The folate receptor is overexpressed in a variety of epithelial-derived malignant cells. Several folate-based tracers have shown the ability to target FR, but excessive renal uptake is a general concern. To decrease renal uptake and achieve high target-to-nontarget ratios, two folate derivatives (DProFA and DAlaFA) were designed and synthesized. Eight complexes with high labeling yields and good in vitro stability were obtained by radiolabeling with technetium-99m and different coligands. The results of both in vitro cell and in vivo normal mice biodistribution studies demonstrated specific binding of eight complexes to the FR. Among them, [99mTc]Tc-DProFA-L1 exhibited lower off-target uptake and high tumor uptake in tumor-bearing mice, and significant inhibition in the biodistribution and SPECT/CT imaging study. The lower renal uptake of [99mTc]Tc-DProFA-L1 may prevent irradiation damage to the kidney. Consequently, [99mTc]Tc-DProFA-L1 is a highly promising candidate probe for the diagnosis of epithelial tumors in clinical nuclear medicine.
Prostate-specific membrane antigen (PSMA), a well-established biological marker for prostate cancer (PCa) imaging and therapy, is overexpressed on the surface of prostate cancer lesions. In this study, a triazole ring was introduced into the linker by click chemistry to generate a HYNIC-derived ligand (
Cyclin-dependent kinases (CDKs), especially cyclin-dependent kinase 4/6 (CDK4/6), have been targets for the development of specific tumor imaging agents. Palbociclib is a highly selective CDK4/6 inhibitor. In this study, to develop a novel 18F-labeled palbociclib derivative for specific tumor imaging, we designed and synthesized a ligand (NOTA-PBB) consisting of palbociclib as the targeted pharmacophore and NOTA as the macrocyclic bifunctional chelator. The corresponding [18F]AlF-NOTA-PBB complex was prepared with high radiochemical purity (98.4 ± 0.15%) and yield (58.7 ± 4.5%) within 35 min without requiring HPLC purification through a simple one-step 18F-labeling strategy of NOTA-AlF chelation chemistry. The radiotracer was lipophilic (log P = 0.095 ± 0.003) and had good stability in vitro and in vivo. The cellular uptake studies performed on the MCF-7 breast cancer cell line (ER-positive and HER2-negative) showed that radioactive uptake was blocked by preincubating with a molar dose of palbociclib and it had a nanomolar binding affinity to CDK4/6 (IC50 = 16.23 ± 1.84 nM), demonstrating a CDK4/6-mediated uptake mechanism. Its ex vivo biodistribution in nude mice-bearing MCF-7 tumors showed obvious tumor uptake and a high tumor/muscle ratio of [18F]AlF-NOTA-PBB, and tumor uptake was inhibited with 100 μg of palbociclib, demonstrating specific binding to CDK4/6. Radioactivity accumulation in MCF-7 tumors was observed in PET imaging with [18F]AlF-NOTA-PBB. Based on the results of this work, [18F]AlF-NOTA-PBB has the promising capability as a CDK4/6-targeted tumor imaging agent.
The specific expression of prostate-specific membrane antigen (PSMA) makes it an ideal target for the diagnosis and treatment of prostate cancer. Currently, many
Heteroatomic groups in alkenes typically direct thermodynamically favored chain walking of C═C bonds toward themselves, thereby facilitating C-H bond functionalization near the heteroatoms. We present herein an efficient cobalt-catalyzed contra-thermodynamic remote hydroboration of alkenylboronates with pinacolborane to synthesize chiral 1,n-diboronates. This protocol features a broad substrate scope, high functional group tolerance, and excellent enantioselectivity. Mechanistic studies indicate the involvement of a chain-walking process. Gram-scale reactions and various product derivatizations further highlight its practicality.
A hallmark of cancer cells is their increased glucose demand, which is mediated by glucose transporters (GLUTs). Mannose is imported into cells via GLUTs, thereby prompting the selection of mannose as the targeting molecule for designing radioactive derivatives for tumor imaging. In this study, five 99mTc-labeled mannose derivatives were prepared and evaluated in vitro and in vivo. The derivatives were conjugated with an isonitrile group and different linkers, including (CH2)5-Dpro, (CH2)6-Dpro, (CH2)7-Dpro, (CH2)5-Lpro, and (CH2)6-Lpro. All five radioactive compounds exhibited hydrophilicity and in vitro stability. A comparative biodistribution study demonstrated that probes modified with D-proline exhibited greater uptake in tumors than those modified with L-proline. [99mTc]Tc-L1 exhibited the highest accumulation in the tumor and the most favorable tumor-to-nontarget ratios. SPECT/CT imaging results of [99mTc]Tc-L1 demonstrated clear accumulation and visualization at the tumor site. Blocking studies in cells and mice bearing S180 tumors revealed that [99mTc]Tc-L1 was transported into cancer cells via a GLUT-mediated mechanism. These findings suggest that [99mTc]Tc-L1 is a promising probe for SPECT tumor imaging and that linker molecules significantly affect biodistribution characteristics.
As an enzyme that plays an important role in DNA repair, poly(ADP-ribose) polymerase-1 (PARP-1) has become a popular target for cancer therapy. Nuclear medicine molecular imaging technology, supplemented by radiolabeled PARP-1 inhibitors, can accurately determine the expression level of PARP-1 at lesion sites to help patients choose an appropriate treatment plan. In this work, niraparib was modified with a hydrazinonicotinamide (HYNIC) group to generate the ligand NPBHYNIC, which has an in vitro affinity (IC50) of 450.90 nM for PARP-1. The ligand NPBHYNIC was labeled with technetium-99m and six different coligands to yield [99mTc]Tc-(X/tricine)-NPBHYNIC (X = TPPTS, TPPMS, PSA, PDA, NIC and ISONIC). These complexes were hydrophilic and exhibited good stability in vitro, and low levels of these complexes were taken up by nontarget organs and tissues in Kunming mice. Among these complexes, [99mTc]Tc-(TPPTS/tricine)-NPBHYNIC and [99mTc]Tc-(NIC/tricine)-NPBHYNIC were selected for biodistribution in HeLa tumor-bearing BALB/c nude mice at 2 h post injection. The results revealed that the tumor uptake of [99mTc]Tc-(TPPTS/tricine)-NPBHYNIC (1.02 ± 0.07% ID/g) was greater than that of [99mTc]Tc-(NIC/tricine)-NPBHYNIC (0.36 ± 0.05% ID/g). Additionally, in biodistribution, single-photon emission computed tomography/computed tomography (SPECT/CT) and radioautography experiments, the tumor uptake of [99mTc]Tc-(TPPTS/tricine)-NPBHYNIC was significantly reduced in the blocked group, indicating PARP-1 specificity. Therefore, it has potential for use as a niraparib-based tumor imaging agent that targets PARP-1.
To develop novel 99mTc-labeled ubiquicidin 29-41 derivatives for bacterial infection SPECT imaging aiming at achieving a high target-to-nontarget ratio and lower nontarget organ uptake, a novel 6-hydrazinoicotinamide (HYNIC) ubiquicidin 29-41 derivative (HYNIC-UBI 29-41) was designed and synthesized. It was then radiolabeled with ternary ligands, including TPPTS, PDA, 2,6-PDA, NIC, ISONIC, PSA, 4-PSA, and PES, to obtain eight 99mTc-labeled HYNIC-UBI 29-41 complexes. All the complexes demonstrated hydrophilicity, exhibited good in vitro stability, and specifically bound Staphylococcus aureus in vitro. Biodistribution studies in mice with bacterial infection demonstrated that [99mTc]Tc-tricine/TPPTS-HYNIC-UBI 29-41 resulted in increased abscess-to-muscle and abscess-to-blood ratios as well as decreased nontarget organ uptake. Furthermore, it was able to distinguish between bacterial infection and sterile inflammation. Single-photon emission computed tomography (SPECT) imaging studies in mice with bacterial infection revealed visible accumulation at the site of infection, indicating that [99mTc]Tc-tricine/TPPTS-HYNIC-UBI 29-41 is a potential radiotracer for imaging bacterial infection.
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