Enantioselective assembly of tertiary stereocenters via multicomponent chemoselective cross-coupling of geminal chloro(iodo)alkanes.

Tertiary stereocenters represent a ubiquitous and highly important motif in many pharmaceutically active compounds and natural products. Development of efficient and straightforward approaches to their enantioselective construction from readily available simple substrates is an important yet challenging goal for synthetic chemistry. Herein we describe an efficient, versatile and facile method for the highly enantioselective construction of tertiary stereocenters via unprecedented consecutive one-pot Suzuki reactions of non-activated racemic 1-chloro-1-iodoalkanes with alkylboranes. It represents the first cross-coupling approach which employs simple and readily available primary alkyl substrates for the direct multicomponent assembly of enantioenriched tertiary stereocenters. A simple and effective preparation of 1-chloro-1-iodoalkanes from ubiquitous α-chloroalkanoic acids is also described. Collectively, the developed methods open a door to efficient catalytic enantioselective synthesis of alkanes bearing tertiary stereocenters from carboxylic acids just in few steps.

[123I]IPCIT and [123I]beta-CIT as SPECT tracers for the dopamine transporter: a comparative analysis in nonhuman primates.

[123I]2beta-carbomethoxy-3beta-(4-iodophenyl)tropane ([123I]-CIT) and its isopropylester analog [123I]PCIT, both of which are phenyltropane derivatives of cocaine with high affinity for the dopamine (DA) transporter, were compared using single photon emission computed tomography in nonhuman primates. Although IPCIT is significantly more selective for the DA transporter than beta-CIT, striatal distribution volumes of specifically bound tracer were similar for both tracers. Compartmental modeling results were compared with a simple peak equilibrium method used previously by this group. The peak equilibrium method is shown to overestimate striatal distribution volumes, primarily due to a difference in the calculated time of peak specific uptake.

Light and electron microscopic analysis of controlled injury to follicular unit grafts.

BACKGROUND: Careful manipulation of hair units is essential for a good yield of transplanted hair. OBJECTIVE: To analyze the morphology of dissected follicular units submitted to crushing, stretching, bending, and drying. METHODS: Follicular units were either crushed, bent, stretched with forceps, or left drying on surgical gloves for 3 minutes. The specimens were fixed and prepared for observation with light microscopy or transmission and scanning electron microscopy. RESULTS: No alterations were detected in follicular units that had been crushed, bent, or stretched. Major damage occurred in samples that were left to dry on gloves. CONCLUSION: Letting the follicular unit dry appears to be the worst mishandling to which the follicular units may be subjected during routine hair transplantation.

Standardizing the classification and description of follicular unit transplantation and mini-micrografting techniques. The American Society for Dermatologic Surgery, Inc.

Previous attempts at classifying small graft transplants have focused mainly upon graft size and have not taken into consideration other technical factors involved in graft production that may influence the outcome of the surgery. The proposed classification attempts to consider these factors by including various technical aspects of harvesting, dissection, and placement, all of which impact the quality and quantity of the small grafts used in the procedure. By standardizing the nomenclature, as well as the description of the other factors involved in the surgery, communication between physicians and patients may be facilitated. In addition, different procedures may be more accurately studied and compared.

SPECT imaging of dopamine transporters in human brain with iodine-123-fluoroalkyl analogs of beta-CIT.

Iodine-123-2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane (beta-CIT) is a useful SPECT tracer for imaging the dopamine transporter. Its slow kinetics, however, necessitate imaging on the day after the injection. Two N-omega-fluoroalkyl analogs of beta-CIT, the fluoropropyl and fluoroethyl compounds (beta-CIT-FP and beta-CIT-FE, respectively), characterized by faster kinetics in baboons, were tested in humans as potential tracers for the dopamine transporter. Four healthy volunteers were injected with [123I]-beta-CIT-FP and another four were injected with [123I]beta-CIT-FE. SPECT data were acquired for 1149 +/- 590 min and 240 +/- 30 min, respectively. Both tracers demonstrated high brain uptake (6.37% +/- 0.37% and 7.8% +/- 1.5% of the injected dose, respectively). Activity concentrated with time in the striatal area, reaching a peak within 30 min, with little or no washout for [123I]beta-CIT-FP and a faster washout for [123I]beta-CIT-FE (14.7% +/- 6.9%). Occipital and midbrain activity showed similar patterns, displaying a peak within 15 min and rapid washout, followed by stable levels at approximately 100 min for both tracers. The ratio of peak specific striatal-to-peak specific midbrain activity was 9.1 +/- 1.8 for [123I]beta-CIT-FP and 7.7 +/- 0.7 for [123I]beta-CIT-FE, showing high in vivo selectivity for the dopamine transporter. These preliminary results suggest that both compounds could be used as SPECT (labeled with 123I) or PET (labeled with 18F) radiotracers to image the dopamine transporters in the living human brain.

Reproducibility of SPECT measurement of benzodiazepine receptors in human brain with iodine-123-iomazenil.

UNLABELLED: Iodine-123-iomazenil is a SPECT radiotracer used to image and quantify benzodiazepine receptors. The reproducibility of the measurement of benzodiazepine receptors in human brain with [123I]iomazenil and SPECT was investigated with a test/retest paradigm. METHODS: Six subjects underwent two experiments during a 1-wk interval. Iodine-123-iomazenil was injected as a single bolus (12 mCi). The time-activity curves of the tracer in the arterial plasma were measured and corrected for metabolites. Regional time-activity curves of five brain regions were measured with the CERASPECT camera for 145 min postinjection with serial 2-min acquisitions. Data were analyzed using three kinetic models that included a two-compartment model, an unconstrained three-compartment model and a three-compartment model with a constraint on the nondisplaceable compartment. RESULTS: The results from the various analyses and fitting strategies were compared. The variability (average absolute difference between test and retest, expressed as a percentage of the mean of both measurements) was 10% to 17%, depending on the outcome measure and the fitting procedure. The most reproducible outcome measure was the regional tracer distribution volume relative to the total arterial concentration (VT'). VT' showed an average regional variability of 10% +/- 2%, with an intraclass correlation coefficient of 0.81. CONCLUSION: SPECT measurement of regional [123I]iomazenil VT' is reproducible and reliable. The use of regional ratios results in a significant loss of information.

Comparison of [123I]beta-CIT and [123I]IPCIT as single-photon emission tomography radiotracers for the dopamine transporter in nonhuman primates.

Single-photon emission tomographic (SPET) imaging with the radiotracer [123I]2 beta-carbomethoxy-3 beta-(4-iodophenyl)tropane ([123I]beta-CIT) has been reported to be a useful in vivo measure of dopamine (DA) transporters. However, in addition to its high DA transporter affinity, beta-CIT also binds with high affinity to serotonin (5-HT) transporters. 2 beta-Carboisopropoxy-3 beta-(4-iodophenyl)tropane (IPCIT) has been demonstrated by in vitro studies to have higher selectivity for the DA transporter. We compared [123I]beta-CIT and [123I]IPCIT SPET imaging and plasma metabolite analyses in baboons to evaluate the potential advantages of [123I]IPCIT for quantitative in vivo measurements of DA transporter densities. Both tracers had low levels (2% of total plasma 123I activity) of lipophilic radiolabeled metabolites at 420 min. [123I]IPCIT had significantly higher binding to plasma proteins. The average percent free (nonprotein bound) [123I]beta-CIT and [123I]IPCIT were 52% +/- 7% and 14% +/- 6%, respectively. Region of interest uptake data were normalized by injected dose and body weight. Consistent with the high density of 5-HT transporters in the midbrain and the lower 5-HT transporter affinity of IPCIT, the normalized peak specific midbrain uptake of [123I]beta-CIT (1.7 +/- 0.5) was higher than that of [123I]IPCIT (0.4 +/- 0.2). Consistent with its greater lipophilicity, [123I]IPCIT had higher nonspecific uptake, such that normalized cerebellar uptake of [123I]IPCIT was about twice that of [123I]beta-CIT. The ratio of specific to nonspecific uptake in striatum was greater for [123I]beta-CIT compared to [123I]IPCIT; however, striatal binding potentials and distribution volumes were not significantly different.(ABSTRACT TRUNCATED AT 250 WORDS)

Evaluation of ultrafiltration for the free-fraction determination of single photon emission computed tomography (SPECT) radiotracers: beta-CIT, IBF, and iomazenil.

An ultrafiltration system was evaluated for the free-fraction measurement of SPECT radiotracers (beta-CIT, IBF, and iomazenil) used in functional brain imaging. The effect of temperature, storage, centrifugal force, tracer concentration, and percentage filtered demonstrated a relative error of < 9%. As a result of the minimal temperature effect, 25 degrees C was employed for all measurements. A comparison of the ultrafiltration system with equilibrium dialysis revealed < 5% difference for beta-CIT and iomazenil, but 16% for IBF. Additionally, the time and ease of operation considerably favored the ultrafiltration system. The precision quantitated by repetition was < 6% for between-run and within-run variability. In conclusion, ultrafiltration provided rapid results, demonstrated minor analytical errors, revealed generally good correlation with equilibrium dialysis, and allowed excellent precision.

Review of carbamazepine-induced hyponatremia.

1. Carbamazepine (CBZ), a commonly prescribed medication in psychiatry and neurology, produces deleterious side effects with an incidence rate ranging from 33-50%; although most of these side effects are mild, transient, and reversible. CBZ-induced hyponatremia is a moderately well described side effect and may be responsible for some of the more highly reported signs and symptoms associated with CBZ adverse effects. 2. Data from case reports and clinical studies are examined to ascertain the characteristics of CBZ-induced hyponatremia. Predisposing risk factors such as: age, dosage/level of CBZ, and polypharmacy have been explored in numerous clinical studies; however, minimal consensus has been found regarding both dosage/level of CBZ and polypharmacy as a predisposing risk factor, whereas age is most probably not a predisposing risk factor in CBZ-induced hyponatremia. 3. Mechanistic studies, both clinical and basic science, also fail to acknowledge the mechanism for the antidiuretic effect of CBZ. The most probable mechanism involves an alteration in either the sensitivity or set point of the osmoreceptor.