2-(2-(dimethylaminomethyl)phenoxy)-5-iodophenylamine: an improved serotonin transporter imaging agent

Imaging serotonin transporters (SERT) is an emerging research tool potentially useful to cast light on the mechanisms of drug action as well as to monitor the treatment of depressed patients. We have prepared two new derivatives of 3, 2-(2-(dimethylaminomethyl)phenoxy)-5-iodophenylamine (4) and 2-(2-(dimethylaminomethyl)benzyl)-5-iodophenylamine (5) (K(i) for SERT = 0.37 and 48.6 nM, respectively). Both [(125)I]4 and [(125)I]5 displayed excellent brain uptakes in rats, and they showed a highest uptake in hypothalamus (between 60 and 240 min), a region populated with the highest density of SERT. The specific uptake of [(125)I]4 in the hypothalamus resulted in a target to nontarget ratio ([hypothalamus-cerebellum]/cerebellum) of 4.3 at 2 h. Autoradiography of rat brain sections (ex vivo at 2 h) of [(125)I]4 showed an excellent regional distribution pattern consistent with known SERT localization. These data suggest that [(123)I]4 may be useful for imaging SERT binding sites in the brain by single photon emission computed tomography (SPECT).     

Management of osteoporosis in Hong Kong

Osteoporosis is among the top 3 medical conditions that are associated with greatest morbidity and reduction of quality of life of Hong Kong elderly subjects. The genetic and environmental risk factors for osteoporosis in southern Chinese as well as the current approach towards managing this growing health problem in Hong Kong are presented.     

Development and evaluation of iodinated tracers targeting amyloid plaques for SPECT imaging

Successful development of iodinated ligands for various neurotransmitter receptors prompted us to explore the feasability of having iodinated ligands to target amyloid plaques of Alzheimer’s disease. Several potential iodinated tracers based on various chemical backbone structures have been successfully prepared and evaluated toward this purpose. High binding affinities for Aβ aggregates were consistently observed for those ligands. However, the desirable in vivo properties were generally missing in the majority of those iodinated ligands. Only ligands with the promising in vitro and in vivo characteristics such as IMPY will likely warrant their success to be potential imaging agents mapping amyloid plaques in living human brain.     

Binding of two potential imaging agents targeting amyloid plaques in postmortem brain tissues of patients with Alzheimer's disease

In vivo imaging of amyloid plaques may be useful for evaluation and diagnosis of Alzheimer's disease (AD) patients. Towards that end, we have developed 6-iodo-2-(4'-dimethylamino-)phenyl-imidazo[1,2]pyridine (IMPY), and 4-N-methylamino-4'-hydroxystilbene (SB-13) as ligands for specifically targeting amyloid plaques. These ligands can be readily radiolabeled with I-123 or C-11, for in vivo imaging using single photon emission computerized tomography (SPECT) or positron emission tomography (PET), respectively. However, in order to be useful in vivo, probes must show selective high affinity binding to a sufficiently abundant binding site on amyloid plaques. Therefore, as a prelude to in vivo imaging studies, we evaluated the binding properties of these two potential imaging agents to amyloid plaques present in human brain tissues. In vitro binding studies were carried out with [(125)I]IMPY and [(3)H]SB-13 in homogenates prepared from postmortem samples of affected cortex and cerebellum of pathologically confirmed AD patients and age-matched controls. Binding parameters such as K(d) and B(max) were estimated. Competition study was designed to evaluate the amyloid plaque binding specificity using human brain tissues. Plaque binding was confirmed by thioflavin-S staining. Specific [(125)I]IMPY or [(3)H]SB-13 binding can be clearly measured in the cortical gray matter, but not in the white matter of AD cases. There was a very low specific binding in cortical tissue homogenates of control brains. Cerebellar homogenates prepared from either AD or control brains did not show any specific [(125)I]IMPY or [(3)H]SB-13 binding. The K(d) values of AD cortical homogenates were 5.3+/-1.0 and 2.4+/-0.2 nM for [(125)I]IMPY and [(3)H]SB-13, respectively. High binding capacity and comparable values were observed for both ligands (14-45 pmol/mg protein). The location and density of specific signal detected by [(125)I]IMPY or [(3)H]SB-13 correlated with the distribution of amyloid plaques in these brain specimens, as confirmed by thioflavin-S staining. Competition profiles of known ligands suggest that the binding is highly selective and comparable to that reported by using preformed Abeta peptide aggregates. [(125)I]IMPY and [(3)H]SB-13 show an abundant binding capacity with high binding affinities for amyloid plaques in affected cortical regions of AD brains. These properties suggest that when labeled with I-123 or C-11, these two ligands may be useful to quantitate amyloid plaque burdens in the living AD patients.     

Chemical and biological assessment of a traditional chinese herbal decoction prepared from Radix Astragali and Radix Angelicae Sinensis: orthogonal array design to optimize the extraction of chemical constituents

Danggui Buxue Tang (DBT) is a simple decoction, having about 800 years of usage in China to treat menopausal irregularity in women, which contains two herbs: Radix Astragali (Huangqi) and Radix Angelicae Sinensis (Danggui). Traditionally, boiling water has been used for preparing DBT; however, the optimized conditions of extraction have not yet been determined. Here, the amounts of Radix Astragali-derived astragaloside IV, calycosin, formononetin, and Radix Angelicae Sinensis-derived ferulic acid and ligustilide were determined in DBT, which were extracted according to an orthogonal array experimental design having three variable parameters: extraction time, extraction volume and number of repeats of the extraction. Our results suggest that extraction time and number of repeats of the extraction are two crucial factors, while extraction volume is a subordinate factor. The optimized conditions for extraction were therefore established. Besides the chemical composition, the estrogenic and anti-platelet aggregation activities of DBT were determined in different groups of the extraction, and the results of bioassays were in line with the amounts of the analyzed chemical ingredients. The results provide a model system for establishing the quality assurance of the herbal preparation.     

Clonal analysis of bilateral mammary carcinomas by clinical evaluation and partial allelotyping

Bilateral breast carcinomas may represent contralateral metastases or new primary tumors. The presence of carcinoma in situ, a lower grade, or a different histotype in the second tumor is considered a clinical criterion for a second primary tumor. In this study, 26 bilateral breast carcinomas from 13 patients were analyzed based on clinical criteria, and the results were compared with those obtained by partial allelotyping using 47 markers at 7 chromosomal arms. Of the 8 synchronous tumors, 5 were concluded to be distinct primary tumors using clinical criteria; some were confirmed by partial allelotyping. In the remaining 3 cases, partial allelotyping showed distinct primary tumors. Five patients had metachronous carcinomas with 3 distinct primary tumors, 1 metastasis, and 1 that was uncertain by clinical criteria. Three cases were confirmed by partial allelotyping, and the uncertain case was shown to be distinct primary tumors. No discrepant results were noted. Stringent application of clinical criteria is accurate for differentiating second primary tumors from metastases.     

Human Oocyte Maturity In Vivo Determines the Outcome of Blastocyst Development In Vitro

PURPOSE: To date, the impact of oocyte maturity at aspiration on the blastocyst formation in vitro has not been fully evaluated. This study was undertaken to assess the influence of oocyte maturity in patients undergoing in vitro fertilization and blastocyst transfer program. METHODS: A total of 1278 oocytes derived from 147-IVF cycles were retrospectivly analyzed. Oocyte maturity was graded on a scale from 1 to 5 based on the morphology of the ooplasm, cumulus mass, corona radiata, and membrana granulosa cells. RESULTS: Mature oocytes yielded the highest fertilization rates. Although the cleavage rates were similar in both groups, the percentage of poor morphology, day-3 embryos from the nonmature-oocyte group was significantly higher than from the mature-oocyte group (54.7% vs. 15.5%, P < 0.001). Although good morphology, day-3 embryos were collected from nonmature oocytes, the incidence of these embryos developing to the blastocyst stage was significantly less than from mature oocytes (33.3% vs. 71.2%, P < 0.001). Although blastocyst stage embryos were collected from nonmature oocytes, the incidence of these embryos developing to the top-scoring blastocysts was significantly less than from mature oocytes (58.3% vs. 89.5%, P < 0.001). CONCLUSIONS: These phenomena suggest that oocyte maturity produced in vivo determine the fertilization potential and subsequent blastocyst quality in vitro.     

Transfer of nonselected transferable day 3 embryos in low embryo producers

OBJECTIVE: To examine the implantation potential of embryos from assisted reproductive technology cycles with low embryo production and to assess the effects of clinical variables and embryo scores (ES) on pregnancy outcome. DESIGN: Prospective clinical study. SETTING: Assisted reproductive technology unit in a tertiary medical center. PATIENT(S): From July 1998 to December 2001, 280 cycles in 229 infertile couples produced a limited number of one, two, or three embryos 3 days after oocyte retrieval and underwent fresh embryo transfer (ET). INTERVENTION(S): Embryos with two or more blastomeres were scored and transferred. MAIN OUTCOME MEASURE(S): ES and implantation rate per ET. RESULT(S): Of 863 fresh ET cycles during the study period, 32.4% (280) were low embryo producers. Among them, there were no significant differences in average ES of individual embryos in single, dual, or triple ET or in embryos obtained from patients with low or high E2 responses, or young or old age. Embryos derived from conventional IVF had a better ES than those derived from intracytoplasmic sperm injection. The clinical pregnancy rate was strongly correlated with the cumulative ES. Implantation rates were similar among and between groups, with an average rate of 15.9%. CONCLUSION(S): Embryos of low embryo producers had an inherently low implantation potential that appeared to be unrelated to the number of embryos transferred, female age, ovarian E2 genesis, or fertilization method. The cumulative ES can serve as a predictor of pregnancy.