Structural insights into vesicular monoamine storage and drug interactions.

Biogenic monoamines-vital transmitters orchestrating neurological, endocrinal and immunological functions1-5-are stored in secretory vesicles by vesicular monoamine transporters (VMATs) for controlled quantal release6,7. Harnessing proton antiport, VMATs enrich monoamines around 10,000-fold and sequester neurotoxicants to protect neurons8-10. VMATs are targeted by an arsenal of therapeutic drugs and imaging agents to treat and monitor neurodegenerative disorders, hypertension and drug addiction1,8,11-16. However, the structural mechanisms underlying these actions remain unclear. Here we report eight cryo-electron microscopy structures of human VMAT1 in unbound form and in complex with four monoamines (dopamine, noradrenaline, serotonin and histamine), the Parkinsonism-inducing MPP+, the psychostimulant amphetamine and the antihypertensive drug reserpine. Reserpine binding captures a cytoplasmic-open conformation, whereas the other structures show a lumenal-open conformation stabilized by extensive gating interactions. The favoured transition to this lumenal-open state contributes to monoamine accumulation, while protonation facilitates the cytoplasmic-open transition and concurrently prevents monoamine binding to avoid unintended depletion. Monoamines and neurotoxicants share a binding pocket that possesses polar sites for specificity and a wrist-and-fist shape for versatility. Variations in this pocket explain substrate preferences across the SLC18 family. Overall, these structural insights and supporting functional studies elucidate the mechanism of vesicular monoamine transport and provide the basis to develop therapeutics for neurodegenerative diseases and substance abuse.

Epigenetic priming of memory updating during reconsolidation to attenuate remote fear memories.

Traumatic events generate some of the most enduring forms of memories. Despite the elevated lifetime prevalence of anxiety disorders, effective strategies to attenuate long-term traumatic memories are scarce. The most efficacious treatments to diminish recent (i.e., day-old) traumata capitalize on memory updating mechanisms during reconsolidation that are initiated upon memory recall. Here, we show that, in mice, successful reconsolidation-updating paradigms for recent memories fail to attenuate remote (i.e., month-old) ones. We find that, whereas recent memory recall induces a limited period of hippocampal neuroplasticity mediated, in part, by S-nitrosylation of HDAC2 and histone acetylation, such plasticity is absent for remote memories. However, by using an HDAC2-targeting inhibitor (HDACi) during reconsolidation, even remote memories can be persistently attenuated. This intervention epigenetically primes the expression of neuroplasticity-related genes, which is accompanied by higher metabolic, synaptic, and structural plasticity. Thus, applying HDACis during memory reconsolidation might constitute a treatment option for remote traumata.

Design and demonstration of high efficiency perfectly vertical grating couplers with a random structure.

Utilizing an automated optimization method, we propose a perfectly vertical grating coupler (PVGC) characterized by random structure, superior performance, simplified fabrication process, and increased minimum feature size (MFS). Within the range of MFS from 60 to 180 nm, the optimized PVGC exhibited a simulated coupling efficiency of approximately -2.0 dB at 1550 nm with a 34 nm 1-dB bandwidth. Experimental results for the PVGCs fabricated by electron beam lithography (EBL) demonstrated coupling efficiencies ranging from -2.5 to -2.8 dB with a 32 nm 1-dB bandwidth while maintaining high manufacturing tolerances. This represents the most outstanding experimental outcome to date regarding the coupling performance of a PVGC fabricated on a 220 nm silicon on insulator (SOI), without requiring any complex processes as reported in the existing literature.

Tyrosine Kinase Inhibitors for Renal Cell Carcinoma: A Bibliometric Analysis via CiteSpace from 2000 to 2022.

BACKGROUND: The aim of the study was to identify the cooperation of authors, countries, institutions and explore the hot spots regarding research of tyrosine kinase inhibitors (TKIs) for renal cell carcinoma (RCC) treatment in the past 22 years. SUMMARY: Relevant original and review articles were obtained from the Web of Science Core Collection from 2000 to 2022. CiteSpace software was used to perform the visualization of scientific productivity and emerging trends. Network maps were generated to evaluate the collaborations between different authors, countries, institutions, and keywords. KEY MESSAGES: A total of 4,951 articles related to TKI for RCC treatment were identified. We observed a gradual increase in the number of publications from 2000 to 2022. The USA dominated the field in all countries, and Mem Sloan Kettering Cancer Centre (USA) had more extensive cooperating relationships with other institutions. Motzer RJ and Escudier B were two of the authority scholars in this specific field with the most publications and co-citations. Journal of Clinical Oncology had the most citations of all the journals. A total of 10 major clusters were explored based on the reference co-citation analysis. From 2000 to 2022, the research hot spots have undergone two dramatic shifts during 2006 and 2019, respectively, relevant topics were TKI and TKI combined with immune checkpoint inhibitors (CPIs). At present, the research hot spots focus on CPI and targeted therapies. Bibliometric analysis is allowing researchers to recognize the current research status by providing a comprehensive overview of the development of scientific literature related to TKI for RCC treatment, and information for further research be demonstrated as well.

A Scientometric Visualization Analysis for Benign Prostatic Hyperplasia from 2016 to 2022.

BACKGROUND: Benign prostatic hyperplasia (BPH) is a common urological disorder leading to dysuria in middle-aged and elderly men and significantly reduces the quality of life of patients. Technology for BPH has made a great progress, while there is still a lack of visual and summary literature to make the summary. SUMMARY: The aims of the study were to identify the cooperation of authors, countries, institutions, and explore hot topics' prospects regarding research of BPH. Relevant original articles were obtained from the Web of Science (WoS) database between 2016 and 2022. CiteSpace software was used to perform the analysis and visualization of scientific productivity and emerging trends. KEY MESSAGES: A total of 4,738 articles related to study of BPH were identified. We observed a gradual increase in the number of publications from 2016 to 2022. The USA dominated the field in all countries. Shanghai Jiao Tong University was the most productive institution in 6 years. Active cooperation between countries and between institutions was not observed. Journal of Urology was the most co-cited journal. Roehrborn CG (41 papers) was the most productive author and had the largest numbers of citations (820 co-citations) during the past 6 years. Close collaboration was not observed between the different authors. The main hot topics included matters related to BPH, urinary tract symptom, prostatic urethral lift, thermal therapy, and prostatic neoplasms. This scientometric study comprehensively reviewed publications related to BPH during the past 6 years using quantitative and qualitative methods, which can be used to forecast future research developments in BPH.

A practical protocol for large-scale copper-mediated radioiodination of organoboronic precursors: Radiosynthesis of [123 I]KX-1 for Auger radiotherapy.

Nucleophilic copper-mediated radioiodination (CMRI) of organoboronic precursors with radioiodides is a promising method of radioiodination. The previously reported CMRI has demonstrated its great potential and scope of labeling for the radiosynthesis of radioiodine-labeled compounds. However, the reported protocols (using a small amount/volume of radioactivity) are practically not reproducible in large-scale CMRI, in which the radioactivity was usually provided in a bulk alkaline solution. A large amount of water and a strong base are incompatible with CMRI. To overcome these issues in large-scale CMRI, we have developed a simple protocol for large-scale CMRI. The bulk water was removed under a flow of inert gas at 110°C, and the strong base (i.e., NaOH) was neutralized with an acid, pyridinium p-toluenesulfonate or p-toluenesulfonic acid. In the model reactions of [123 I]KX-1, a PARP-1 radioligand for Auger radiotherapy, radiochemical conversions were significantly improved after neutralization of the base, and the addition of additional acids was tolerated and favorable for the reactions. Using this protocol, [123 I]KX-1 was radiosynthesized from 20 mCi (0.74 GBq) of [123 I]iodide in high radiochemical yields, high radiochemical purity, and high molar activity. This protocol should be applicable to the radiosynthesis of other compounds with radioiodine via CMRI.

Preclinical Efficacy of a PARP-1 Targeted Auger-Emitting Radionuclide in Prostate Cancer.

There is an unmet need for better therapeutic strategies for advanced prostate cancer. Poly (ADP-ribose) polymerase-1 (PARP-1) is a chromatin-binding DNA repair enzyme overexpressed in prostate cancer. This study evaluates whether PARP-1, on account of its proximity to the cell's DNA, would be a good target for delivering high-linear energy transfer Auger radiation to induce lethal DNA damage in prostate cancer cells. We analyzed the correlation between PARP-1 expression and Gleason score in a prostate cancer tissue microarray. A radio-brominated Auger emitting inhibitor ([77Br]Br-WC-DZ) targeting PARP-1 was synthesized. The ability of [77Br]Br-WC-DZ to induce cytotoxicity and DNA damage was assessed in vitro. The antitumor efficacy of [77Br]Br-WC-DZ was investigated in prostate cancer xenograft models. PARP-1 expression was found to be positively correlated with the Gleason score, thus making it an attractive target for Auger therapy in advanced diseases. The Auger emitter, [77Br]Br-WC-DZ, induced DNA damage, G2-M cell cycle phase arrest, and cytotoxicity in PC-3 and IGR-CaP1 prostate cancer cells. A single dose of [77Br]Br-WC-DZ inhibited the growth of prostate cancer xenografts and improved the survival of tumor-bearing mice. Our studies establish the fact that PARP-1 targeting Auger emitters could have therapeutic implications in advanced prostate cancer and provides a strong rationale for future clinical investigation.

The interactions of dopamine and oxidative damage in the striatum of patients with neurodegenerative diseases.

The striatum with a number of dopamine containing neurons, receiving projections from the substantia nigra and ventral tegmental area; plays a critical role in neurodegenerative diseases of motor and memory function. Additionally, oxidative damage to nucleic acid may be vital in the development of age-associated neurodegeneration. The metabolism of dopamine is recognized as one of the sources of reactive oxygen species through the Fenton mechanism. The proposed interactions of oxidative insults and dopamine in the striatum during the progression of diseases are the hypotheses of most interest to our study. This study investigated the possibility of significant interactions between these molecules that are involved in the late-stage of Alzheimer's disease (AD), Parkinson disease (PD), Parkinson disease dementia, dementia with Lewy bodies, and controls using ELISA assays, autoradiography, and mRNA in situ hybridization assay. Interestingly, lower DNA/RNA oxidative adducts levels in the caudate and putamen of diseased brains were observed with the exception of an increased DNA oxidative product in the caudate of AD brains. Similar changes were found for dopamine concentration and vesicular monoamine transporter 2 densities. We also found that downstream pre-synaptic dopamine D1 Receptor binding correlated with dopamine loss in Lewy body disease groups, and RNA damage and ß-site APP cleaving enzyme 1 in the caudate of AD. This is the first demonstration of region-specific alterations of DNA/RNA oxidative damage which cannot be viewed in isolation, but rather in connection with the interrelationship between different neuronal events; chiefly DNA oxidative adducts and density of vesicular monoamine transporter 2 densities in AD and PD patients.

Microglia Implicated in Tauopathy in the Striatum of Neurodegenerative Disease Patients from Genotype to Phenotype.

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 across all samples. However, associations between TSPO and BIN1 gene polymorphisms and TSPO, MPO, TREM2, and PAR level variations were found. PAR levels reduced significantly in the caudate of LBDs. TSPO density and tau fibrils decreased remarkably in the striatum of LBDs but increased in AD. Oxidative damage, induced by misfolded tau proteins and dopamine metabolism, causes microglia dystrophy or senescence during the late stage of LBDs. Consequently, microglia dysfunction conversely reduces tau propagation. The G allele of the BIN1 gene is a potential risk factor for tauopathy.

Radiolabeled 6-(2, 3-Dichlorophenyl)-N4-methylpyrimidine-2, 4-diamine (TH287): A Potential Radiotracer for Measuring and Imaging MTH1.

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 assays show that TH287 has an IC50 of 2.2 nM in inhibiting MTH1 hydrolase activity and a Ki of 1.3 nM from kinetics assays, these results are consistent with our radioligand binding assays. Furthermore, MicroPET imaging shows that [11C]TH287 gets into the brain with rapid clearance from the brain, kidney, and heart. The results presented here indicate that radiolabeled TH287 has favorable properties to be a useful tool for measuring MTH1 in vitro and for further evaluation for in vivo PET imaging MTH1 of brain tumors and other central nervous system disorders.

Cross-inhibition of NMBR and GRPR signaling maintains normal histaminergic itch transmission.

We previously showed that gastrin-releasing peptide receptor (GRPR) in the spinal cord is important for mediating nonhistaminergic itch. Neuromedin B receptor (NMBR), the second member of the mammalian bombesin receptor family, is expressed in a largely nonoverlapping pattern with GRPR in the superficial spinal cord, and its role in itch transmission remains unclear. Here, we report that Nmbr knock-out (KO) mice exhibited normal scratching behavior in response to intradermal injection of pruritogens. However, mice lacking both Nmbr and Grpr (DKO mice) showed significant deficits in histaminergic itch. In contrast, the chloroquine (CQ)-evoked scratching behavior of DKO mice is not further reduced compared with Grpr KO mice. These results suggest that NMBR and GRPR could compensate for the loss of each other to maintain normal histamine-evoked itch, whereas GRPR is exclusively required for CQ-evoked scratching behavior. Interestingly, GRPR activity is enhanced in Nmbr KO mice despite the lack of upregulation of Grpr expression; so is NMBR in Grpr KO mice. We found that NMB acts exclusively through NMBR for itch transmission, whereas GRP can signal through both receptors, albeit to NMBR to a much lesser extent. Although NMBR and NMBR(+) neurons are dispensable for histaminergic itch, GRPR(+) neurons are likely to act downstream of NMBR(+) neurons to integrate NMB-NMBR-encoded histaminergic itch information in normal physiological conditions. Together, we define the respective function of NMBR and GRPR in itch transmission, and reveal an unexpected relationship not only between the two receptors but also between the two populations of interneurons in itch signaling.

Sigma-2 receptor binding is decreased in female, but not male, APP/PS1 mice.

The sigma-2 receptor is a steroid-binding membrane-associated receptor which has been implicated in cell survival. Sigma-2 has recently been shown to bind amyloid-ß (Aß) oligomers in Alzheimer's disease (AD) brain. Furthermore, blocking this interaction was shown to prevent or reverse the effects of Aß to cause cognitive impairment in mouse models and synaptic loss in neuronal cultures. In the present work, the density of sigma-2 receptors was measured in a double transgenic mouse model of amyloid-ß deposition (APP/PS1). Comparisons were made between males and females and between transgenic and wt animals. Sigma-2 receptor density was assessed by quantitative autoradiography performed on coronal brain slices using [(3)H]N-[4-(3,4-dihydro-6,7-dimethoxyisoquinolin-2(1H)-yl)butyl]-2-methoxy-5-methyl-benzamide ([(3)H]RHM-1), which has a 300-fold selectivity for the sigma-2 receptor over the sigma-1 receptor. The translocator protein of 18 kDa (TSPO) is expressed on activated microglia and is a marker for neuroinflammation. TSPO has been found to be upregulated in neurodegenerative disorders, including AD. Therefore, in parallel with the sigma-2 autoradiography experiments, we measured TSPO expression using the selective radioligand, [(3)H]PBR28. We also quantified Aß plaque burden in the same animals using a monoclonal antibody raised against aggregated Aß. Sigma-2 receptor density was significantly decreased in piriform and motor cortices as well as striata of 16-month old female, but not male, APP/PS1 mice as compared to their wt counterparts. [(3)H]PBR28 binding and immunostaining for Aß plaques were significantly increased in piriform and motor cortices of both male and female transgenic mice. In striatum however, significant increases were observed only in females.

Synthesis, pharmacological evaluation and molecular modeling studies of triazole containing dopamine D3 receptor ligands.

A series of 2-methoxyphenyl piperazine analogues containing a triazole ring were synthesized and their in vitro binding affinities at human dopamine D2 and D3 receptors were evaluated. Compounds 5b, 5c, 5d, and 4g, demonstrate high affinity for dopamine D3 receptors and moderate selectivity for the dopamine D3 versus D2 receptor subtypes. To further examine their potential as therapeutic agents, their intrinsic efficacy at both D2 and D3 receptors was determined using a forskolin-dependent adenylyl cyclase inhibition assay. Affinity at dopamine D4 and serotonin 5-HT1A receptors was also determined. In addition, information from previous molecular modeling studies of the binding of a panel of 163 structurally-related benzamide analogues at dopamine D2 and D3 receptors was applied to this series of compounds. The results of the modeling studies were consistent with our previous experimental data. More importantly, the modeling study results explained why the replacement of the amide linkage with the hetero-aromatic ring leads to a reduction in the affinity of these compounds at D3 receptors.

Functional assays to define agonists and antagonists of the sigma-2 receptor.

The sigma-2 receptor has been identified as a biomarker in proliferating tumors. To date there is no well-established functional assay for defining sigma-2 agonists and antagonists. Many sigma-2 ligands with diverse structures have been shown to induce cell death in a variety of cancer cells by triggering caspase-dependent and independent apoptosis. Therefore, in the current study, we used the cell viability assay and the caspase-3 activity assay to determine sigma-2 agonists and antagonists. Three classes of sigma-2 ligands developed in our laboratory were evaluated for their potency to induce cell death in two tumor cell lines, mouse breast cancer cell line EMT-6 and human melanoma cell line MDA-MB-435. The data showed that the EC50 values of the sigma-2 ligands using the cell viability assay ranged from 11.4µM to >200µM, which were comparable with the EC50 values obtained using the caspase-3 assay. Based on the cytotoxicity of a sigma-2 ligand relative to that of siramesine, a commonly accepted sigma-2 agonist, we have categorized our sigma-2 ligands into agonists, partial agonists, and antagonists. The establishment of functional assays for defining sigma-2 agonists and antagonists will facilitate functional characterization of sigma-2 receptor ligands and sigma-2 receptors.

Development of a PET radiotracer for non-invasive imaging of the reactive oxygen species, superoxide, in vivo.

Reactive oxygen species (ROS) have been implicated in the pathogenesis of a wide range of human disease states and drug toxicities, but development of imaging tools to study ROS biology in vivo remains a challenge. Here we synthesized and validated a novel PET tracer (12) and its (18)F radiolabeled version [(18)F]12 to allow PET ( positron emission tomography) imaging of superoxide in vivo. Initial analysis of ROS reaction kinetics found that compound 12 was rapidly and selectively oxidized by superoxide, but not other ROS. Cell culture studies in EMT6 cells exposed to the cancer chemotherapeutic agent Doxorubicin (DOX), which activates the superoxide-generating enzyme, NADPH oxidase, showed that compound 12 was a sensitive and specific probe for superoxide in cells. The microPET imaging of heart in mice with DOX-induced cardiac inflammation observed 2-fold greater oxidation of [(18)F]12 in the DOX-treated mice compared to controls (p = 0.02), the results were confirmed by distribution studies on organs subsequently removed from the mice and HPLC analysis of [(18)F] radioactivity compounds. These data indicate that compound 12 is a useful PET tracer to imaging ROS in vivo.

Synthesis, [¹8F] radiolabeling, and evaluation of poly (ADP-ribose) polymerase-1 (PARP-1) inhibitors for in vivo imaging of PARP-1 using positron emission tomography.

Imaging of poly (ADP-ribose) polymerase-1 (PARP-1) expression in vivo is a potentially powerful tool for developing PARP-1 inhibitors for drug discovery and patient care. We have synthesized several derivatives of benzimidazole carboxamide as PARP-1 inhibitors, which can be (18)F-labeled easily for positron emission tomographic (PET) imaging. Of the compounds synthesized, 12 had the highest inhibition potency for PARP-1 (IC50=6.3 nM). [(18)F]12 was synthesized under conventional conditions in high specific activity with 40-50% decay-corrected yield. MicroPET studies using [(18)F]12 in MDA-MB-436 tumor-bearing mice demonstrated accumulation of [(18)F]12 in the tumor that was blocked by olaparib, suggesting that the uptake of [(18)F]12 in the tumor is specific to PARP-1 expression.

Exploration of Directing-Group-Assisted, Copper-Mediated Radiofluorination and Radiosynthesis of [18F]Olaparib.

Copper-mediated radiofluorination (CMRF) of organoboronic precursors is the method of choice for late-stage radiofluorination of aromatic compounds as positron emission tomography (PET) radiotracers. However, CMRF generally requires harsh reaction conditions, a large amount of substrates, and harsh solvents (e.g., DMA) to proceed, affording variable radiochemical yields (RCYs). Using [18F]tosyl fluoride as the source of [18F]fluoride, we have found a highly efficient CMRF of organoboronic precursors, assisted by a directing group (DG) at the ortho position. The reaction can be carried out under mild conditions (even at room temperature) in acetonitrile and results in high RCYs, providing a novel strategy for the radiofluorination of aromatic compounds. The exploration of this strategy also provided more information about side reactions in CMRF. Using this strategy, [18F]olaparib has been radiosynthesized in high RCYs, with high molar activity and high chemical and radiochemical purities, demonstrating the great potential of DG-assisted CMRF in the preparation of 18F-labeled PET radiotracers.

Bioinspired Suspended Sensing Membrane Array with Modulable Wedged-Conductive Channels for Crosstalk-Free and High-Resolution Detection.

High spatial-resolution detection is essential for biomedical applications and human-machine interaction. However, as the sensor array density increases, the miniaturization will lead to interference between adjacent units and deterioration in sensing performance. Here, inspired by the cochlea's sensing structure, a high-density flexible pressure sensor array featuring with suspended sensing membrane with sensitivity-enhanced customized channels is presented for crosstalk-free and high-resolution detection. By imitating the basilar membrane attached to spiral ligaments, a sensing membrane is fixed onto a high-stiffness substrate with cavities, forming a stable braced isolation to provide an excellent crosstalk-free capability (crosstalk coefficient: 47.24 dB) with high-density integration (100 units within 1 cm2). Similar to the opening of ion channels in hair cells, the wedge-type expansion of the embedded cracks introduced by stress concentration structures enables a high sensitivity (0.19 kPa-1) and a large measuring range (400 kPa). Finally, it demonstrates promising applications in distributed displays and the condition monitoring of medical-surgical intubation.

Positron emission tomography imaging of dopamine D2 receptors using a highly selective radiolabeled D2 receptor partial agonist.

A series of microPET imaging studies were conducted in anesthetized rhesus monkeys using the dopamine D2-selective partial agonist, [(11)C]SV-III-130. There was a high uptake in regions of brain known to express a high density of D2 receptors under baseline conditions. Rapid displacement in the caudate and putamen, but not in the cerebellum, was observed after injection of the dopamine D2/3 receptor nonselective ligand S(-)-eticlopride at a low dosage (0.025mg/kg/i.v.); no obvious displacement in the caudate, putamen and cerebellum was observed after the treatment with a dopamine D3 receptor selective ligand WC-34 (0.1mg/kg/i.v.). Pretreatment with lorazepam (1mg/kg, i.v. 30min) to reduce endogenous dopamine prior to tracer injection resulted in unchanged binding potential (BP) values, a measure of D2 receptor binding in vivo, in the caudate and putamen. d-Amphetamine challenge studies indicate that there is a significant displacement of [(11)C]SV-III-130 by d-Amphetamine-induced increases in synaptic dopamine levels.

Dopamine D3 Receptor in Parkinson Disease: A Prognosis Biomarker and an Intervention Target.

Parkinson disease (PD) dementia, pathologically featured as nigrostriatal dopamine (DA) neuronal loss with motor and non-motor manifestations, leads to substantial disability and economic burden. DA therapy targets the DA D3 receptor (D3R) with high affinity and selectivity. The pathological involvement of D3R is evidenced as an effective biomarker for disease progression and DA agnostic interventions, with compensations of increased DA, decreased aggregates of α-synuclein (α-Syn), enhanced secretion of brain-derived neurotrophic factors (BDNF), attenuation of neuroinflammation and oxidative damage, and promoting neurogenesis in the brain. D3R also interacts with D1R to reduce PD-associated motor symptoms and alleviate the side effects of levodopa (L-DOPA) treatment. We recently found that DA D2 receptor (D2R) density decreases in the late-stage PDs, while high D3R or DA D1 receptor (D1R) + D3R densities in the postmortem PD brains correlate with survival advantages. These new essential findings warrant renewed investigations into the understanding of D3R neuron populations and their cross-sectional and longitudinal regulations in PD progression.