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Biomedical subjects

C Hou

Publications and source records attributed to C Hou.

At least 37 records · Page 2Linked to original sources
PubMed2000

Selective in vitro and in vivo binding of [(125)I]ADAM to serotonin transporters in rat brain.

An improved iodinated tracer, ADAM (2-((2-((dimethylamino)methyl)- phenyl)thio)-5-iodophenylamine) for imaging serotonin transporters (SERT) with single photon emission computerized tomography (SPECT), was prepared and characterized. Scatchard analysis of saturation binding of [(125)I]ADAM to rat frontal cortical membrane homogenates gave a K(d) value of 0.15 +/- 0.03 nM and a B(max) value of 194 +/- 65 fmol/mg protein. Biodistribution of [(125)I]ADAM in rat brain after an iv injection showed a high specific binding in the regions of hypothalamus, cortex, striatum, and hippocampus, where SERT are concentrated and the specific binding peaked at 120-240 min postinjection [(hypothalamus-cerebellum)/cerebellum = 4.3 at 120 min post-iv injection]. Moreover, the specific hypothalamic uptake was blocked by pretreatment with SERT selective competing drugs, such as paroxetine and (+)McN5652, while other noncompeting drugs, such as ketanserin, raclopride, and methylphenidate, showed no effect. The radioactive material recovered from rat brain homogenates at 120 min after [(125)I]ADAM injection showed primarily the original compound (>90%), a good indication of in vivo stability in the brain tissues. Both male and female rats showed similar and comparable organ distribution pattern and regional brain uptakes. Ex vivo autoradiograms of rat brain sections (120 min after iv injection of [(125)I]ADAM) showed intense labeling in several regions (olfactory tubercle, lateral septal nucleus, hypothalamic and thalamic nuclei, globus pallidus, central gray, superior colliculus, substantia nigra, interpeduncular nucleus, dorsal and median raphes, and locus coerulus), which parallel known SERT density. These results strongly suggest that the novel tracer ADAM is superior to the congers (i.e., IDAM) reported previously. When labeled with I-123, ADAM will be an improved and useful SPECT imaging agent for SERT in the brain.

Animals↗
PubMed2000

The presence of an aqueous cavity in the proton-pumping pathway of the pyridine nucleotide transhydrogenase of Escherichia coli is suggested by the reaction of the enzyme with sulfhydryl inhibitors.

The pyridine nucleotide transhydrogenase of Escherichia coli carries out transmembrane proton translocation coupled to transfer of a hydride ion equivalent between NAD(+) and NADP(+). The membrane domain (domain II) of the enzyme is composed of 13 transmembrane helices. Previous studies (N. A. Glavas et al., Biochemistry 34, 7694-7702, 1995) have suggested that betaHis91 in transmembrane helix 9 is involved in the translocation pathway of protons across the membrane. In this study we have replaced amino acid residues on the same face of helix 9 as betaHis91 by single cysteine residues. We then examined the effect of the sulfhydryl inhibitors N-ethylmaleimide (NEM) and p-chloromercuriphenylsulfonate (pCMPS) on enzyme activity and, in the case of [(14)C]NEM, as an enzyme label. The pattern of enzyme inhibition and labelling is consistent with the presence of an aqueous cavity through domain II from the cytosolic surface to the region of betaHis91. Residue betaAsn222 in helix 13, which appears also to be involved in the proton pathway across domain II, may interface with this aqueous cavity. A further series of mutants of betaGlu124 on helix 10 confirms the proposal (P. D. Bragg and C. Hou, Arch. Biochem. Biophys. 363, 182-190, 1999) that this residue is involved in passive permeation of protons across domain II.

4-Chloromercuribenzenesulfonate↗
PubMed2000

Crosslinking between alpha and beta subunits defines the orientation and spatial relationship of some of the transmembrane helices of the proton-translocating pyridine nucleotide transhydrogenase of Escherichia coli.

The proton-translocating pyridine nucleotide transhydrogenase of Escherichia coli is composed of two types of subunits, alpha and beta, organized as an alpha(2)beta(2) tetramer. The protein contains three recognizable domains, of which domain II is the transmembrane region of the molecule containing the pathway for proton translocation. Domain II is composed of four transmembrane helices at the carboxyl-terminus of the alpha subunit and either eight or nine transmembrane helices at the amino-terminal region of the beta subunit. We have introduced pairs of cysteine residues into a cysteine-free transhydrogenase by site-directed mutagenesis. Disulfide bond formation between some of these cysteine residues occurred spontaneously or on treatment with cupric 1, 10-phenanthrolinate. Analysis of crosslinked products confirmed that there are nine transmembrane helices in the domain II region of the beta subunit. The proximity to one another of several of the transmembrane helices was determined. Thus, helices 2 and 4 are close to helix 6 (nomenclature of Meuller and Rydström, J. Biol. Chem. 274, 19072-19080, 1999), and helix 3 and the carboxyl-terminal eight residues of the alpha subunit are close to helix 7. In the alpha(2)beta(2) tetramer, helices 2 and 4 of one alpha subunit are close to the same pair of transmembrane helices of the other alpha subunit, and helix 6 of one beta subunit is close to helix 6 of the other beta subunit.

Amino Acid Sequence↗
PubMed2000

2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine (ADAM): an improved serotonin transporter ligand.

Serotonin transporters (SERT) are target-sites for commonly used antidepressants, such as fluoxetine, paroxetine, sertraline, and so on. Imaging of these sites in the living human brain may provide an important tool to evaluate the mechanisms of action as well as to monitor the treatment of depressed patients. Synthesis and characterization of an improved SERT imaging agent, ADAM (2-((2-((dimethylamino)methyl)phenyl)thio)-5-iodophenylamine)(7) was achieved. The new compound, ADAM(7), displayed an extremely potent binding affinity toward SERT ( K(i)=0.013 nM, in membrane preparations of LLC-PK(1)-cloned cell lines expressing the specific monoamine transporter). ADAM(7) also showed more than 1,000-fold selectivity for SERT over norepinephrine transporter (NET) and dopamine transporter (DAT) ( K(i)=699 and 840 nM, for NET and DAT, respectively). The radiolabeled compound [(125)I]ADAM(7) showed an excellent brain uptake in rats (1.41% dose at 2 min post intravenous [IV] injection), and consistently displayed the highest uptake (between 60-240 min post IV injection) in hypothalamus, a region with the highest density of SERT. The specific uptake of [(125)I]ADAM(7) in the hypothalamus exhibited the highest target-to-nontarget ratio ([hypothalamus - cerebellum]/cerebellum was 3.97 at 120 min post IV injection). The preliminary imaging study of [(123)I]ADAM in the brain of a baboon by single photon emission computed tomography (SPECT) at 180-240 min post IV injection indicated a specific uptake in midbrain region rich in SERT. These data suggest that the new ligand [(123)I]ADAM(7) may be useful for SPECT imaging of SERT binding sites in the human brain.

Animals↗
PubMed2000

A novel serotonin transporter ligand: (5-iodo-2-(2-dimethylaminomethylphenoxy)-benzyl alcohol.

The serotonin transporters (SERT) are the primary binding sites for selective serotonin reuptake inhibitors, commonly used antidepressants such as fluoxetine, sertraline, and paroxetine. Imaging of SERT with positron emission tomography and single photon emission computed tomography in humans would provide a useful tool for understanding how alterations of this system are related to depressive illnesses and other psychiatric disorders. In this article the synthesis and characterization of [(125)I]ODAM [(5-iodo-2-(2-dimethylaminomethylphenoxy)-benzyl alcohol, 9)] as an imaging agent in the evaluation of central nervous system SERT are reported. A new reaction scheme was developed for the preparation of compound 9, ODAM, and the corresponding tri-n-butyltin derivative 10. Upon reacting 10 with hydrogen peroxide and sodium[(125)I]iodide, the radiolabeled [(125)95%). In an initial binding study using cortical membrane homogenates of rat brain, ODAM displayed a good binding affinity with a value of K(i) = 2.8 +/- 0.88 nM. Using LLC-PK(1) cells specifically expressing the individual transporter (i.e. dopamine [DAT], norepinephrine [NET], and SERT, respectively), ODAM showed a strong inhibition on SERT (K(i) = 0.12 +/- 0.02 nM). Inhibition constants for the other two transporters were lower (K(i) = 3.9 +/- 0.7 microM and 20.0 +/- 1.9 nM for DAT and NET, respectively). Initial biodistribution study in rats after an intravenous (IV) injection of [(125)I]ODAM showed a rapid brain uptake and washout (2.03, 1.49, 0.79, 0.27, and 0.07% dose/organ at 2, 30, 60, 120, and 240 min, respectively). The hypothalamus region where the serotonin neurons are located exhibited a high specific uptake. Ratios of hypothalamus-cerebellum/cerebellum based on percent dose per gram of these two regions showed values of 0.35, 0. 86, 0.86, 0.63, and 0.34 at 2, 30, 60, 120, and 240 min, post-IV injection, respectively. The specific uptake in hypothalamus can be effectively blocked by pretreatment of known SERT ligands. The results suggest that this novel ligand displays desirable in vitro and in vivo properties as a potential SERT imaging agent.

Animals↗
PubMed2000

Incidence and associated factors of neutralizing anti-interferon antibodies among chronic hepatitis C patients treated with interferon in Taiwan.

BACKGROUND: The administration of interferon (IFN) could be complicated by the development of neutralizing anti-interferon antibodies (NA). This study evaluates the frequency and associated factors of NA among chronic hepatitis C patients treated with different IFNs. METHODS: Ninety-five chronic hepatitis C patients were randomized to be treated with recombinant IFN-alpha2a (n = 28), IFN-alpha2b (n = 39) or lymphoblastoid IFN-alpha1 (n = 28) given intramuscularly, 3-6 million units, thrice weekly for 24 weeks. Serum samples collected before, during and after the cessation of treatment were checked for NA. RESULTS: Three patients were withdrawn from treatment. All patients were negative for NA before treatment and 13 (14%) patients developed neutralizing antibodies. Of the 26 patients treated with IFN-alpha2a, 6 (23.1%) developed NA. whereas NA were detected in only 6 (15.4%) of 39 and 1 (3.7%) of 27 patients treated with IFN-alpha2b and IFN-alphanl, respectively. Age, gender, HCV genotype, ALT level, IFN total dose and liver histology were not associated with the development of NA. By using multivariate logistic regression it was shown that pretreatment HCV RNA level and IFN preparation were the two major factors related to the production of NA. The response of treatment was related to pretreatment viremia but not to the presence of NA. CONCLUSIONS: The frequency of development of NA among Taiwanese patients with chronic hepatitis C might be related to different IFN preparations and pretreatment HCV RNA level. The response of treatment was related to pretreatment HCV RNA level but not to the presence of NA.

Adult↗
PubMed2000

Autistic savants. [correction of artistic].

OBJECTIVE: The objectives of this study were to examine common patterns in the lives and artwork of five artistic savants previously described and to report on the clinical, neuropsychological, and neuroimaging findings from one newly diagnosed artistic savant. BACKGROUND: The artistic savant syndrome has been recognized for centuries, although its neuroanatomic basis remains a mystery. METHODS: The cardinal features, strengths, and weaknesses of the work of these six savants were analyzed and compared with those of children with autism in whom artistic talent was absent. An anatomic substrate for these behaviors was considered in the context of newly emerging theories related to paradoxical functional facilitation, visual thinking, and multiple intelligences. RESULTS: The artists had features of "pervasive developmental disorder," including impairment in social interaction and communication as well as restricted repetitive and stereotyped patterns of behavior, interest, and activities. All six demonstrated a strong preference for a single art medium and showed a restricted variation in artistic themes. None understood art theory. Some autistic features contributed to their success, including attention to visual detail, a tendency toward ritualistic compulsive repetition, the ability to focus on one topic at the expense of other interests, and intact memory and visuospatial skills. CONCLUSIONS: The artistic savant syndrome remains rare and mysterious in origin. Savants exhibit extraordinary visual talents along with profound linguistic and social impairment. The intense focus on and ability to remember visual detail contributes to the artistic product of the savant. The anatomic substrate for the savant syndrome may involve loss of function in the left temporal lobe with enhanced function of the posterior neocortex.

Adolescent↗
PubMed2000

The epidemiology of TT virus (TTV) infection in a hepatitis C and B virus hyperendemic area of southern Taiwan.

TT virus (TTV) is a newly isolated DNA virus from the serum of a patient with posttransfusion hepatitis of unknown etiology in 1997. To evaluate the clinical and molecular characteristics of TT virus (TTV) in a hepatitis C virus (HCV) and B (HBV) hyperendemic area (Masago), 200 residents were enrolled in the study. The sera were tested for alanine aminotransferase (ALT), HCV RNA and GB virus C/Hepatitis G virus (HGV) RNA, TTV DNA, HBsAg, anti-HCV and antibodies to HGV E2-protein (anti-E2). TTV DNA was positive in 99 of the 200 sera with a prevalence rate of 49.5%. The prevalence of HBsAg, anti-HCV, HCV RNA, HGV RNA, anti-E2 and HGV exposure (defined as positive for serum HGV RNA and/or anti-E2) was 38.9%, 69.5%, 64.5%, 17.0%, 25.5% and 39.5%, respectively. Neither clinical nor virological factors were associated with TTV viremia. The rate of ALT abnormality was significantly elevated in HCV RNA-positive (34.9%) than -negative (7.0%) residents (p < 0.001). HCV viremia was the only factor significantly associated with ALT elevation by multiple logistic regression (odds ratio: 6.96; 95% C.I.: 2.60-18.7). We concluded that in this HCV/HBV hyperendemic area, the prevalence of TTV DNA was high. No significant clinical factor was observed to be associated with TTV infection. TTV infection is not related to abnormal ALT levels and ALT abnormality was mainly attributable to HCV but not TTV, HBV or HGV infection.

Adult↗
PubMed2000

[Computerized surgical simulation with 3D reconstruction of upper limbs].

This paper reports our study on how to realize computerized surgical simulation through reconstructing 3D anatomy of upper limbs. CT images and serial sections of upper limbs were matched to reconstruct 3D images. We compiled the computer programs of 3D reconstruction and surgical simulation with borland C++ computer language, and built 3D digital model of anatomic structure of upper limbs. The results showed that all structures reconstructed could be displayed alone, in any group or totally. While operating, we could choose one of three segments of the upper limbs model and operate on any parts and in any direction. The surgical simulation system could be used to design operative schemes, choose the best operative paths, and teach the processes of operations and anatomy. It could run in 586-personal computers.

Arm↗
PubMed2000

[Effect of flooding stress on transpiration of poplar I-69/55].

The rates of transpiration(Tr) and photosynthesis(Pn) of poplar I-69/55 trees were measured under flooding stress. Flooding stress caused Pn and Tr decreasing, while in the period of measurement, Pn almost didn't change. The longer the period of flooding stress was, the more the Tr and stomatal conductance (Gs) decreased. Undre no stress, Pn and Tr of test trees displayed daily double-peak curves and seasonal variations, with the maximum in summer. Water use efficiency also displayed seasonal variation, with the maximum in autumn. Under no stress, Tr obviously changed with tree ages, with the order of 1 year-old > 3 year-old > 7 year-old. The rate of Tr/Pn in spring, summer and autumn was higher than that of other deciduous broad-leaved trees in the same region, especially in summer. The high Tr/Pn ratio means a high water consumption, which is beneficial to water loss of poplar I-69/55. In shoal sites, the temperature of leaf surface in summer and autumn is the most important factor that affects the transpiration rate of poplar I-69/55, suggesting that decreasing the temperature of leaf suface is beneficial to increase the transpiration rate. During the two days after flooding, the temperature of leaf surface is still the important factor that affects transpiration rate.

Disasters↗
PubMed2000

[Clinical study on chitosan for prevention of elbow adhesion].

OBJECTIVE: To study the clinical effect of chitosan on prevention of elbow adhesion after elbow arthrolysis. METHODS: Twenty six patients with elbow ankylosis were performed elbow arthrolysis, which divided into two groups, in chitosan group, 12 patients were injected 2% chitosan into the elbow joint cavity, and no chitosan used in the other 14 patients as control group. The average range of extension and flexion of elbow joint was detected to evaluate the clinical results. RESULTS: All patients were followed up 8 to 51 months, averaged 24 months. In the chitosan group, the average range of extension and flexion of elbow joint was restored to 92.9 degrees +/- 20.9 degrees, with an average increase of 55.0 degrees +/- 15.9 degrees compared with preoperation. In the control group, the average range of extension and flexion of elbow joint was restored to 75.4 degrees +/- 17.5 degrees, with an average increase of 38.2 degrees +/- 11.9 degrees. The outcome showed significant difference between the chitosan group and the control group (P < 0.01). CONCLUSION: Chitosan can prevent or reduce elbow adhesion after elbow arthrolysis.

Adolescent↗
PubMed2000

[Experimental and clinical study of gentamicin-loaded chitosan drug delivery system].

OBJECTIVE: To conduct a clinical study and release test for a drug delivery system (DDS) of gentamicin-loaded chitosan bar in attempt to extend its clinical application. METHODS: The diffusion behavior of gentamicin from chitosan DDS was detected using in vitro, in vivo release test. Eighteen cases of chronic osteomyelitis were treated by chitosan DDS. The clinical result was evaluated by wound healing and clinical and X-radiographic manifestation. RESULTS: Concentration of gentamicin about 926.7 microg/bar/day was released from DDS within the first 24 hours by in vitro diffusion test. It fell and sustained by 25th day with rate of 4.0 microg x bar(-1) x day(-1). In in vivo study, serum gentamicin concentration reached its peak level (0.92 microg/ml) 24 hours after implantation. No increase was observed in the concentration of BUN and Cr. In all bone tissue around the bar, 8 weeks after oderation the gentamicin concentration exceeded the minimum inhibitory concentration for the common causative organisms of osteomyelitis. The follow up time was 24.8 months (6 - 34). The initial cure ratio was 2/18 and the recurrence ratio zero. CONCLUSION: The gentamicin-loaded chitosan bar is a good DDS with sustained antibiotic effect in vivo and in vitro. It is an effective method for the treatment of bone infection.

Animals↗
PubMed2000

[The detection of disparity evoked potentials in anisometropes].

OBJECTIVE: To investigate the affection of anisometropia on stereopsis and its mechanism. METHODS: A new set of static random-dot stereograms was utilized as a stimulus to elicit evoked potentials in 20 anisometropes and 40 normal subjects. RESULTS: Under the stimulus of different degrees of disparity in anisometropes, the P(250) waves related to stereopsis could be recorded. However, the percentage of their P(250) wave amplitude over the plane figure was significantly lower than that of normal persons (P < 0.05). The P(250) wave mean amplitude of severe anisometropes (aniseikonia >or= 5%) in fine disparity (14' and 23') was lower than that in mild anisometropes (aniseikonia < 5%, P < 0.05). CONCLUSIONS: Anisometropia may affect and disturb the stereopsis. The degree of disturbance is related to the degree of anisometropia. The higher the degree of anisometropia, the lower the amplitude of the P(250) potential, and the main defect is at the part of fine disparity.

Adolescent↗
PubMed1999

Effect of NBD chloride (4-chloro-7-nitrobenzo-2-oxa-1,3-diazole) on the pyridine nucleotide transhydrogenase of Escherichia coli.

Pyridine nucleotide transhydrogenases of bacterial cytosolic membranes and mitochondrial inner membranes are proton pumps in which hydride transfer between NADP(+) and NAD(+) is coupled to proton translocation across cytosolic or mitochondrial membranes. The pyridine nucleotide transhydrogenase of Escherichia coli is composed of two subunits (alpha and beta). Three domains are recognized. The extrinsic cytosolic domain 1 of the amino-terminal region of the alpha subunit bears the NAD(H)-binding site. The NADP(H)-binding site is present in domain 3, the extrinsic cytosolic carboxyl-terminal region of the beta subunit. Domain 2 is composed of the membrane-intrinsic carboxyl-terminal region of the alpha subunit and the membrane-intrinsic amino-terminal region of the beta subunit. Treatment of the transhydrogenase of E. coli with 4-chloro-7-nitrobenzo-2-oxa-1,3-diazole (NBD chloride) inhibited enzyme activity. Analysis of inhibition revealed that several sites on the enzyme were involved. NBD chloride modified two (betaCys-147 and betaCys-260) of the seven cysteine residues present in the transhydrogenase. Modification of betaCys-260 in domain 2 resulted in inhibition of enzyme activity. Modification of residues other than cysteine residues also resulted in inhibition of transhydrogenation as shown by use of a cysteine-free mutant enzyme. The beta subunit was modified by NBD chloride to a greater extent than the alpha subunit. Reaction of domain 2 and domain 3 was prevented by NADPH. Modification of domain 3 is probably not associated with inhibition of enzyme activity. Modification of domain 2 of the beta subunit resulted in a decreased binding affinity for NADPH at its binding site in domain 3. The product resulting from the reaction of NBD chloride with NADPH was a very effective inhibitor of transhydrogenation. In experiments with NBD chloride in the presence of NADPH it is likely that all of the sites of reaction described above will contribute to the inhibition observed. The NBD-NADPH adduct will likely be more useful than NBD chloride in investigations of the pyridine nucleotide transhydrogenase.

4-Chloro-7-nitrobenzofurazan↗
PubMed1999

Mutation of conserved polar residues in the transmembrane domain of the proton-pumping pyridine nucleotide transhydrogenase of Escherichia coli.

The pyridine nucleotide transhydrogenase carries out transmembrane proton translocation coupled to transfer of a hydride ion equivalent between NAD+ and NADP+. Previous workers (E. Holmberg et al. Biochemistry 33, 7691-7700, 1994; N. A. Glavas et al. Biochemistry 34, 7694-7702, 1995) had examined the role in proton translocation of conserved charged residues in the transmembrane domain. This study was extended to examine the role of conserved polar residues of the transmembrane domain. Site-directed mutagenesis of these residues did not produce major effects on hydride transfer or proton translocation activities except in the case of betaAsn222. Most mutants of this residue were drastically impaired in these activities. Three phenotypes were recognized. In betaN222C both activities were impaired maximally by 70%. The retention of proton translocation indicated that betaAsn222 was not directly involved in proton translocation. In betaN222H both activities were drastically reduced. Binding of NADP+ but not of NADPH was impaired. In betaN222R, by contrast, NADP+ remained tightly bound to the mutant transhydrogenase. It is concluded that betaAsn222, located in a transmembrane alpha-helix, is part of the conformational pathway by which NADP(H) binding, which occurs outside of the transmembrane domain, is coupled to proton translocation. Some nonconserved or semiconserved polar residues of the transmembrane domain were also examined by site-directed mutagenesis. Interaction of betaGlu124 with the proton translocation pathway is proposed.

Amino Acid Sequence↗
PubMed1999

In vivo imaging of serotonin transporters with [99mTc]TRODAT-1 in nonhuman primates.

[99mTc]TRODAT-1 was the first 99mTc-labeled imaging agent to show specific binding to dopamine transporters (DAT) in the striatum (STR) of human brain. Additionally, in vitro binding and autoradiographic experiments demonstrated that this tracer also binds to serotonin transporters (SERT) in the midbrain/hypothalamus (MB) area. In this study, [99mTc]TRODAT-1 was investigated as a potentially useful ligand to image SERT in the MB of living brain. A total of eight single-photon emission tomography (SPET) scans were performed in two baboons (Papio anubis) after intravenous (i.v.) injection of 740 MBq (20 mCi) of [99mTc]TRODAT-1 using a triple-head gamma camera equipped with ultra-high-resolution fan-beam collimators (scan time: 0-210 min). In four blocking studies, baboons were pretreated with (+)McN5652 (1 mg/kg, i.v.) or methylphenidate (1 mg/kg, i.v.) to specifically block SERT or DAT, respectively. After co-registration with magnetic resonance images of the same baboon, a region of interest analysis was performed using predefined templates to calculate specific uptake in the midbrain area and the striatum, with the cerebellum as the background region [(MB-CB)/CB, (STR-CB)/CB]. Additionally, two PET scans of the same baboons were performed after i.v. injections of 74-111 MBq (2-3 mCi) of [11C](+)McN5652 to identify the SERT sites. In [99mTc]TRODAT-1/SPET scans, the SERT sites in the MB region were clearly visualized. Semiquantitative analysis revealed a specific uptake in MB ([MB-CB]/CB) of 0.30+/-0.02, which was decreased to 0. 040+/-0.005 after pretreatment with nonradioactive (+)McN5652, a selective SERT ligand. Pretreatment with methylphenidate reduced the specific binding of [99mTc]TRODAT-1 to DAT sites [(STR-CB)/CB] from 2.45+/-0.13 to 0.32+/-0.04 without any effect on its binding to SERT sites [(MB-CB)/CB], which was confirmed by the co-registration of the [11C](+)McN5652/PET scans. This preliminary study suggests that specific binding of [99mTc]TRODAT-1 to SERT sites can be detected by in vivo SPET imaging despite the low target to background ratio. These findings provide impetus for further development of similar compounds with improved binding affinity and selectivity to SERT sites.

Adrenergic Uptake Inhibitors↗
PubMed1999

Characterization of [(123)I]IDAM as a novel single-photon emission tomography tracer for serotonin transporters.

Development of selective serotonin transporter (SERT) tracers for single-photon emission tomography (SPET) is important for studying the underlying pharmacology and interaction of specific serotonin reuptake site inhibitors, commonly used antidepressants, at the SERT sites in the human brain. In search of a new tracer for imaging SERT, IDAM (5-iodo-2-[[2-2-[(dimethylamino)methyl]phenyl]thio]benzyl alcohol) was developed. In vitro characterization of IDAM was carried out with binding studies in cell lines and rat tissue homogenates. In vivo binding of [(125)I]IDAM was evaluated in rats by comparing the uptakes in different brain regions through tissue dissections and ex vivo autoradiography. In vitro binding study showed that IDAM displayed an excellent affinity to SERT sites (K(i)=0.097 nM, using membrane preparations of LLC-PK(1) cells expressing the specific transporter) and showed more than 1000-fold of selectivity for SERT over norepinehrine and dopamine (expressed in the same LLC-PK(1) cells). Scatchard analysis of [(125)I]IDAM binding to frontal cortical membrane homogenates prepared from control or p-chloroamphetamine (PCA)-treated rats was evaluated. As expected, the control membranes showed a K(d) value of 0.25 nM+/-0.05 nM and a B(max) value of 272+/-30 fmol/ mg protein, while the PCA-lesioned membranes displayed a similar K(d), but with a reduced B(max) (20+/-7 fmol/ mg protein). Biodistribution of [(125)I]IDAM (partition coefficient =473; 1-octanol/buffer) in the rat brain showed a high initial uptake (2.44%dose at 2 min after i.v. injection) with the specific binding peaked at 60 min postinjection (hypothalamus-cerebellum/cerebellum =1.75). Ex vivo autoradiographs of rat brain sections (60 min after i.v. injection of [(125)I]IDAM) showed intense labeling in several regions (olfactory tubercle, lateral septal nucleus, hypothalamic and thalamic nuclei, globus pallidus, central gray, superior colliculus, substantia nigra, interpeduncular nucleus, dorsal and median raphes and locus coeruleus), which parallel known SERT density. This novel tracer has excellent characteristics for in vivo SPET imaging of SERT in the brain.

Animals↗