Dopamine D2‐like receptors – mainly dopamine D2 receptors (D2R) and dopamine D3 receptors (D3R) –... more Dopamine D2‐like receptors – mainly dopamine D2 receptors (D2R) and dopamine D3 receptors (D3R) – are believed to be greatly involved in the pathology of Parkinson disease (PD) progression. However, these receptors have not been precisely examined in PD patients. Our aim was to quantitatively calculate the exact densities of dopamine D1 receptors (D1R), D2R, and D3R in control, Alzheimer disease (AD), and Lewy body disease (LBD) patients (including PD, Dementia with Lewy bodies, and Parkinson disease dementia); and analyze the relationship between dopamine receptors and clinical PD manifestations.
Poly (ADP-ribose) polymerase-1 (PARP-1) is a critical enzyme in the DNA repair process and the ta... more Poly (ADP-ribose) polymerase-1 (PARP-1) is a critical enzyme in the DNA repair process and the target of several FDA-approved inhibitors. Several of these inhibitors have been radiolabeled for non-invasive imaging of PARP-1 expression or targeted radiotherapy of PARP-1 expressing tumors. In particular, derivatives of olaparib and rucaparib, which have reduced trapping potency by PARP-1 compared to talazoparib, have been radiolabeled for these purposes. Here, we report the first radiosynthesis of [18F]talazoparib and its in vitro and in vivo evaluation. Talazoparib (3a″) and its bromo- or iodo-derivatives were synthesized as racemic mixtures (3a, 3b and 3c), and these compounds exhibit high affinity to PARP-1 (Ki for talazoparib (3a″): 0.65 ± 0.07 nM; 3a: 2.37 ± 0.56 nM; 3b: 1.92 ± 0.41 nM; 3c: 1.73 ± 0.43 nM; known PARP-1 inhibitor Olaparib: 1.87 ± 0.10 nM; non-PARP-1 compound Raclopride: >20,000 nM) in a competitive binding assay using a tritium-labeled PARP-1 radioligand [3H]WC...
Many diseases, including cancer, can lead to neuropathic pain (NP). NP is one of the accompanying... more Many diseases, including cancer, can lead to neuropathic pain (NP). NP is one of the accompanying symptoms of suffering in many conditions and the life quality of NP patient is seriously affected. Due to complex causes, the effects of clinical treatments have been very unsatisfactory. Many experts have found that neuron-microglia interaction plays an essential role in NP occurrence and development. Therefore, the activation of microglia, related inflammatory mediators and molecular and cellular signaling pathways have become the focus of NP research. With the help of modern functional imaging technology, advanced pre-and clinical studies have been carried out and NP interventions have been attempted by using the different pharmaceuticals and the extracted active components of various traditional herbal medicines. In this communication, we review the mechanism of microglia on NP formation and treatment and molecular imaging technology’s role in the clinical diagnosis and evaluation o...
MTH1 (MutT homolog 1) or NUDT1 (Nudix Hydrolase 1), also known as oxidized purine nucleoside trip... more MTH1 (MutT homolog 1) or NUDT1 (Nudix Hydrolase 1), also known as oxidized purine nucleoside triphosphatase, has potential as a biomarker for monitoring cancer progression and quantifying target engagement for relevant therapies. In this study, we validate one MTH1 inhibitor TH287 as a PET MTH1 radiotracer. TH287 was radiolabeled with tritium and the binding of [3H]TH287 to MTH1 was evaluated in live glioblastoma cells (U251MG) through saturation and competitive binding assays, together with in vitro enzymatic assays. Furthermore, TH287 was radiolabeled with carbon-11 for in vivo microPET studies. Saturation binding assays show that [3H]TH287 has a dissociation constant (Kd) of 1.97 ± 0.18 nM, Bmax of 2676 ± 122 fmol/mg protein for U251MG cells, and nH of 0.98 ± 0.02. Competitive binding assays show that TH287 (Ki: 3.04 ± 0.14 nM) has a higher affinity for MTH1 in U251MG cells compared to another well studied MTH1 inhibitor: (S)-crizotinib (Ki: 153.90 ± 20.48 nM). In vitro enzymatic...
Reactive oxygen species (ROS) are produced during normal metabolic reactions in living cells. ROS... more Reactive oxygen species (ROS) are produced during normal metabolic reactions in living cells. ROS causes oxidative damage to many types of biomolecules. An age-related increase in oxidative damage to DNA and RNA has been described in the human neurons, which play a vital role in the progression of age-associated neurodegeneration. As dopamine metabolism is believed to be the primary source of ROS, oxidative insults correlate with dopamine levels in the striatum during the progression of neurodegenerative diseases. Parallel changes in dopamine concentrations and vesicular monoamine transporter 2 (VMAT2) binding densities in the striatum were observed. Besides Fenton oxidation taking place, the packing of cytosolic dopamine into synaptic vesicles by VMAT2 inhibits its autoxidation and subsequent decay of dopaminergic neurons. The female bias in the DNA damage in the late-stage Parkinson disease (PD) patients suggests that the sex-determining region of the Y chromosome (SRY) genes are ...
We found interactions between dopamine and oxidative damage in the striatum involved in advanced ... more We found interactions between dopamine and oxidative damage in the striatum involved in advanced neurodegeneration, which probably change the microglial phenotype. We observed possible microglia dystrophy in the striatum of neurodegenerative brains. To investigate the interactions between oxidative damage and microglial phenotype, we quantified myeloperoxidase (MPO), poly (ADP-Ribose) (PAR), and triggering receptors expressed on myeloid cell 2 (TREM2) using enzyme-linked immunosorbent assay (ELISA). To test the correlations of microglia dystrophy and tauopathy, we quantified translocator protein (TSPO) and tau fibrils using autoradiography. We chose the caudate and putamen of Lewy body diseases (LBDs) (Parkinson’s disease, Parkinson’s disease dementia, and Dementia with Lewy body), Alzheimer’s disease (AD), and control brains and genotyped for TSPO, TREM2, and bridging integrator 1 (BIN1) genes using single nucleotide polymorphisms (SNP) assays. TREM2 gene variants were absent acros...
Microglia and astrocytes play important roles in mediating the immune processes and nutritional s... more Microglia and astrocytes play important roles in mediating the immune processes and nutritional support in the central nervous system (CNS). Neuroinflammation has been indicated in the progression of neurodegenerative diseases Alzheimer’s disease (AD) and Parkinson’s disease (PD). Chronic neuroinflammation with sustained activation of microglia and astrocytes may affect white matter tracts and disrupt communication between neurons. Recent studies indicate astrogliosis may inhibit remyelination in demyelinating disorders such as multiple sclerosis. In this study, we investigated the relationship between neuroinflammation and myelin status in postmortem human brain tissue (n = 15 including 6 AD, 5 PD, and 4 age-matched, neurologically normal controls (NC)). We conducted systematic and quantitative immunohistochemistry for glial fibrillary acidic protein (GFAP), ionized calcium-binding adaptor molecule 1 (Iba1), amyloid beta, and highly phosphorylated tau (tauopathy). White matter inta...
The dopamine D2 receptor (D2R) couples to inhibitory Gi/o proteins and is targeted by antipsychot... more The dopamine D2 receptor (D2R) couples to inhibitory Gi/o proteins and is targeted by antipsychotic and antiparkinsonian drugs. Beta-arrestin2 binds to the intracellular regions of the agonist-occupied D2R to terminate G protein activation and promote internalization, but also to initiate downstream signaling cascades which have been implicated in psychosis. Functional magnetic resonance imaging (fMRI) has proven valuable for measuring dopamine receptor-mediated changes in neuronal activity, and might enable beta-arrestin2 function to be studied in vivo. The present study examined fMRI blood oxygenation level dependent (BOLD) signal changes elicited by a dopamine agonist in wild-type (WT) and beta-arrestin2 knockout (KO) mice, to investigate whether genetic deletion of beta-arrestin2 prolongs or otherwise modifies D2R-dependent responses. fMRI BOLD data were acquired on a 9.4 T system. During scans, animals received 0.2 mg/kg apomorphine, i.v. In a subset of experiments, animals wer...
American journal of nuclear medicine and molecular imaging, 2016
The utility of [(18)F]WC-4-116, a PET tracer for imaging caspase-3 activation, was evaluated in a... more The utility of [(18)F]WC-4-116, a PET tracer for imaging caspase-3 activation, was evaluated in an animal model of myocardial apoptosis. [(18)F]WC-4-116 was injected into rats at 3 hours after a 30 min period of ischemia induced by temporary occlusion of the left anterior descending coronary artery in Sprague-Dawley rats. [(18)F]WC-4-116 uptake was quantified by 1) autoradiography, 2) microPET imaging studies, and 3) post-PET biodistribution studies. MicroPET imaging also assessed uptake of the non-caspase-3-targeted tracer [(18)F]ICMT-18 at 3 hours postischemia. Enzyme assays and Western blotting assessed caspase-3 activation in both at-risk and not-at-risk regions. Caspase-3 enzyme activity increased in the at-risk but not in the not-at-risk myocardium. Quantitative autoradiographic analysis of [(18)F]WC-4-116 demonstrated nearly 2-fold higher uptake in the ischemia-reperfusion (IR) versus sham animals. [(18)F]WC-4-116 microPET imaging studies demonstrated that the IR animals was ...
A series of 3-(benzylidine)indolin-2-one derivatives were synthesized and evaluated for their in ... more A series of 3-(benzylidine)indolin-2-one derivatives were synthesized and evaluated for their in vitro binding to alpha synuclein (α-syn), beta amyloid (Aβ), and tau fibrils. Compounds with a single double bond in the 3-position had only a modest affinity for α-syn and no selectivity for α-syn versus Aβ or tau fibrils. Homologation to the corresponding diene analogues yielded a mixture of Z,E and E,E isomers; substitution of the indoline nitrogen with an N-benzyl group resulted in increased binding to α-syn and reasonable selectivity for α-syn versus Aβ and tau. Introduction of a para-nitro group into the benzene ring of the diene enabled separation of the Z,E and E,E isomers and led to the identification of the Z,E configuration as the more active regioisomer. The data described here provide key structural information in the design of probes which bind preferentially to α-syn versus Aβ or tau fibrils.
Non-invasive imaging of reactive oxygen species (ROS) in vivo was investigated using a dihydroeth... more Non-invasive imaging of reactive oxygen species (ROS) in vivo was investigated using a dihydroethidium analog [18F]12 as a PET radiotracer. The data shown indicates that [18F]12 is a promising PET tracer for non-invasive imaging of ROS in vivo.
Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL The sigma-2 recepto... more Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL The sigma-2 receptor is overexpressed in various human tumors. Sigma-2 receptor selective radiotracers have been shown to target various solid tumors in rodents and in human patients using positron emission tomography. Sigma-2 receptor ligands can be internalized into tumor cells by the endocytotic pathway. Therefore, sigma-2 receptor ligands are excellent candidates as tumor-targeted delivery agents when covalently attached to drugs. Smac is a protein released from mitochondria into the cytosol in response to apoptotic stimuli. Small-molecule Smac mimetic compounds (SMC) have been developed by several laboratories as anticancer drugs. In this study we validate sigma-2 ligand as a tumor-targeting drug delivery agent for treating ovarian cancer. We have synthesized sigma-2 ligand-conjugated SMC (SSMC), SW III-123. Our data show that SW III-123 has adequate sigma-2 receptor binding affinities (Kiα2 =190 nM and Kiα1 =2046 nM). SW III-123 exhibits potent antitumor activities with EC50 values at 4.0 μM, 2.3 μM and 2.4 μM in human ovarian cancer cell lines SKOV-3, CaOV-3, and BG-1, respectively. In contrast, unconjugated SMC, SW IV-52s, shows little cytotoxicity in these cell lines (EC50 > 200 μM). These results suggest that the sigma-2 ligand has successfully delivered SMC into ovarian cancer cells. Western blot results show that SW III-123 degrades inhibitor of apoptosis proteins (IAPs), XIAP and cIAP-1, in SKOV-3 cells, possibly by interacting with the baculovirus IAP repeat (BIR) domains of IAPs. SW III-123 cleaves caspase-3, 8, and 9 dose-dependently in SKOV-3 cells, indicating that SW III-123 kills ovarian cancer cells by activating both intrinsic and extrinsic apoptotic pathways. In conclusion, sigma-2 ligand is a promising tumor-targeting drug delivery agent. SSMC will likely offer a novel class of therapeutic drugs for treating ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5690. doi:1538-7445.AM2012-5690
Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Sigma-2 receptor bi... more Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Sigma-2 receptor binding sites, recently identified as progesterone receptor membrane component 1 (PGRMC1) (Nature Communications, 2011; 2:380), are highly expressed in tumor cells. We have previously reported that measuring the sigma-2 receptor expression is a novel strategy for evaluating the proliferative status of tumors in vivo using the non-invasive imaging technique, positron emission tomography (PET). Our group has developed a series of sigma-2 receptor radioligands as PET imaging probes, one sigma-2 receptor radiotracer [18F]ISO-1 is under clinical evaluation for imaging the proliferation status in the patients with different types of cancers. PGRMC1 depleted human ovarian SKOV-3 cancer cells have been reported to lack tumor formation in mice and PGRMC1 depleted tumors displayed poor microvasculature system (Endocrinology, 2009; 150:4846-4854). To further understand the regulation of PGRMC1 in cell cycle and cancer proliferation, we have stably transfected PGRMC1-eYFP, enhanced yellow fluorescent protein conjugated PGRMC1, into human pancreatic BxPC3 cancer cells and those cells were transplanted into immunodeficient nude mice to grow into solid tumors; subsequently, a traditional fluorescence imaging system and an optical-resolution photoacoustic microscopy (OR-PAM) were utilized for in vivo monitoring of BxPC3 cancer cells growth and observing the surrounding microvasculature development for those tumors under conditions of sigma-2 receptor/PGRMC1 overexpression. Tumor tissue sections were prepared and in vitro fluorescence microscopy analysis of PGRMC1-eYFP cells revealed that PGRMC1-eYFP overexpressed cells form cluster patterns which may represent the proliferation priority created by PGRMC1 overexpression. The subcellular localization of PGRMC1-eYFP appeared to be similar to that of sigma-2 receptors reported previously by our group using the sigma-2 receptor fluorescent probes (Cancer Res 2007; 67, 6708-6716). PGRMC1-eYFP BxPC3 cells were surrounded by fully developed microvasculature system. Further application of this in vivo imaging platform for evaluating the sigma-2 receptor pharmacology and imaging proliferation is ongoing in our group. (Supported by CA 102869 and CA136398). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 356. doi:1538-7445.AM2012-356
Dopamine D2‐like receptors – mainly dopamine D2 receptors (D2R) and dopamine D3 receptors (D3R) –... more Dopamine D2‐like receptors – mainly dopamine D2 receptors (D2R) and dopamine D3 receptors (D3R) – are believed to be greatly involved in the pathology of Parkinson disease (PD) progression. However, these receptors have not been precisely examined in PD patients. Our aim was to quantitatively calculate the exact densities of dopamine D1 receptors (D1R), D2R, and D3R in control, Alzheimer disease (AD), and Lewy body disease (LBD) patients (including PD, Dementia with Lewy bodies, and Parkinson disease dementia); and analyze the relationship between dopamine receptors and clinical PD manifestations.
Poly (ADP-ribose) polymerase-1 (PARP-1) is a critical enzyme in the DNA repair process and the ta... more Poly (ADP-ribose) polymerase-1 (PARP-1) is a critical enzyme in the DNA repair process and the target of several FDA-approved inhibitors. Several of these inhibitors have been radiolabeled for non-invasive imaging of PARP-1 expression or targeted radiotherapy of PARP-1 expressing tumors. In particular, derivatives of olaparib and rucaparib, which have reduced trapping potency by PARP-1 compared to talazoparib, have been radiolabeled for these purposes. Here, we report the first radiosynthesis of [18F]talazoparib and its in vitro and in vivo evaluation. Talazoparib (3a″) and its bromo- or iodo-derivatives were synthesized as racemic mixtures (3a, 3b and 3c), and these compounds exhibit high affinity to PARP-1 (Ki for talazoparib (3a″): 0.65 ± 0.07 nM; 3a: 2.37 ± 0.56 nM; 3b: 1.92 ± 0.41 nM; 3c: 1.73 ± 0.43 nM; known PARP-1 inhibitor Olaparib: 1.87 ± 0.10 nM; non-PARP-1 compound Raclopride: >20,000 nM) in a competitive binding assay using a tritium-labeled PARP-1 radioligand [3H]WC...
Many diseases, including cancer, can lead to neuropathic pain (NP). NP is one of the accompanying... more Many diseases, including cancer, can lead to neuropathic pain (NP). NP is one of the accompanying symptoms of suffering in many conditions and the life quality of NP patient is seriously affected. Due to complex causes, the effects of clinical treatments have been very unsatisfactory. Many experts have found that neuron-microglia interaction plays an essential role in NP occurrence and development. Therefore, the activation of microglia, related inflammatory mediators and molecular and cellular signaling pathways have become the focus of NP research. With the help of modern functional imaging technology, advanced pre-and clinical studies have been carried out and NP interventions have been attempted by using the different pharmaceuticals and the extracted active components of various traditional herbal medicines. In this communication, we review the mechanism of microglia on NP formation and treatment and molecular imaging technology’s role in the clinical diagnosis and evaluation o...
MTH1 (MutT homolog 1) or NUDT1 (Nudix Hydrolase 1), also known as oxidized purine nucleoside trip... more MTH1 (MutT homolog 1) or NUDT1 (Nudix Hydrolase 1), also known as oxidized purine nucleoside triphosphatase, has potential as a biomarker for monitoring cancer progression and quantifying target engagement for relevant therapies. In this study, we validate one MTH1 inhibitor TH287 as a PET MTH1 radiotracer. TH287 was radiolabeled with tritium and the binding of [3H]TH287 to MTH1 was evaluated in live glioblastoma cells (U251MG) through saturation and competitive binding assays, together with in vitro enzymatic assays. Furthermore, TH287 was radiolabeled with carbon-11 for in vivo microPET studies. Saturation binding assays show that [3H]TH287 has a dissociation constant (Kd) of 1.97 ± 0.18 nM, Bmax of 2676 ± 122 fmol/mg protein for U251MG cells, and nH of 0.98 ± 0.02. Competitive binding assays show that TH287 (Ki: 3.04 ± 0.14 nM) has a higher affinity for MTH1 in U251MG cells compared to another well studied MTH1 inhibitor: (S)-crizotinib (Ki: 153.90 ± 20.48 nM). In vitro enzymatic...
Reactive oxygen species (ROS) are produced during normal metabolic reactions in living cells. ROS... more Reactive oxygen species (ROS) are produced during normal metabolic reactions in living cells. ROS causes oxidative damage to many types of biomolecules. An age-related increase in oxidative damage to DNA and RNA has been described in the human neurons, which play a vital role in the progression of age-associated neurodegeneration. As dopamine metabolism is believed to be the primary source of ROS, oxidative insults correlate with dopamine levels in the striatum during the progression of neurodegenerative diseases. Parallel changes in dopamine concentrations and vesicular monoamine transporter 2 (VMAT2) binding densities in the striatum were observed. Besides Fenton oxidation taking place, the packing of cytosolic dopamine into synaptic vesicles by VMAT2 inhibits its autoxidation and subsequent decay of dopaminergic neurons. The female bias in the DNA damage in the late-stage Parkinson disease (PD) patients suggests that the sex-determining region of the Y chromosome (SRY) genes are ...
We found interactions between dopamine and oxidative damage in the striatum involved in advanced ... more We found interactions between dopamine and oxidative damage in the striatum involved in advanced neurodegeneration, which probably change the microglial phenotype. We observed possible microglia dystrophy in the striatum of neurodegenerative brains. To investigate the interactions between oxidative damage and microglial phenotype, we quantified myeloperoxidase (MPO), poly (ADP-Ribose) (PAR), and triggering receptors expressed on myeloid cell 2 (TREM2) using enzyme-linked immunosorbent assay (ELISA). To test the correlations of microglia dystrophy and tauopathy, we quantified translocator protein (TSPO) and tau fibrils using autoradiography. We chose the caudate and putamen of Lewy body diseases (LBDs) (Parkinson’s disease, Parkinson’s disease dementia, and Dementia with Lewy body), Alzheimer’s disease (AD), and control brains and genotyped for TSPO, TREM2, and bridging integrator 1 (BIN1) genes using single nucleotide polymorphisms (SNP) assays. TREM2 gene variants were absent acros...
Microglia and astrocytes play important roles in mediating the immune processes and nutritional s... more Microglia and astrocytes play important roles in mediating the immune processes and nutritional support in the central nervous system (CNS). Neuroinflammation has been indicated in the progression of neurodegenerative diseases Alzheimer’s disease (AD) and Parkinson’s disease (PD). Chronic neuroinflammation with sustained activation of microglia and astrocytes may affect white matter tracts and disrupt communication between neurons. Recent studies indicate astrogliosis may inhibit remyelination in demyelinating disorders such as multiple sclerosis. In this study, we investigated the relationship between neuroinflammation and myelin status in postmortem human brain tissue (n = 15 including 6 AD, 5 PD, and 4 age-matched, neurologically normal controls (NC)). We conducted systematic and quantitative immunohistochemistry for glial fibrillary acidic protein (GFAP), ionized calcium-binding adaptor molecule 1 (Iba1), amyloid beta, and highly phosphorylated tau (tauopathy). White matter inta...
The dopamine D2 receptor (D2R) couples to inhibitory Gi/o proteins and is targeted by antipsychot... more The dopamine D2 receptor (D2R) couples to inhibitory Gi/o proteins and is targeted by antipsychotic and antiparkinsonian drugs. Beta-arrestin2 binds to the intracellular regions of the agonist-occupied D2R to terminate G protein activation and promote internalization, but also to initiate downstream signaling cascades which have been implicated in psychosis. Functional magnetic resonance imaging (fMRI) has proven valuable for measuring dopamine receptor-mediated changes in neuronal activity, and might enable beta-arrestin2 function to be studied in vivo. The present study examined fMRI blood oxygenation level dependent (BOLD) signal changes elicited by a dopamine agonist in wild-type (WT) and beta-arrestin2 knockout (KO) mice, to investigate whether genetic deletion of beta-arrestin2 prolongs or otherwise modifies D2R-dependent responses. fMRI BOLD data were acquired on a 9.4 T system. During scans, animals received 0.2 mg/kg apomorphine, i.v. In a subset of experiments, animals wer...
American journal of nuclear medicine and molecular imaging, 2016
The utility of [(18)F]WC-4-116, a PET tracer for imaging caspase-3 activation, was evaluated in a... more The utility of [(18)F]WC-4-116, a PET tracer for imaging caspase-3 activation, was evaluated in an animal model of myocardial apoptosis. [(18)F]WC-4-116 was injected into rats at 3 hours after a 30 min period of ischemia induced by temporary occlusion of the left anterior descending coronary artery in Sprague-Dawley rats. [(18)F]WC-4-116 uptake was quantified by 1) autoradiography, 2) microPET imaging studies, and 3) post-PET biodistribution studies. MicroPET imaging also assessed uptake of the non-caspase-3-targeted tracer [(18)F]ICMT-18 at 3 hours postischemia. Enzyme assays and Western blotting assessed caspase-3 activation in both at-risk and not-at-risk regions. Caspase-3 enzyme activity increased in the at-risk but not in the not-at-risk myocardium. Quantitative autoradiographic analysis of [(18)F]WC-4-116 demonstrated nearly 2-fold higher uptake in the ischemia-reperfusion (IR) versus sham animals. [(18)F]WC-4-116 microPET imaging studies demonstrated that the IR animals was ...
A series of 3-(benzylidine)indolin-2-one derivatives were synthesized and evaluated for their in ... more A series of 3-(benzylidine)indolin-2-one derivatives were synthesized and evaluated for their in vitro binding to alpha synuclein (α-syn), beta amyloid (Aβ), and tau fibrils. Compounds with a single double bond in the 3-position had only a modest affinity for α-syn and no selectivity for α-syn versus Aβ or tau fibrils. Homologation to the corresponding diene analogues yielded a mixture of Z,E and E,E isomers; substitution of the indoline nitrogen with an N-benzyl group resulted in increased binding to α-syn and reasonable selectivity for α-syn versus Aβ and tau. Introduction of a para-nitro group into the benzene ring of the diene enabled separation of the Z,E and E,E isomers and led to the identification of the Z,E configuration as the more active regioisomer. The data described here provide key structural information in the design of probes which bind preferentially to α-syn versus Aβ or tau fibrils.
Non-invasive imaging of reactive oxygen species (ROS) in vivo was investigated using a dihydroeth... more Non-invasive imaging of reactive oxygen species (ROS) in vivo was investigated using a dihydroethidium analog [18F]12 as a PET radiotracer. The data shown indicates that [18F]12 is a promising PET tracer for non-invasive imaging of ROS in vivo.
Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL The sigma-2 recepto... more Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL The sigma-2 receptor is overexpressed in various human tumors. Sigma-2 receptor selective radiotracers have been shown to target various solid tumors in rodents and in human patients using positron emission tomography. Sigma-2 receptor ligands can be internalized into tumor cells by the endocytotic pathway. Therefore, sigma-2 receptor ligands are excellent candidates as tumor-targeted delivery agents when covalently attached to drugs. Smac is a protein released from mitochondria into the cytosol in response to apoptotic stimuli. Small-molecule Smac mimetic compounds (SMC) have been developed by several laboratories as anticancer drugs. In this study we validate sigma-2 ligand as a tumor-targeting drug delivery agent for treating ovarian cancer. We have synthesized sigma-2 ligand-conjugated SMC (SSMC), SW III-123. Our data show that SW III-123 has adequate sigma-2 receptor binding affinities (Kiα2 =190 nM and Kiα1 =2046 nM). SW III-123 exhibits potent antitumor activities with EC50 values at 4.0 μM, 2.3 μM and 2.4 μM in human ovarian cancer cell lines SKOV-3, CaOV-3, and BG-1, respectively. In contrast, unconjugated SMC, SW IV-52s, shows little cytotoxicity in these cell lines (EC50 > 200 μM). These results suggest that the sigma-2 ligand has successfully delivered SMC into ovarian cancer cells. Western blot results show that SW III-123 degrades inhibitor of apoptosis proteins (IAPs), XIAP and cIAP-1, in SKOV-3 cells, possibly by interacting with the baculovirus IAP repeat (BIR) domains of IAPs. SW III-123 cleaves caspase-3, 8, and 9 dose-dependently in SKOV-3 cells, indicating that SW III-123 kills ovarian cancer cells by activating both intrinsic and extrinsic apoptotic pathways. In conclusion, sigma-2 ligand is a promising tumor-targeting drug delivery agent. SSMC will likely offer a novel class of therapeutic drugs for treating ovarian cancer. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5690. doi:1538-7445.AM2012-5690
Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Sigma-2 receptor bi... more Proceedings: AACR 103rd Annual Meeting 2012‐‐ Mar 31‐Apr 4, 2012; Chicago, IL Sigma-2 receptor binding sites, recently identified as progesterone receptor membrane component 1 (PGRMC1) (Nature Communications, 2011; 2:380), are highly expressed in tumor cells. We have previously reported that measuring the sigma-2 receptor expression is a novel strategy for evaluating the proliferative status of tumors in vivo using the non-invasive imaging technique, positron emission tomography (PET). Our group has developed a series of sigma-2 receptor radioligands as PET imaging probes, one sigma-2 receptor radiotracer [18F]ISO-1 is under clinical evaluation for imaging the proliferation status in the patients with different types of cancers. PGRMC1 depleted human ovarian SKOV-3 cancer cells have been reported to lack tumor formation in mice and PGRMC1 depleted tumors displayed poor microvasculature system (Endocrinology, 2009; 150:4846-4854). To further understand the regulation of PGRMC1 in cell cycle and cancer proliferation, we have stably transfected PGRMC1-eYFP, enhanced yellow fluorescent protein conjugated PGRMC1, into human pancreatic BxPC3 cancer cells and those cells were transplanted into immunodeficient nude mice to grow into solid tumors; subsequently, a traditional fluorescence imaging system and an optical-resolution photoacoustic microscopy (OR-PAM) were utilized for in vivo monitoring of BxPC3 cancer cells growth and observing the surrounding microvasculature development for those tumors under conditions of sigma-2 receptor/PGRMC1 overexpression. Tumor tissue sections were prepared and in vitro fluorescence microscopy analysis of PGRMC1-eYFP cells revealed that PGRMC1-eYFP overexpressed cells form cluster patterns which may represent the proliferation priority created by PGRMC1 overexpression. The subcellular localization of PGRMC1-eYFP appeared to be similar to that of sigma-2 receptors reported previously by our group using the sigma-2 receptor fluorescent probes (Cancer Res 2007; 67, 6708-6716). PGRMC1-eYFP BxPC3 cells were surrounded by fully developed microvasculature system. Further application of this in vivo imaging platform for evaluating the sigma-2 receptor pharmacology and imaging proliferation is ongoing in our group. (Supported by CA 102869 and CA136398). Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 356. doi:1538-7445.AM2012-356
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