Chronic inflammatory diseases are often progressive, resulting not only in physical damage to patients but also social and economic burdens, making early diagnosis of them critical. Nuclear medicine techniques can enhance the detection of inflammation by providing functional as well as anatomical information when combined with other modalities such as magnetic resonance imaging, computed tomography or ultrasonography. Although small molecules and peptides were mainly used for the treatment and imaging of chronic inflammatory diseases in the past, antibodies and their fragments have also been emerging for chronic inflammatory diseases as they show high specificity to their targets and can have various biological half-lives depending on how they are engineered. In addition, imaging with antibodies or their fragments can visualize the in vivo biodistribution of the probes or help monitor therapeutic responses, thereby providing physicians with a greater understanding of drug behavior in vivo and another means of monitoring their patients. In this review, we introduce various targets and radiolabeled antibody-based probes for the molecular imaging of chronic inflammatory diseases in preclinical and clinical studies. Targets can be classified into three different categories: 1) cell-adhesion molecules, 2) surface markers on immune cells, and 3) cytokines or enzymes. The limitations and future directions of using radiolabeled antibodies for imaging inflammatory diseases are also discussed. 相似文献
Photoimmunotherapy (PIT) is an upcoming potential cancer treatment modality, the effect of which is improved in combination with chemotherapy. PIT causes a super-enhanced permeability and retention (SUPR) effect. Here, we quantitatively evaluated the SUPR effect using radiolabeled drugs of varying molecular weights (18F-5FU, 111In-DTPA, 99mTc-HSA-D, and 111In-IgG) to determine the appropriate drug size. PIT was conducted with an indocyanine green-labeled anti-HER2 antibody and an 808 nm laser irradiation. Mice were subcutaneously inoculated with HER2-positive cells in both hindlimbs. The tumor on one side was treated with PIT, and the contralateral side was not treated. The differences between tumor accumulations were evaluated using positron emission tomography or single-photon emission computed tomography. Imaging studies found increased tumor accumulation of agents after PIT. PIT-treated tumors showed significantly increased uptake of 18F-5FU (p < 0.001) and 99mTc-HSA-D (p < 0.001). A tendency toward increased accumulation of 111In-DTPA and 111In-IgG was observed. These findings suggest that some low- and medium-molecular-weight agents are promising candidates for combined PIT, as are macromolecules; hence, administration after PIT could enhance their efficacy. Our findings encourage further preclinical and clinical studies to develop a combination therapy of PIT with conventional anticancer drugs. 相似文献
Metastatic castration-resistant prostate cancer (mCRPC) represents a condition of progressive disease in spite of androgen deprivation therapy (ADT), with a broad spectrum of manifestations ranging from no symptoms to severe debilitation due to bone or visceral metastatization. The management of mCRPC has been profoundly modified by introducing novel therapeutic tools such as antiandrogen drugs (i.e., abiraterone acetate and enzalutamide), immunotherapy through sipuleucel-T, and targeted alpha therapy (TAT). This variety of approaches calls for unmet need of biomarkers suitable for patients’ pre-treatment selection and prognostic stratification. In this scenario, imaging with positron emission computed tomography (PET/CT) presents great and still unexplored potential to detect specific molecular and metabolic signatures, some of whom, such as the prostate specific membrane antigen (PSMA), can also be exploited as therapeutic targets, thus combining diagnosis and therapy in the so-called “theranostic” approach. In this review, we performed a web-based and desktop literature research to investigate the prognostic and theranostic potential of several PET imaging probes, such as 18F-FDG, 18F-choline and 68Ga-PSMA-11, also covering the emerging tracers still in a pre-clinical phase (e.g., PARP-inhibitors’ analogs and the radioligands binding to gastrin releasing peptide receptors/GRPR), highlighting their potential for defining personalized care pathways in mCRPC. 相似文献
To date, a wide variety of potential PET-apoptosis imaging radiopharmaceuticals targeting apoptosis-induced cell membrane asymmetry and acidification, as well as caspase 3 activation (substrates and inhibitors) have been developed with the purpose of rapidly assessing the response to treatment in cancer patients. Many of these probes were shown to specifically bind to their apoptotic target in vitro and their uptake to be enhanced in the in vivo-xenografted tumours in mice treated by means of chemotherapy, however, to a significantly variable degree. This may, in part, relate to the tumour model used given the fact that different tumour cell lines bear a different sensitivity to a similar chemotherapeutic agent, to differences in the chemotherapeutic concentration and exposure time, as well as to the different timing of imaging performed post-treatment. The best validated cell membrane acidification and caspase 3 targeting radioligands, respectively 18F-ML-10 from the Aposense family and the radiolabelled caspase 3 substrate 18F-CP18, have also been injected in healthy individuals and shown to bear favourable dosimetric and safety characteristics. However, in contrast to, for instance, the 99mTc-HYNIC-Annexin V, neither of both tracers was taken up to a significant degree by the bone marrow in the healthy individuals under study. Removal of white and red blood cells from the bone marrow through apoptosis plays a major role in the maintenance of hematopoietic cell homeostasis. The major apoptotic population in normal bone marrow are immature erythroblasts. While an accurate estimate of the number of immature erythroblasts undergoing apoptosis is not feasible due to their unknown clearance rate, their number is likely substantial given the ineffective quote of the erythropoietic process described in healthy subjects. Thus, the clinical value of both 18F-ML-10 and 18F-CP18 for apoptosis imaging in cancer patients, as suggested by a small number of subsequent clinical phase I/II trials in patients suffering from primary or secondary brain malignancies using 18F-ML-10 and in an ongoing trial in patients suffering from cancer of the ovaries using 18F-CP18, remains to be proven and warrants further investigation. 相似文献
Synthesis, biological activity, and structure–selectivity relationship (SSR) studies of a novel series of potential dopamine D3 receptor radioligands as imaging agents for positron emission tomography (PET) are reported. Considering a structurally diverse library of D3 ligands, SSR studies were performed for a new series of fluorinated pyridinylphenyl amides using CoMFA and CoMSIA methods. The in vitro D3 affinities of the predicted series of biphenyl amide ligands 9 a – d revealed single‐digit to sub‐nanomolar potencies (Ki=0.52–1.6 nM ), displaying excellent D3 selectivity over the D2 subtype of 110‐ to 210‐fold for the test compounds 9 a – c . Radiofluorination by nucleophilic substitution of Br or NO2 by 18F led to radiochemical yields of 66–92 % for [18F] 9 a – d . However, the specific activities of [18F] 9 b and [18F] 9 d were insufficient, rendering their use for in vivo studies impossible. Biodistribution studies of [18F] 9 a and [18F] 9 c using rat brain autoradiography revealed accumulation in the ventricles, thus indicating insufficient biokinetic properties of [18F] 9 a and [18F] 9 c for D3 receptor imaging in vivo.相似文献
Chemical probes can be used to understand the complex biological nature of diseases. Due to the diversity of cancer types and dynamic regulatory pathways involved in the disease, there is a need to identify signaling pathways and associated proteins or enzymes that are traceable or detectable in tests for cancer diagnosis and treatment. Currently, fluorogenic chemical probes are widely used to detect cancer-associated proteins and their binding partners. These probes are also applicable in photodynamic therapy to determine drug efficacy and monitor regulating factors. In this review, we discuss the synthesis of chemical probes for different cancer types from 2016 to the present time and their application in monitoring the activity of transferases, hydrolases, deacetylases, oxidoreductases, and immune cells. Moreover, we elaborate on their potential roles in photodynamic therapy. 相似文献
Disturbances of neutrotransmission at the dopamine D3 receptor are related to several neuropsychiatric diseases and in particular to drug addiction. Herein, we report the computer-assisted prediction of D3 selectivities of new fluoroalkoxy-substituted receptor ligands by means of 3D-QSAR analysis. As close analogues of the D3-selective lead compound FAUC 346 and BP 879, the (19)F-substituted test compounds 4 a-d were synthesized and evaluated. In vitro investigation of their binding characteristics in transfected Chinese Hamster Ovary (CHO) cells led to excellent K(i) values between 0.12 and 0.69 nM at the dopamine D3 subtype. The benzothiophene-substituted carboxamide 4 a (K(i)=0.12 nM) displayed 133 and 283-fold selectivity over the structurally related D2(Long) and D4 subtypes, respectively. Mitogenesis assays showed the behavior of partial agonists. Based on these data, we synthesized the [(18)F]fluoroethoxy-substituted radioligands [(18)F]4 a-d. The N-[4-[4-(2-hydroxyphenyl)piperazin-1-yl]butyl]-2-carboxamides 3 a-d were prepared and labeled with 2-[(18)F]fluoroethyltosylate in a two-step procedure. Optimization of the (18)F-labeling conditions led to radiochemical yields between 24 and 65 %. 相似文献
Early life stress (ELS) is strongly associated with psychiatric disorders such as anxiety, depression, and schizophrenia in adulthood. To date, biological, behavioral, and structural aspects of ELS have been studied extensively, but their functional effects remain unclear. Here, we examined NeuroPET studies of dopaminergic, glutamatergic, and serotonergic systems in ELS animal models. Maternal separation and restraint stress were used to generate single or complex developmental trauma. Body weights of animals exposed to single trauma were similar to those of control animals; however, animals exposed to complex trauma exhibited loss of body weight when compared to controls. In behavioral tests, the complex developmental trauma group exhibited a decrease in time spent in the open arm of the elevated plus-maze and an increase in immobility time in the forced swim test when compared to control animals. In NeuroPET studies, the complex trauma group displayed a reduction in brain uptake values when compared to single trauma and control groups. Of neurotransmitter systems analyzed, the rate of decrease in brain uptake was the highest in the serotonergic group. Collectively, our results indicate that developmental trauma events induce behavioral deficits, including anxiety- and depressive-like phenotypes and dysfunction in neurotransmitter systems. 相似文献
A series of novel fluorine‐containing cyclooxygenase‐2 (COX‐2) inhibitors was designed and synthesized based on the previously reported fluorescent COX‐2 imaging agent celecoxib–NBD ( 3 ; NBD=7‐nitrobenzofurazan). In vitro COX‐1/COX‐2 inhibitory data show that N‐(4‐fluorobenzyl)‐4‐(5‐p‐tolyl‐3‐trifluoromethylpyrazol‐1‐yl)benzenesulfonamide ( 5 ; IC50=0.36 μM , SI>277) and N‐fluoromethyl‐4‐(5‐p‐tolyl‐3‐trifluoromethylpyrazol‐1‐yl)benzenesulfonamide ( 6 ; IC50=0.24 μM , SI>416) are potent and selective COX‐2 inhibitors. Compound 5 was selected for radiolabeling with the short‐lived positron emitter fluorine‐18 (18F) and evaluated as a positron emission tomography (PET) imaging agent. Radiotracer [18F] 5 was analyzed in vitro and in vivo using human colorectal cancer model HCA‐7. Although radiotracer uptake into COX‐2‐expressing HCA‐7 cells was high, no evidence for COX‐2‐specific binding was found. Radiotracer uptake into HCA‐7 tumors in vivo was low and similar to that of muscle, used as reference tissue. 相似文献
The FOXM1 protein controls the expression of essential genes related to cancer cell cycle progression, metastasis, and chemoresistance. We hypothesize that FOXM1 inhibitors could represent a novel approach to develop 18F-based radiotracers for Positron Emission Tomography (PET). Therefore, in this report we describe the first attempt to use 18F-labeled FOXM1 inhibitors to detect triple-negative breast cancer (TNBC). Briefly, we replaced the original amide group in the parent drug FDI-6 for a ketone group in the novel AF-FDI molecule, to carry out an aromatic nucleophilic (18F)-fluorination. AF-FDI dissociated the FOXM1-DNA complex, decreased FOXM1 levels, and inhibited cell proliferation in a TNBC cell line (MDA-MB-231). [18F]AF-FDI was internalized in MDA-MB-231 cells. Cell uptake inhibition experiments showed that AF-FDI and FDI-6 significantly decreased the maximum uptake of [18F]AF-FDI, suggesting specificity towards FOXM1. [18F]AF-FDI reached a tumor uptake of SUV=0.31 in MDA-MB-231 tumor-bearing mice and was metabolically stable 60 min post-injection. These results provide preliminary evidence supporting the potential role of FOXM1 to develop PET radiotracers. 相似文献
Radiolabeled biomolecules with short half‐life times are of increasing importance for positron emission tomography (PET) imaging studies. Herein, we demonstrate an improved and generalized method for synthesizing a [radiometal]‐unsaturated aldehyde as a lysine‐labeling probe that can be easily conjugated into various biomolecules through the RIKEN click reaction. As a case study, 68Ga‐PET imaging of U87MG xenografted mice is demonstrated by using the 68Ga‐DOTA‐RGDyK peptide, which is selective to αVβ3 integrins. 相似文献
P‐Glycoprotein (P‐gp) is an efflux transporter widely expressed at the human blood–brain barrier. It is involved in xenobiotics efflux and in onset and progression of neurodegenerative disorders. For these reasons, there is great interest in the assessment of P‐gp expression and function by noninvasive techniques such as positron emission tomography (PET). Three radiolabeled aryloxazole derivatives: 2‐[2‐(2‐methyl‐(11C)‐5‐methoxyphenyl)oxazol‐4‐ylmethyl]‐6,7‐dimethoxy‐1,2,3,4‐tetrahydroisoquinoline ([11C]‐ 5 ); 2‐[2‐(2‐fluoromethyl‐(18F)‐5‐methoxyphenyl)oxazol‐4‐ylmethyl]‐6,7‐dimethoxy‐1,2,3,4‐tetra‐hydroisoquinoline ([18F]‐ 6 ); and 2‐[2‐(2‐fluoroethyl‐(18F)‐5‐methoxyphenyl)oxazol‐4‐ylmethyl]‐6,7‐dimethoxy‐1,2,3,4‐tetrahydroisoquinoline ([18F]‐ 7 ), were tested in several in vitro biological assays to assess the effect of the aryl substituent in terms of potency and mechanism of action toward P‐gp. Methyl derivative [11C]‐ 5 is a potent P‐gp substrate, whereas the corresponding fluoroethyl derivative [18F]‐ 7 is a P‐gp inhibitor. Fluoromethyl compound [18F]‐ 6 is classified as a non‐transported P‐gp substrate, because its efflux increases after cyclosporine A modulation. These studies revealed a promising substrate and inhibitor, [11C]‐ 5 and [18F]‐ 7 , respectively, for in vivo imaging of P‐gp by using PET. 相似文献
报道了9-[(4氟-)-3羟-基甲基丁基]鸟嘌呤(FHBG,Ⅱ)的改进合成方法,对起始原料喷昔洛韦(Ⅲ)的氨基和一个羟基用4-甲氧基氯化三苯甲烷保护,对另一个羟基磺酯化,得到N2-(p-甲氧基苯酰基二苯基甲基)-9-[(4甲-苯磺酰)-3-p-甲氧基苯酰基二苯基-甲氧基甲基丁基]鸟嘌呤(Ⅴ),收率为70.5%;再用四丁基氟化铵(TBAF)对化合物Ⅴ亲核取代4-甲苯磺酰基团,水解脱去保护基,即得FHBG。产品经1HNMR、IR、MS表征,并用HPLC分析了Ⅴ和Ⅱ,保留时间分别为5.89 m in和4.41 m in,积分计算质量分数分别为w(Ⅴ)=99.5%和w(Ⅱ)=99.3%。 相似文献
A highly efficient 18F‐labeling synthon for universal protein labeling is reported. Diverse 18F‐labeled proteins of 66–144 kDa were prepared with [18F]SiFA‐isothiocyanate synthesized by an isotopic 19F for 18F exchange at the silicon atom. Overall preparative radiochemical yields were 20–40 % after 40–50 min. No bone uptake of 18F radioactivity was detected until 90 min post‐injection of 18F‐SiFA‐RSA; this demonstrates the metabolic stability of the [18F]SiFA moiety.
The enzyme butyrylcholinesterase (BChE) represents a promising target for imaging probes to potentially enable early diagnosis of neurodegenerative diseases like Alzheimer's disease (AD) and to monitor disease progression in some forms of cancer. In this study, we present the design, facile synthesis, in vitro and preliminary ex vivo and in vivo evaluation of a morpholine-based, selective inhibitor of human BChE as a positron emission tomography (PET) tracer with a pseudo-irreversible binding mode. We demonstrate a novel protecting group strategy for 18F radiolabeling of carbamate precursors and show that the inhibitory potency as well as kinetic properties of our unlabeled reference compound were retained in comparison to the parent compound. In particular, the prolonged duration of enzyme inhibition of such a morpholinocarbamate motivated us to design a PET tracer, possibly enabling a precise mapping of BChE distribution. 相似文献
N‐4‐Fluorobut‐2‐yn‐1‐yl‐2β‐carbomethoxy‐3β‐phenyltropane (PR04.MZ) has been developed as dopamine transporter (DAT) ligand for molecular imaging. It contains a terminally fluorinated, conformationally constrained nitrogen substituent that is well suited for the introduction of fluorine‐18. The present report describes the pharmacological characterisation of [18F]PR04.MZ. The ligand shows an IC50 value of 2 nM against human DAT, whereas the IC50 value against human serotonin transporter and human noradrenalin transporter are lower (110 nM and 22 nM , respectively). Furthermore, its ex vivo organ distribution, its binding profile in the rat brain and reversibility of binding were examined. A μPET study illuminates a fast kinetic profile and specific binding to rat DAT.相似文献
下载免费PDF全文