RESUMO
Poly ADP-ribose polymerase (PARP) plays an important role in the DNA repair process and has become an attractive target for cancer therapy in recent years. Given that niraparib has good clinical efficacy as a PARP inhibitor, this study aimed to develop radiolabeled niraparib derivatives for tumor imaging to detect PARP expression and improve the accuracy of stratified patient therapy. The niraparib isonitrile derivative (CNPN) was designed, synthesized, and radiolabeled to obtain the [99mTc]Tc-CNPN complex with high radiochemical purity (>95%). It was lipophilic and stable in vitro. In HeLa cell experiments, the uptake of [99mTc]Tc-CNPN was effectively inhibited by the ligand CNPN, indicating the binding affinity for PARP. According to the biodistribution studies of HeLa tumor-bearing mice, [99mTc]Tc-CNPN has moderate tumor uptake and can be effectively inhibited, demonstrating its specificity for targeting PARP. The SPECT imaging results showed that [99mTc]Tc-CNPN had tumor uptake at 2 h postinjection. All of the results of this study indicated that [99mTc]Tc-CNPN is a promising tumor imaging agent that targets PARP.
Assuntos
Indazóis , Piperidinas , Inibidores de Poli(ADP-Ribose) Polimerases , Animais , Humanos , Camundongos , Piperidinas/química , Piperidinas/farmacocinética , Indazóis/química , Indazóis/farmacocinética , Células HeLa , Inibidores de Poli(ADP-Ribose) Polimerases/farmacocinética , Inibidores de Poli(ADP-Ribose) Polimerases/farmacologia , Inibidores de Poli(ADP-Ribose) Polimerases/química , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Compostos Radiofarmacêuticos/farmacocinética , Compostos Radiofarmacêuticos/química , Poli(ADP-Ribose) Polimerase-1/metabolismo , Feminino , Tecnécio/química , Nitrilas/química , Nitrilas/farmacocinética , Camundongos Nus , Camundongos Endogâmicos BALB CRESUMO
To develop a novel 99mTc-labeled ubiquicidin 29-41 derivative for bacterial infection single-photon emission computed tomography (SPECT) imaging with improved target-to-nontarget ratio and lower nontarget organ uptake, a series of isocyanide ubiquicidin 29-41 derivatives (CNnUBI 29-41, n = 5-9) with different carbon linkers were designed, synthesized and radiolabeled with the [99mTc]Tc(I)+ core, [99mTc][Tc(I)(CO)3(H2O)3]+ core and [99mTc][Tc(V)N]2+ core. All the complexes are hydrophilic, maintain good stability and specifically bind Staphylococcus aureus in vitro. The biodistribution in mice with bacterial infection and sterile inflammation demonstrated that [99mTc]Tc-CN5UBI 29-41 was able to distinguish bacterial infection from sterile inflammation, which had an improved abscess uptake and a greater target-to-nontarget ratio. SPECT imaging study of [99mTc]Tc-CN5UBI 29-41 in bacterial infection mice showed that there was a clear accumulation in the infection site, suggesting that this radiotracer could be a potential radiotracer for bacterial infection imaging.
Assuntos
Proteínas Ribossômicas , Infecções Estafilocócicas , Animais , Camundongos , Distribuição Tecidual , Infecções Estafilocócicas/diagnóstico por imagem , Tomografia Computadorizada de Emissão de Fóton Único , Cianetos , Inflamação/diagnóstico por imagemRESUMO
To seek a novel 99mTc-labeled quinolone derivative for bacterial infection SPECT imaging that aims to lower nontarget organ uptake, a novel norfloxacin 6-hydrazinoicotinamide (HYNIC) derivative (HYNICNF) was designed and synthesized. It was radiolabeled with different coligands, such as tricine, trisodium triphenylphosphine-3,3',3â³-trisulfonate (TPPTS), sodium triphenylphosphine-3-monosulfonate (TPPMS), and ethylenediamine-N,N'-diacetic acid (EDDA), to obtain three 99mTc-labeled norfloxacin HYNIC complexes, namely, [99mTc]Tc-tricine-TPPTS-HYNICNF, [99mTc]Tc-tricine-TPPMS-HYNICNF, and [99mTc]Tc-EDDA-HYNICNF. These complexes were purified (RCP > 95%) and evaluated in vitro and in vivo for targeting bacteria. All three complexes are hydrophilic, maintain good stability, and specifically bind Staphylococcus aureus in vitro. The biodistribution in mice with bacterial infection demonstrated that [99mTc]Tc-EDDA-HYNICNF showed a higher abscess uptake and lower nontarget organ uptake and was able to distinguish bacterial infection and sterile inflammation. Single photon emission computed tomography (SPECT) image study in bacterial infection mice showed there was a visible accumulation in the infection site, suggesting that [99mTc]Tc-EDDA-HYNICNF is a potential radiotracer for bacterial infection imaging.
Assuntos
Infecções Bacterianas , Tecnécio , Camundongos , Animais , Norfloxacino , Distribuição Tecidual , Compostos de Organotecnécio/metabolismo , Compostos Radiofarmacêuticos/metabolismoRESUMO
Fibroblast activation protein (FAP) is a potential target for tumor diagnosis and treatment because it is selectively expressed on the cell membrane of cancer-associated fibroblasts in most solid tumor stroma. The aim of this study was to develop a 99mTc-labeled fibroblast activation protein inhibitor (FAPI) tracer, evaluate its imaging efficacy in nude mice, and further explore its biodistribution in healthy volunteers and uptake in tumor patients. An FAPI-derived ligand (DP-FAPI) containing d-proline was designed and synthesized as a linker, and a stable hydrophilic 99mTc-labeled complex ([99mTc]Tc-DP-FAPI) was obtained by kit formulation. In vitro cellular uptake and saturation binding assays were performed in FAP-transfected HT-1080 cells (FAP-HT-1080). The biodistribution was characterized, and micro-single-photon emission computed tomography (SPECT) imaging was performed in BALB/c nude mice bearing U87 MG tumors. Furthermore, a first-in-man application was performed in four healthy volunteers and three patients with gastrointestinal tumors. In vitro, the nanomolar Kd values of [99mTc]Tc-DP-FAPI indicated that it had significantly high target affinity for FAP. Biodistribution and micro-SPECT imaging studies showed that [99mTc]Tc-DP-FAPI exhibited high uptake and high tumor-to-nontargeted ratios. The calculated effective dose for [99mTc]Tc-DP-FAPI was approximately <5 mSv in four healthy volunteers. In three patients with gastrointestinal tumors, [99mTc]Tc-DP-FAPI quantitative SPECT/CT revealed high and reliable uptake. [99mTc]Tc-DP-FAPI exhibited high selectivity and affinity for FAP in vitro. The safety and effectiveness of [99mTc]Tc-DP-FAPI in primary tumor imaging have been confirmed by animal and clinical studies, revealing the potential clinical application value of this tracer.
Assuntos
Neoplasias , Animais , Humanos , Camundongos , Fibroblastos/metabolismo , Camundongos Nus , Neoplasias/genética , Neoplasias/metabolismo , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único/métodosRESUMO
Fibroblast activation protein (FAP) is overexpressed in cancer-associated fibroblasts (CAFs) in a majority of human epithelial cancers. With low expression in normal organs, FAP has become a promising molecular target for tumor theranostics. To develop a lower cost and more widely available alternative to positron emission tomography (PET), two isocyanide-containing FAP inhibitors (CN-C5-FAPI and CN-PEG4-FAPI) were synthesized and radiolabeled with 99mTc to obtain [99mTc][Tc-(CN-C5-FAPI)6]+ and [99mTc][Tc-(CN-PEG4-FAPI)6]+ in high yields (>95%). They showed good stability in saline and mouse serum. The partition coefficient (logâ¯P) values of [99mTc][Tc-(CN-C5-FAPI)6]+ and [99mTc][Tc-(CN-PEG4-FAPI)6]+ were -0.86 ± 0.03 and -2.38 ± 0.07, respectively, indicating that they were good hydrophilic complexes. The low nanomolar IC50 values of CN-C5-FAPI and CN-PEG4-FAPI indicated that they had specificity to FAP. In vitro cellular uptake and blocking experiments implied a FAP-targeted uptake mechanism. The nanomolar Kd values from the saturation binding assay indicated that they had significantly high target affinity to FAP. The biodistribution and blocking study in BALB/c nude mice bearing U87MG tumors showed that both exhibited specific tumor uptake. [99mTc][Tc-(CN-PEG4-FAPI)6]+ showed a higher tumor uptake and a higher tumor/nontarget ratio than [99mTc][Tc-(CN-C5-FAPI)6]+. The results of micro-single-photon emission computed tomography (SPECT) imaging studies of [99mTc][Tc-(CN-C5-FAPI)6]+ and [99mTc][Tc-(CN-PEG4-FAPI)6]+ were in accordance with the biodistribution results, suggesting that [99mTc][Tc-(CN-PEG4-FAPI)6]+ is a promising tumor imaging agent for targeting FAP.
Assuntos
Proteínas de Membrana/antagonistas & inibidores , Compostos Radiofarmacêuticos , Tecnécio , Animais , Linhagem Celular Tumoral , Endopeptidases/metabolismo , Feminino , Glioblastoma/metabolismo , Humanos , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos BALB C , Camundongos Nus , Transplante de Neoplasias , Tomografia Computadorizada de Emissão de Fóton ÚnicoRESUMO
In order to develop 99mTc-labeled complexes with bisphosphonate isocyanide as novel bone imaging agents, two bisphosphonate isocyanide derivatives (CNALN and CNPAM) were synthesized and radiolabeling was performed for preparing the corresponding [99mTc]Tc(I) complexes. [99mTc]Tc-CNALN and [99mTc]Tc-CNPAM were obtained with high radiochemical purity and showed good in vitro stability. Both of them were hydrophilic and had high affinity to hydroxyapatite. The biodistribution studies in mice revealed [99mTc]Tc-CNALN showed higher bone/background ratios at 60 min post-injection. In single photon emission computed tomography (SPECT) imaging study, [99mTc]Tc-CNALN had an obvious accumulation in bone, suggesting it would be a promising bone-seeking agent.
Assuntos
Difosfonatos , Compostos de Organotecnécio , Animais , Cianetos , Difosfonatos/química , Camundongos , Compostos de Organotecnécio/química , Compostos Radiofarmacêuticos/farmacologia , Tecnécio/química , Distribuição Tecidual , Tomografia Computadorizada de Emissão de Fóton Único/métodosRESUMO
In order to find a 99mTc-labeled deferoxamine radiotracer for bacterial infection imaging, deferoxamine dithiocarbamate (DFODTC) was successfully synthesized and it was radiolabeled with [99mTcN]2+ core to prepare the 99mTcN(DFODTC)2 complex. 99mTcN(DFODTC)2 was obtained with high radiochemical purity without further purification. The complex was lipophilic and exhibited good in vitro stability. According to the result of bacterial binding study, the binding of 99mTcN(DFODTC)2 to bacteria was specific. Biodistribution in mice study indicated that 99mTcN(DFODTC)2 had a higher uptake in bacterial infection tissues than in turpentine-induced abscesses at 120 min after injection, which showed that the radiotracer could differentiate between bacterial infection and sterile inflammation. SPECT/CT images showed that there was a clear accumulation in infection sites, suggesting that 99mTcN(DFODTC)2 could be a potential bacterial infection imaging radiotracer.
Assuntos
Infecções Bacterianas/diagnóstico por imagem , Desferroxamina/química , Compostos de Organotecnécio/química , Compostos Radiofarmacêuticos/química , Tiocarbamatos/química , Animais , Inflamação/diagnóstico por imagem , Camundongos , Estrutura Molecular , Compostos de Organotecnécio/síntese química , Compostos Radiofarmacêuticos/síntese químicaRESUMO
In order to seek novel technetium-99m folate receptor-targeting agents, two folate derivatives (CN5FA and CNPFA) were synthesized and radiolabeled to obtain [99mTc]Tc-CN5FA and [99mTc]Tc-CNPFA complexes, which exhibited high radiochemical purity (>95%) without purification, hydrophilicity, and good stability in vitro. The KB cell competitive binding experiments indicated that [99mTc]Tc-CN5FA and [99mTc]Tc-CNPFA had specificity to folate receptor. Biodistribution studies in KB tumor-bearing mice illustrated that [99mTc]Tc-CN5FA and [99mTc]Tc-CNPFA had specific tumor uptake. Compared with [99mTc]Tc-CN5FA, the tumor/muscle ratios of [99mTc]Tc-CNPFA were higher, resulting in a better SPECT/CT imaging background. According to the results, the two 99mTc complexes have potential as tumor imaging agents to target folate receptors.
Assuntos
Diagnóstico por Imagem/métodos , Receptores de Folato com Âncoras de GPI/metabolismo , Ácido Fólico/química , Rim/diagnóstico por imagem , Nitrilas/química , Compostos Radiofarmacêuticos/síntese química , Tomografia Computadorizada de Emissão de Fóton Único/métodos , Animais , Ligação Competitiva , Estabilidade de Medicamentos , Receptores de Folato com Âncoras de GPI/genética , Ácido Fólico/farmacocinética , Expressão Gênica , Humanos , Interações Hidrofóbicas e Hidrofílicas , Células KB , Rim/metabolismo , Camundongos , Ligação Proteica , Compostos Radiofarmacêuticos/farmacocinética , Tecnécio/química , Distribuição TecidualRESUMO
18F-2-fluoro-2-deoxy-d-glucose ([18F]FDG) has been the most used positron emission tomography imaging agent for clinical applications. Single photon emission computed tomography (SPECT) imaging is cheaper and used more widely for diagnostic use, but there is no SPECT tumor imaging agent for clinical applications comparable to [18F]FDG. Mannose is a C2 epimer of glucose and can also be transported into tumor cells via glucose transporters (GLUTs). To develop a novel SPECT tumor imaging agent with satisfactory tumor uptake and tumor/nontarget ratios, here a mannose derivative (CN7DM) was synthesized and radiolabeled with technetium-99m to prepare [99mTc]Tc-CN7DM. The six-coordinated structure of [99mTc]Tc-CN7DM was confirmed by the corresponding rhenium compound (Re-CN7DM). [99mTc]Tc-CN7DM was transported into cancer cells via GLUTs and may be trapped in the cancer cells by electrostatic attraction. The probe exhibited high uptake in tumors and low uptake in nontarget tissues in mice bearing different tumors, indicating that [99mTc]Tc-CN7DM exhibited promising potential for SPECT tumor imaging and warranted further clinical investigation.
RESUMO
Fibroblast activation protein (FAP), which is expressed on the cell membranes of fibroblasts in most solid tumors, has become an important target for tumor diagnosis and treatment. However, previously reported 99mTc-labeled FAPI-04 complexes have high blood uptake, limiting their use in the clinic. In this work, six 99mTc-labeled FAPI-46 derivatives with different linkers (different amino acids, peptides, or polyethylene glycol) were prepared and evaluated. They had good in vitro stability, hydrophilicity, and good specificity for FAP. The biodistribution and MicroSPECT images revealed that they all had high specific tumor uptake for FAP, and their blood uptake was significantly decreased. Among them, [99mTc]Tc-6-1 exhibited the highest target-to-nontarget ratios (tumor/blood: 6.06 ± 1.19; tumor/muscle: 10.26 ± 0.44) and good tumor uptake (16.15 ± 0.83%ID/g), which also had significantly high affinity for FAP, good in vivo stability, and safety. Therefore, [99mTc]Tc-6-1 holds great potential as a promising molecular tracer for FAP tumor imaging.
Assuntos
Quinolinas , Transporte Biológico , Linhagem Celular Tumoral , Compostos Radiofarmacêuticos/química , Distribuição Tecidual , Tecnécio/químicaRESUMO
In association rule mining, evaluating an association rule needs to repeatedly scan database to compare the whole database with the antecedent, consequent of a rule and the whole rule. In order to decrease the number of comparisons and time consuming, we present an attribute index strategy. It only needs to scan database once to create the attribute index of each attribute. Then all metrics values to evaluate an association rule do not need to scan database any further, but acquire data only by means of the attribute indices. The paper visualizes association rule mining as a multiobjective problem rather than a single objective one. In order to make the acquired solutions scatter uniformly toward the Pareto frontier in the objective space, elitism policy and uniform design are introduced. The paper presents the algorithm of attribute index and uniform design based multiobjective association rule mining with evolutionary algorithm, abbreviated as IUARMMEA. It does not require the user-specified minimum support and minimum confidence anymore, but uses a simple attribute index. It uses a well-designed real encoding so as to extend its application scope. Experiments performed on several databases demonstrate that the proposed algorithm has excellent performance, and it can significantly reduce the number of comparisons and time consumption.
Assuntos
Algoritmos , Mineração de Dados/métodos , Sistemas de Gerenciamento de Base de Dados , Bases de Dados Factuais , Técnicas de Apoio para a DecisãoRESUMO
Fibroblast activation protein (FAP) is a potential target for tumor diagnosis and treatment due to its selective expression on cancer-associated fibroblasts (CAFs) in most solid tumor stroma. Two FAP inhibitor (FAPI) derived ligands (L1 and L2) containing different lengths of DPro-Gly (PG) repeat units as linkers were designed and synthesized with high affinity for FAP. Two stable hydrophilic 99mTc-labeled complexes ([99mTc]Tc-L1 and [99mTc]Tc-L2) were obtained. In vitro cellular studies show that the uptake mechanism is correlated with FAP uptake, and [99mTc]Tc-L1 shows a higher cell uptake and specific binding to FAP. A nanomolar Kd value for [99mTc]Tc-L1 indicates its significantly high target affinity for FAP. The biodistribution and microSPECT/CT images obtained for U87MG tumor mice show that [99mTc]Tc-L1 has high tumor uptake with specificity to FAP and high tumor-to-nontarget ratios. As an inexpensive, easily made, and widely available tracer, [99mTc]Tc-L1 holds great promise for clinical applications.
Assuntos
Diagnóstico por Imagem , Fibroblastos , Camundongos , Animais , Linhagem Celular Tumoral , Distribuição Tecidual , Transporte BiológicoRESUMO
To develop novel tumor imaging agents with high tumor uptake and excellent tumor/non-target ratios, a glucose derivative containing cyclohexane (CNMCHDG) was synthesized and labeled with Tc-99m. [99mTc]Tc-CNMCHDG was prepared by a kit formulation that was straightforward to operate and fast. Without purification, [99mTc]Tc-CNMCHDG had a high radiochemical purity of over 95% and great in vitro stability and hydrophilicity (log P = -3.65 ± 0.10). In vitro cellular uptake studies showed that the uptake of [99mTc]Tc-CNMCHDG was significantly inhibited by pre-treatment with D-glucose and increased by pre-treatment with insulin. Preliminary cellular studies have demonstrated that the mechanism by which the complex enters into cells may be related to GLUTs. The results of biodistribution and SPECT imaging studies displayed high tumor uptake and good retention of [99mTc]Tc-CNMCHDG in A549 tumor-bearing mice (4.42 ± 0.36%ID/g at 120 min post-injection). Moreover, [99mTc]Tc-CNMCHDG exhibited excellent tumor-to-non-target ratios and a clean imaging background and is a potential candidate for clinical transformation.
RESUMO
There are a huge amount of neural units in brain networks. Some of the neural units have tight connection and form neural unit modules. These unit modules are helpful to the disease detection and target therapy. A good method can find neural unit modules accurately and effectively. The study proposes a new algorithm to analyze a brain network and obtain its neural unit modules. The proposed algorithm combines the uniform design and the fruit fly optimization algorithm (FOA); therefore, we called it as UFOA. It makes the utmost of their respective merits of the uniform design and the FOA, so as to acquire the feasible solutions scattered uniformly over the vector domain and find the optimal solution as quickly as possible. When compared with other existing methods, FOA and the uniform design are integrated first, and UFOA is first utilized to find unit modules from brain networks. 37 TD resting-state functional MRI brain networks are used to testify the performance of UFOA. The obtained experimental results manifest that UFOA is clearly superior to the other five methods in terms of modularity, and is comparable with the other five methods in terms of conductance. Additionally, the comparative analysis of UFOA and FOA also demonstrates that the uniform design brings benefit to the improvement of UFOA.