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Purpose: Preferential binding of FP-TZTP at the M2 receptor in vivo led to investigation of [18F]FP-TZTP as a potential PET tracer for Alzheimer's disease, in which a substantial reduction of M2 receptors has been observed in autopsy studies. We hereby investigated in vitro the FP-TZTP behavior to further elucidate the properties of FP-TZTP that lead to its M2 selectivity. Methods: Chinese hamster ovarian cells expressing the five subtypes of human muscarinic receptor as well as the wild type were harvested in culture to assess equilibrium binding. Specific binding was calculated by subtraction of non-specific binding from total binding. Internal specific binding was calculated by subtraction of external specific binding from the total specific binding. Saturation assays were also performed to calculate Bmax, Ki, and IC50. In addition, equilibrium binding and dissociation kinetic studies were performed on rat brain tissue. Selected regions of interest were drawn on the digital autoradiograms and [18F]FP-TZTP off-rates were determined by measurement of the rate of release into a buffer solution of [18F]FP-TZTP from slide-bound cells that had been preincubated with [18F]FP-TZTP. Results: At equilibrium in vitro, M2 subtype selectivity of [18F]FP-TZTP was not evident. We demonstrated that ATP-dependent mechanisms are not responsible for FP-TZTP M2 selectivity. In vitro off-rate studies from rat brain tissue showed that the off-rate of FP-TZTP varied with the percentage of M2 subtype in the tissue region. Conclusion: The slower dissociation kinetics of FP-TZTP from M2 receptors compared with the four other muscarinic receptor subtypes may be a factor in its M2 selectivity. [ABSTRACT FROM AUTHOR]

Fabry disease is an X-linked lysosomal disorder characterized by deficient α-galactosidase A activity and intracellular accumulations of glycosphingolipids, mainly globotriaosylceramide (Gb3). Clinically, patients occasionally present CNS dysfunction. To examine the pathophysiology underlying brain dysfunction, we examined glucose utilization (CMR[sub glc]) and cerebral blood flow (CBF) globally and locally in 18 brain structures in the α-galactosidase A gene knockout mouse. Global CMR[sub glc] was statistically significantly reduced by 22% in Fabry mice (p < 0.01). All 18 structures showed decreases in local CMR[sub glc] ranging from 14% to 33%. The decreases in all structures of the diencephalon, caudate-putamen, brain stem, and cerebellar cortex were statistically significant (p < 0.05). Global cerebral blood flow (CBF) and local CBF measured in the same 18 structures were lower in Fabry mice than in control mice, but none statistically significantly. Histological examination of brain revealed no cerebral infarcts but abundant Gb3 deposits in the walls of the cerebral vessels with neuronal deposits localized to the medulla oblongata. These results indicate an impairment in cerebral energy metabolism in the Fabry mice, but one not necessarily due to circulatory insufficiency. [ABSTRACT FROM AUTHOR]

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Human cord dorsum potential (CDP) was recorded from the posterior epidural space at the levels of cervical and lumbar enlargements, using epidural catheters as the recording electrodes, in 15 normal volunteers and six patients suffering from amyotrophic lateral sclerosis. In normal subjects the CDP elicited by descending volleys consisted of spike potentials followed by sharp negative and slow positive waves which were very similar to the P1, N1, and P2 potentials, respectively, of the CDP evoked segmentally. By contrast, in all patients with amyotrophic lateral sclerosis both the sharp negative and slow positive waves were absent in the CDP elicited by descending volleys, while the pattern of each component of the segmentally evoked CDP remained unchanged. Thus, the sharp negative and slow positive waves of human CDP elicited by descending volleys might reflect the activity of interneurones and primary afferent depolarisation respectively, produced by impulses through the corticospinal tract. [ABSTRACT FROM AUTHOR]