PET imaging for receptor occupancy: meditations on calculation and simplification

This invited mini-review briefly summarizes procedures and challenges of measuring receptor occupancy with positron emission tomography. Instead of describing the detailed analytic procedures of in vivo ligand-receptor imaging, the authors provide a pragmatic alJproach, along with personal perspectives, for conducting positron emission tomography imaging for receptor occupancy, and systematically elucidate the mathematics of receptor occupancy calculations in practical ways that can be understood with elementary algebra. The authors also share insights regarding positron emission tomography imaging for receptor occupancy to facilitate applications for the development of drugs targeting receptors in the central nervous system.

^(99m)Tc-YIGSR as a Receptor Tracer in Imaging the Ehrlich Ascites Tumor-bearing Mice as Compared with ^(99m)Tc-MIBI

The validity of ^99mTc-YIGSR, a novel receptor radio-tracer, in imaging the Ehrlich ascites tumor was evaluated. YIGSR, a pentapeptide of laminin, was labeled with ^99mTc by using a bifunctional chelator S-Acetly-NH3-MAG3. The MIBI was labeled with ^99mTc by following the kit instruction. The mice of tumor group were intravenously injected 1-2 mCi of ^99mTc-YIGSR or ^99mTc-MIBI via caudal vein, immobilized and imaged under a Gamma camera. The same procedure was performed in mice of blockade group, in which the unlabeled YIGSR was previously injected to block the receptor-recognition sites, and inflammation group serving as control. The reverse-phase Sep-Pak C18 chromatogram was found to have an essentially complete conjugation between YIGSR and S-Acetly-NH3-MAG3. The conjugated YIGSR could be radio-labeled successfully with ^99mTC at room temperature and neutral pH, with a radio-labeling yield of 62%. Without the chelator S-Acetly-NH3-MAG3, the YIGSR was labeled with ^99mTc at an efficiency of 4%. The imagological study revealed obvious tumor accumulation of ^99mTc-YIGSR 15 min after the injection, and the uptake peaked after 3 h with a tumor-to-muscle ratio （T/M） of 11.36. The radio-tracer was slowly cleared up and resulted in a T/M of 3.01 at the 8th h after the injection. As for blocked group, the tumor uptake of radiotracer was significantly lower, with the highest T/M being 4.61 after 3 h and 0.89 after 8 h. The T/M was 3.72 at the 3rd h and 1.29 at the 8th h after the ^99mTc-YIGSR injection in the inflammatory group. The T/M was significantly higher in tumor group than in inflammatory group or control group （P〈0.001）. In the ^99mTc-MIBI group, the T/M was 1.40 at the 3rd h and 0.55 at the 8th h after the injection, which showed a significant difference as compared with ^99mTc-YIGSR （P〈0.001）. It is concluded that YIGSR can be successfully radiolabelled by using S-Acetly-NH3-MAG3. ^99mTc-YIGSR has many advantages in tumor imaging, such as quick and clear visualization, high sensitivity and specificity, and satisfactory target/non-target ratio （N/NT）. It promises to be tumor radio-tracer.

Laparoscopic resection of gastrointestinal neuroendocrine tumors with special contribution of radionuclide imaging

The surgical treatment of neuroendocrine tumors(NETs) draws on experience and guidelines more than on prospective randomized trials. The incidence of NET is increasing in all parts of the gastrointestinal tract. A variety of classifications introduced over the last decade may have led to difficulties in judging clinical relevance and determining the right surgical strategy. The North American Neuroendocrine Tumor Society and the European Neuroendocrine Tumor Society have developed usable guidelines from the available literature. For more than 20 years laparoscopy has developed as the gold standard for various surgical indications. Nevertheless, few trials have compared open and laparoscopic surgery with regard to NET. This review summarizes the recent literature on surgery for NET and incorporates the evidence on laparoscopy for cancer which might be also applied for NET.

Feasibility on Systemic Delivery of Asialoorosomucoid Complex to Hepatic Origin Cells Mediated by Asialoglycoprotein Receptor

Receptor mediated gene delivery is a new gene transfer strategy. Asialoglycoprotein receptor (ASGP-R), the receptor of asialoorosomucoid (Asor), is specially expressed on the surface of hepatocyte. In this paper, the nuclide 131I was combined with Asor to form a kind of soluble nuclide-protein complex, which can be specifically endocytosed into hepatocyte by ASGP-R. After intravenous injection of the complex into experimental animals, the deposition of Asor in vivo and the targeting quality of hepatocyte was detected by ECT. This research testified the feasibility of targeting Asor complex delivery to hepatocyte mediated by ASGP-R in vivo, and provided foundation for the genetic diagnosis and gene therapy of hepatic cell-related diseases.

Gastric neuroendocrine neoplasms: A review

Gastric neuroendocrine neoplasms(g-NENs)or neuroendocrine tumors are generally slow-growing tumors with increasing incidence.They arise from enterochromaffin like cells and are divided into four types according to clinical characteristic features.Type 1 and 2 are gastrin dependent,whereas type 3 and 4 are sporadic.The reason for hypergastrinemia is atrophic gastritis in type 1,and gastrin releasing tumor(gastrinoma)in type 2 g-NEN.The diagnosis of g-NENs needs histopathological investigation taken by upper gastrointestinal endoscopy.g-NENs are positively stained with chomogranin A and synaptophysin.Grading is made with mitotic index and ki-67 proliferation index on histopathological analysis.It is crucial to discriminate between types of g-NENs,because the management,treatment and prognosis differ significantly between subtypes.Treatment options for g-NENs include endoscopic resection,surgical resection with or without antrectomy,medical treatment with somatostatin analogues,netazepide or chemotherapy regimens.Follow-up without excision is another option in appropriate cases.The prognosis of type 1 and 2 g-NENs are good,whereas the prognosis of type 3 and 4 g-NENs are close to the prognosis of gastric adenocancer.

History of the dopamine hypothesis of antipsychotic action

The dopamine hypothesis of how antipsychotic drugs exert their beneficial effect in psychotic illness has an interesting history that dates back to 1950.This hypothesis is not to be confused with the dopamine hypothesis of schizophrenia;the aim of the latter is to explain the etiology of schizophrenia.The present review does not deal with schizophrenia but,rather,with the historical development of our current understanding of the dopamine-associated actions of the drugs that reduce the symptoms of psychosis.This historical review begins with the serendipitous discovery of chlorpromazine,a drug synthesized around a chemical core that initially served to produce man-made dyes.This molecular core subsequently contributed to the chemistry of antihistamines.It was with the aim of producing a superior antihistamine that chlorpromazine was synthesized;instead,it revolutionized the treatment of psychosis.The first hypothesis of how this drug worked was that it induced hypothermia,a cooling of the body that led to a tranquilization of the mind.The new,at the time,discoveries of the presence of chemical transmitters in the brain soon steered investigations away from a temperature-related hypothesis toward questioning how this drug,and other drugs with similar properties and effects,modulated endogenous neurotransmission.As a result,over the years,researchers from around the world have begun to progressively learn what antipsychotic drugs do in the brain.

Epidermal growth factor receptor-targeted ultra-small superparamagnetic iron oxide particles for magnetic resonance molecular imaging of lung cancer cells in vitro

Background Magnetic resonance （MR） molecular imaging can detect abnormalities associated with disease at the level of cell and molecule. The epidermal growth factor receptor （EGFR） plays an important role in the development of lung cancer. This study aimed to explore new MR molecular imaging targeting of the EGFR on lung cancer cells. Methods We attached ultra-small superparamagnetic iron oxide （USPIO） particles to cetuximab （C225） anti-human IgG using the carbodiimide method. We made the molecular MR contrast agents C225-USPIO and IgG-USPIO, the latter as a control reagent, and determined concentrations according to the Fe content. Lung cancer A549 cells were cultured and immunocytochemistry （SP） was used to detect the expression of EGFR on cells. We detected the binding rate of C225-USPIO to A549 cells with immunofluorescence staining and flow cytometry. We cultured A549 cells with C225-USPIO at a Fe concentration of 50 pg/ml and assayed the binding of C225-USPIO after 1 hour with Prussian blue staining and transmission electron microscopy （TEM）. We determined the effects on imaging of the contrast agent targeted to cells using a 4.7T MRI. We did scanning on the cells labeled with C225-USPIO, IgG-USPIO, and distilled water, respectively. The scanning sequences included axial T1WI, T2WI. Results Immunocytochemical detection of lung cancer A549 cells found them positive for EGFR expression. Immunofluorescence staining and flow cytometry after cultivation with different concentrations of C225-USPIO showed the binding rate higher than the control. Prussian blue staining and transmission electron microscopy revealed that in the C225-USPIO contrast agent group of cells the particle content of Fe in cytoplasmic vesicles or on surface was more than that in the control group. The 4.7T MR imaging （MRI） scan revealed the T2WI signal in the C225-USPIO group of cells decreased significantly more than in unlabeled cells, but there was no significant difference between the time gradients. Conclusions We successfully constructed the molecular imaging agent C225-USPIO targeting the EGFR of A549 lung cancer cells. The imaging agent showed good targeting effect and specificity, and reduced MRI T2 value significantly, thus such molecular contrast agents could provide a new way to measure EGFR levels.

Single-molecule imaging reveals the stoichiometry change of epidermal growth factor receptor during transactivation by β_2-adrenergic receptor

Stimulation of G protein-coupled receptors(GPCRs) can lead to the transactivation of the epidermal growth factor receptors(EGFR). The cross-communication between the two signaling pathways regulates several important physiological or pathological processes. However, the molecule mechanism underlying EGFR transactivation remains poorly understood. Here, we aim to study the GPCR-mediated EGFR transactivation process using the single-molecule fluorescence imaging and tracking approach.We found that although EGFR existed as monomers at the plasma membrane of resting cells, they became dimers and thus diffused slower following the activation of β2-adrenergic receptor(β2-AR) by isoproterenol(ISO). We further proved thatβ2-AR-mediated changes of EGFR in stoichiometry and dynamics were mediated by Src kinase. Thus, the observations obtained via the single-molecule imaging and tracking methods shed new insights into the molecular mechanism of EGFR transactivation at single molecule level.

An association study of protein tyrosine phosphatase receptor type R gene polymorphism and the resting-state functional magnetic resonance imaging in major depressive disorder

Objective To explore the influence of a polymorphism of protein tyrosine phosphatase receptor type R(PTPRR)gene rs1513105 on abnormal brain activities in resting-state patients with major depressive disorder(MDD)using the gene-imaging technology.Methods 54MDD and 43 gender-,age-,and education-matched con-