Diffuse optical spectroscopic imaging of subcutaneous adipose tissue metabolic changes during weight loss.

BACKGROUND: Changes in subcutaneous adipose tissue (AT) structure and metabolism have been shown to correlate with the development of obesity and related metabolic disorders. Measurements of AT physiology could provide new insight into metabolic disease progression and response to therapy. An emerging functional imaging technology, diffuse optical spectroscopic imaging (DOSI), was used to obtain quantitative measures of near infrared (NIR) AT optical and physiological properties. METHODS: Ten overweight or obese adults were assessed during 3 months on calorie-restricted diets. DOSI-derived tissue concentrations of hemoglobin, water and lipid and the wavelength-dependent scattering amplitude (A) and slope (b) obtained from 30 abdominal locations and three time points (T0, T6, T12) were calculated and analyzed using linear mixed-effects models and were also used to form 3D surface images. RESULTS: Subjects lost a mean of 11.7±3.4% of starting weight, while significant changes in A (+0.23±0.04 mm(-1), adj. P<0.001),b (-0.17±0.04, adj. P<0.001), tissue water fraction (+7.2±1.1%, adj. P<0.001) and deoxyhemoglobin (1.1±0.3 µM, adj. P<0.001) were observed using mixed-effect model analysis. DISCUSSION: Optical scattering signals reveal alterations in tissue structure that possibly correlate with reductions in adipose cell volume, while water and hemoglobin dynamics suggest improved AT perfusion and oxygen extraction. These results suggest that DOSI measurements of NIR optical and physiological properties could be used to enhance understanding of the role of AT in metabolic disorders and provide new strategies for diagnostic monitoring of obesity and weight loss.

Structure-activity relationships at monoamine transporters and muscarinic receptors for N-substituted-3alpha-(3'-chloro-, 4'-chloro-, and 4',4''-dichloro-substituted-diphenyl)methoxytropanes.

The design, synthesis, and evaluation of 3alpha-(diphenylmethoxy)tropane (benztropine) analogues have provided potent and selective probes for the dopamine transporter. Structure-activity relationships (SARs) have been developed that contrast with those described for cocaine, despite significant structural similarity. Furthermore, behavioral evaluation of many of the benztropine analogues in animal models of cocaine abuse has suggested that these two classes of tropane-based dopamine uptake inhibitors have distinct pharmacological profiles. In general, the benztropine analogues do not demonstrate efficacious locomotor stimulation in mice, do not fully substitute for a cocaine discriminative stimulus, and are not appreciably self-administered in rhesus monkeys. These compounds are generally more potent than cocaine as dopamine uptake inhibitors in vitro, although their actions in vivo are not consistent with this action. These observations suggest that differing binding profiles at the serotonin and norepinephrine transporters as well as at muscarinic receptors might have significant impact on the pharmacological actions of these compounds. In addition, by varying the structures of the parent compounds and thereby modifying their physical properties, pharmacokinetics as well as pharmacodynamics will be directly affected. Therefore, in an attempt to systematically evaluate the impact of chemical modification on these actions, a series of N-substituted (H, CH3, allyl, benzyl, propylphenyl, and butylphenyl) analogues of 3'-chloro-, 4'-chloro-, and 4,4''-dichloro-3alpha-(diphenylmethoxy)tropanes were synthesized. These compounds were evaluated for displacement, in rat tissue, of [3H]WIN 35,428 from the dopamine transporter, [3H]citalopram from the serotonin transporter, [3H]nisoxetine from the norepinephrine transporter, and [3H]pirenzepine from muscarinic m1 receptors. SARs were developed and compared to a series of N-substituted-3alpha-(bis-4'-fluorophenyl)methoxytropanes. The present SARs followed previously reported studies with the single exception of the N-butylphenyl substituent, which did not provide the high affinity binding in any of these three sets of analogues, as it did in the 4',4''-difluoro series. X-ray crystallographic analyses of the three parent ligands (1a, 2a, and 3a) were compared to that of 3alpha-(bis-4'-fluorophenyl)methoxytropane which provided supportive evidence toward the proposal that the combination of steric bulk in both the 3-position and the N-substituent, in this class of compounds, is not optimal for binding at the dopamine transporter. These studies provide binding profile data that can now be used to correlate with future behavioral analyses of these compounds and may provide insight into the kind of binding profile that might be targeted as a potential treatment for cocaine abuse.