positron emission tomography can quantify regional changes in transporter function in the rat brain at baseline and 48 h after a pilocarpine-induced status epilepticus. P-glycoprotein expression was additionally quantified by immunohistochemistry. To reveal putative seizure-induced changes in blood-brain barrier integrity, we performed gadolinium-enhanced magnetic resonance scans on a 7.0 tesla small-animal scanner. Before P-glycoprotein modulation, brain uptake of (R)-[(11)C]verapamil was low in all regions investigated in control and post-status epilepticus rats. After administration of 3 mg/kg tariquidar, which inhibits P-glycoprotein only partially, we observed increased regional differentiation in brain activity uptake in post-status epilepticus versus control rats, which diminished after maximal P-glycoprotein inhibition. Regional increases in the efflux rate constant k(2), but not in distribution volume V(T) or influx rate constant K(1), correlated significantly with increases in P-glycoprotein expression measured by immunohistochemistry. This imaging protocol proves to be suitable to detect seizure-induced regional changes in P-glycoprotein activity and is readily applicable to humans, with the aim to detect relevant mechanisms of pharmacoresistance in epilepsy in vivo.
Assuntos
Membro 1 da Subfamília B de Cassetes de Ligação de ATP/metabolismo , Barreira Hematoencefálica/metabolismo , Tomografia por Emissão de Pósitrons , Convulsões/diagnóstico por imagem , Convulsões/patologia , Membro 1 da Subfamília B de Cassetes de Ligação de ATP/antagonistas & inibidores , Análise de Variância , Animais , Área Sob a Curva , Barreira Hematoencefálica/diagnóstico por imagem , Barreira Hematoencefálica/efeitos dos fármacos , Bloqueadores dos Canais de Cálcio/farmacocinética , Isótopos de Carbono/farmacocinética , Simulação por Computador , Modelos Animais de Doenças , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Compostos Heterocíclicos , Imageamento por Ressonância Magnética/métodos , Modelos Químicos , Compostos Organometálicos , Pilocarpina/toxicidade , Quinolinas/farmacologia , Ratos , Ratos Sprague-Dawley , Escopolamina/toxicidade , Convulsões/induzido quimicamente , Fatores de Tempo , Verapamil/farmacocinéticaRESUMO
PURPOSE: One important mechanism for chemoresistance of tumours is overexpression of the adenosine triphosphate-binding cassette transporter P-glycoprotein (Pgp). Pgp reduces intracellular concentrations of chemotherapeutic drugs. The aim of this study was to compare the suitability of the radiolabelled Pgp inhibitors [(11)C]tariquidar and [(11)C]elacridar with the Pgp substrate radiotracer (R)-[(11)C]verapamil for discriminating tumours expressing low and high levels of Pgp using small-animal PET imaging in a murine breast cancer model. METHODS: Murine mammary carcinoma cells (EMT6) were continuously exposed to doxorubicin to generate a Pgp-overexpressing, doxorubicin-resistant cell line (EMT6AR1.0 cells). Both cell lines were subcutaneously injected into female athymic nude mice. One week after implantation, animals underwent PET scans with [(11)C]tariquidar (n = 7), [(11)C]elacridar (n = 6) and (R)-[(11)C]verapamil (n = 7), before and after administration of unlabelled tariquidar (15 mg/kg). Pgp expression in tumour grafts was evaluated by Western blotting. RESULTS: [(11)C]Tariquidar showed significantly higher retention in Pgp-overexpressing EMT6AR1.0 compared with EMT6 tumours: the mean ± SD areas under the time-activity curves in scan 1 from time 0 to 60 min (AUC(0-60)) were 38.8 ± 2.2 min and 25.0 ± 5.3 min (p = 0.016, Wilcoxon matched pairs test). [(11)C]Elacridar and (R)-[(11)C]verapamil were not able to discriminate Pgp expression in tumour models. Following administration of unlabelled tariquidar, both EMT6Ar1.0 and EMT6 tumours showed increases in uptake of [(11)C]tariquidar, [(11)C]elacridar and (R)-[(11)C]verapamil. CONCLUSION: Among the tested radiotracers, [(11)C]tariquidar performed best in discriminating tumours expressing high and low levels of Pgp. Therefore [(11)C]tariquidar merits further investigation as a PET tracer to assess Pgp expression levels in solid tumours.