Your browser doesn't support javascript.
loading
Show: 20 | 50 | 100
Results 1 - 7 de 7
Filter
Add more filters










Database
Language
Publication year range
1.
Mol Pharm ; 21(7): 3321-3329, 2024 Jul 01.
Article in English | MEDLINE | ID: mdl-38843501

ABSTRACT

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.


Subject(s)
Indazoles , Piperidines , Poly(ADP-ribose) Polymerase Inhibitors , Animals , Humans , Mice , Piperidines/chemistry , Piperidines/pharmacokinetics , Indazoles/chemistry , Indazoles/pharmacokinetics , HeLa Cells , Poly(ADP-ribose) Polymerase Inhibitors/pharmacokinetics , Poly(ADP-ribose) Polymerase Inhibitors/pharmacology , Poly(ADP-ribose) Polymerase Inhibitors/chemistry , Tissue Distribution , Tomography, Emission-Computed, Single-Photon/methods , Radiopharmaceuticals/pharmacokinetics , Radiopharmaceuticals/chemistry , Poly (ADP-Ribose) Polymerase-1/metabolism , Female , Technetium/chemistry , Nitriles/chemistry , Nitriles/pharmacokinetics , Mice, Nude , Mice, Inbred BALB C
2.
J Med Chem ; 67(4): 3190-3202, 2024 Feb 22.
Article in English | MEDLINE | ID: mdl-38320123

ABSTRACT

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.


Subject(s)
Quinolines , Biological Transport , Cell Line, Tumor , Radiopharmaceuticals/chemistry , Tissue Distribution , Technetium/chemistry
3.
Int J Mol Sci ; 25(2)2024 Jan 15.
Article in English | MEDLINE | ID: mdl-38256119

ABSTRACT

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.


Subject(s)
Ribosomal Proteins , Staphylococcal Infections , Animals , Mice , Tissue Distribution , Staphylococcal Infections/diagnostic imaging , Tomography, Emission-Computed, Single-Photon , Cyanides , Inflammation/diagnostic imaging
4.
J Med Chem ; 66(7): 4952-4960, 2023 04 13.
Article in English | MEDLINE | ID: mdl-36972467

ABSTRACT

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.


Subject(s)
Diagnostic Imaging , Fibroblasts , Mice , Animals , Cell Line, Tumor , Tissue Distribution , Biological Transport
5.
Pharmaceutics ; 14(10)2022 Oct 15.
Article in English | MEDLINE | ID: mdl-36297631

ABSTRACT

To develop novel radiolabeled amino acid tumor imaging agents, 4-methoxy-L-phenylalanine dithiocarbamate (MOPADTC) was synthesized successfully, and two kinds of 99mTc-labeled complexes ([99mTc]TcN-MOPADTC and [99mTc]TcO-MOPADTC) with high radiochemical purities (RCP > 95%) were obtained. The in vitro stability and partition coefficient were determined, and the results show that both of these complexes have good in vitro stability; [99mTc]TcO-MOPADTC is hydrophilic, while [99mTc]TcN-MOPADTC is slightly lipophilic. The biodistribution of [99mTc]TcN-MOPADTC and [99mTc]TcO-MOPADTC in mice bearing S180 tumors shows that the tumor uptake and tumor/muscle ratio of [99mTc]TcO-MOPADTC were higher than the tumor uptake and tumor/muscle ratio of [99mTc]TcN-MOPADTC. In addition, the tumor retention of [99mTc]TcO-MOPADTC is better than the tumor retention of [99mTc]TcN-MOPADTC. A competitive inhibition assay was performed, and the results indicate that [99mTc]TcO-MOPADTC may enter cells primarily via the L-alanine/L-serine/L-cysteine (ASC) system. Single-photon emission computed tomography (SPECT) imaging of [99mTc]TcO-MOPADTC shows obvious accumulation in tumor sites, suggesting that [99mTc]TcO-MOPADTC is a novel potential tumor-imaging agent.

6.
Bioorg Med Chem Lett ; 73: 128918, 2022 10 01.
Article in English | MEDLINE | ID: mdl-35926798

ABSTRACT

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.


Subject(s)
Diphosphonates , Organotechnetium Compounds , Animals , Cyanides , Diphosphonates/chemistry , Mice , Organotechnetium Compounds/chemistry , Radiopharmaceuticals/pharmacology , Technetium/chemistry , Tissue Distribution , Tomography, Emission-Computed, Single-Photon/methods
7.
Mol Pharm ; 19(1): 160-171, 2022 01 03.
Article in English | MEDLINE | ID: mdl-34904839

ABSTRACT

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 (log 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.


Subject(s)
Membrane Proteins/antagonists & inhibitors , Radiopharmaceuticals , Technetium , Animals , Cell Line, Tumor , Endopeptidases/metabolism , Female , Glioblastoma/metabolism , Humans , Membrane Proteins/metabolism , Mice , Mice, Inbred BALB C , Mice, Nude , Neoplasm Transplantation , Tomography, Emission-Computed, Single-Photon
SELECTION OF CITATIONS
SEARCH DETAIL
...