Transferrin sialic acid contents of patients with hereditary hemochromatosis

Recent evidence suggests that asialotransferrin may enhance hepatic uptake of trivalent metal ions through the asialoglycoprotein-receptor pathway. In hereditary hemochromatosis, there is preferential uptake of iron by hepatocytes. We purified transferrin from two patients with this disease. Their transferrins had normal electrophoretic patterns and contained normal amounts of sialic acid. We conclude that the preferential uptake of iron by hepatocytes in hereditary hemochromatosis is not due to the presence of asialotransferrin in their plasma.     

Kinetic analysis of [11C]McN5652: a serotonin transporter radioligand.

The impulse response function of a radioligand is the most fundamental way to describe its pharmacokinetics and to assess its tissue uptake and retention pattern. This study investigates the impulse response function of [11C](+)McN5652, a radioligand used for positron emission tomography (PET) imaging of the serotonin transporter (SERT) in the brain. Dynamic PET studies were performed in eight healthy volunteers injected with [11C](+)McN5652 and subsequently with its pharmacologically inactive enantiomer [11C](-)McN5652. The impulse response function was calculated by deconvolution analysis of regional time-activity curves, and its peak value (f(max)), its retention value at 75 minutes (fT), and its normalized retention (f(rel) = fT/f(max)) were obtained. Alternatively, compartmental models were applied to calculate the apparent total distribution volume (DV(T)) and its specific binding component (DV(S)). Both the noncompartmental (fT,f(rel)) and the compartmental parameters (DV) were investigated with and without correction for nonspecific binding by simple subtraction of the corresponding value obtained with [11C](-)McN5652. The impulse response function obtained by deconvolution analysis demonstrated high tracer extraction followed by a slow decline in the form of a monoexponential function. Statistical analysis revealed that the best compartmental model in terms of analysis of variance F and condition number of the parameter variance-covariance matrix was the one that was based on a single tissue compartment with parameters k1 and k2 and that also included the parameter of regional cerebral blood volume (BV). The parameter f(rel) demonstrated low between-subject variance (coefficient of variation [CV] = 19%), a midbrain to cerebellum ratio of 1.85, and high correlation with the known density of SERT (r = 0.787 where r is the coefficient of linear correlation between the parameter and the known density of SERT). After correction for nonspecific binding, f(rel) demonstrated further improvement in correlation (r = 0.814) and midbrain to cerebellum ratio (3.09). The variance of the distribution volumes was acceptable when the logarithmic transform lnDV was used instead of DV (17% for the three-parameter model), but correlation of this compartmental parameter was slightly less (r = 0.652 for the three-parameter model) than the correlation of the noncompartmental f(rel) with the known density of SERT, and the midbrain to cerebellum ratio was only 1.5 (uncorrected) and 1.8 (corrected). At the expense of increasing variance, the correlation was increased after correction for nonspecific binding using the inactive enantiomer (r = 0.694; CV = 22%). These results indicate that the kinetics of [11C](+)McN5652 can best be described by a one-tissue compartment model with three parameters (k1, k2, and BV), and that both the noncompartmental parameter f(rel) and the compartmental distribution volumes have the potential for quantitative estimation of the density of SERT. Further validation of the radioligand in experimental and clinical situations is warranted.     

Nicotine induced up-regulation of nicotinic receptors in CD-1 mice demonstrated with an in vivo radiotracer: Gender differences

Up-regulation of brain nicotinic receptors (nAChRs) by chronic nicotine treatment has chiefly been demonstrated by in vitro binding assays. Here, we report that up-regulation of nAChRs in CD-1 mice can be detected using a specific in vivo radioligand for nAChRs, [¹²⁵I]IPH. After 10 days of (−)-nicotine administration, male and female mice demonstrated a significant elevation of [¹²⁵I]IPH binding in all brain regions studied. [¹²⁵I]lPH uptake also displayed significant gender differences with male animals showing a more pronounced increase in [¹²⁵I]IPH accumulation. Synapse 29: 116–118, 1998. © 1998 Wiley-Liss, Inc.     

In vivo detection of short- and long-term MDMA neurotoxicity—a positron emission tomography study in the living baboon brain

The present study evaluated short- and long-term effects of MDMA (3,4-methylenedioxymethamphetamine) in the baboon brain using PET and [¹¹C](+)McN 5652, a potent 5-HT transporter ligand, as well as [¹¹C]RTI-55, a cocaine derivative which labels both 5-HT and dopamine transporters. Following baseline PET scans with [¹¹C](+)McN5652, [¹¹C](−)McN5652 (the inactive enantiomer of the active enantiomer [¹¹C](+)McN5652) and [¹¹C]RTI-55, a baboon was treated with MDMA (5 mg/kg, s.c., twice daily for four consecutive days). PET studies at 13, 19, and 40 days post-MDMA revealed decreases in mean radioactivity levels in all brain regions when using [¹¹C](+)McN 5652, but not with [¹¹C](−)McN5652 or [¹¹C]RTI-55. Reductions in specific [¹¹C](+)McN5652 binding (calculated as the difference in radioactivity concentrations between (+) and (−)[¹¹C]McN5652) ranged from 44% in the pons to 89% in the occipital cortex. PET studies at 9 and 13 months showed regional differences in the apparent recovery of 5-HT transporters, with increases in some brain regions (e.g., hypothalamus) and persistent decreases in others (e.g., neocortex). Data obtained from PET studies correlated well with regional 5-HT axonal marker concentrations in the CNS measured after sacrifice of the animal. The results of these studies indicate that PET imaging of the living nonhuman primate brain with [¹¹C](+)McN 5652 can detect changes in regional 5-HT transporter density secondary to MDMA-induced neurotoxicity. Using PET, it should also be feasible to use [¹¹C](+)McN5652 to determine whether human MDMA users are also susceptible to MDMA's neurotoxic effects. Synapse 29:183–192, 1998. © 1998 Wiley-Liss, Inc.