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18F Labelled MR18445 (4-[4-(4-[18F]fluorobenzyl)piperazino]-7-methoxypyrrolo++ +[1,2-alpha] quinoxaline), a selective 5-HT3 receptor partial agonist with nanomolar affinity, was synthesized and examined as a potential radioligand for PET imaging of brain 5HT3 receptors. Radiotracer was prepared by N-alkylation of the MR18491 precursor with 4-[18F]fluorobenzyl iodide. This latter was synthesized in a three-step procedure from 4-[18F]fluorobenzaldehyde obtained by 18F-nucleophilic displacement of 4-nitrobenzaldehyde, subsequently reduced to 4-[18F]fluorobenzyl alcohol and converted into reactive 4-[18F]fluorobenzyl iodide. The reduction step was performed on a column filled with NaBH4/Al2O3 and 4-[18F]fluorobenzyl alcohol was obtained with high reproducible yield (82-93% from 4-[18F]fluorobenzaldehyde) if there were traces of water in the system. The radiosynthesis of [18F]MR18445 required approximately 120 min. Semi-preparative HPLC purification followed by formulation gave injectable solutions of [18F]MR18445 with a radiochemical purity > 99%. The overall yield of the synthesis was mainly dependent upon the first step efficiency of aromatic incorporation of 18F- and varied from 12% to 29%. All the synthetic procedure was realized on a ZYMARK robotic system. Biological in vivo studies in rats showed that uptake of [18F]MR18445 in brain was rapid and high. No evidence of radiolabeled metabolites could be observed in the brain as late as 40 min after injection, despite the rapid appearance of metabolites in the plasma. However, neither phosphorimaging autoradiographic studies in rats nor PET experiments in baboons revealed specific binding of the radiotracer in brain, suggesting [18F]MR18445 is not suitable for 5-HT3 receptors PET studies.

The present study was designed to search for concomitant age-related changes in memory subsystems, defined according to current structural theories, and resting oxygen consumption in selected brain regions. We have investigated a sample of subjects between 20 and 68 years of age and strictly screened for their good health. We applied in the same subjects a battery of neuropsychological tests selected to investigate several memory subsystems, and high-resolution positron imaging with stereotaxic localization to study a purposely limited number of cerebral structures, selected on a priori hypotheses to match the different memory subsystems. Our results showed significant age-related changes in performance on some tests, consistent with the literature, including an increase in semantic memory and a decrease in both working memory (central executive system) and verbal episodic and explicit memory. There was also an age-related linear decrease in global brain oxygen consumption which regionally reached statistical significance for the neocortical areas and the left thalamus. There was a limited number of significant, age-independent correlations between the raw psychometric test scores and resting regional oxidative metabolism. Consistent with our present understanding of the functional anatomy of memory, the Associate Learning scores (verbal episodic and explicit memory) were positively correlated with left hippocampal and thalamic metabolism. The positive relationships found between right hippocampal metabolism and performance in the Associate Learning and the Brown-Peterson tests were less expected but would be consistent with findings from recent PET activation studies. The results from this investigation are discussed in the light of current knowledge concerning the neuropsychology and the neurobiology of both aging and memory.

A 60-year-old lady with previous hypertension was studied with PET in the acute (early recovery) phase of an otherwise typical episode of transient global amnesia (TGA). Follow-up over > 1 year was uneventful, and delayed CT scans and MRI showed no brain damage. No medical cause was disclosed despite extensive work-up. The PET study revealed a matched reduction in cerebral blood flow and oxygen consumption over the entire lateral frontal cortex on the right side, with an associated, less significant reduction in ipsilateral thalamic and lentiform nucleus metabolism, but sparing the hippocampal area. These changes, which had resolved at a repeat PET study 3 months later, suggest right prefrontal metabolic depression, possibly secondary to thalamic dysfunction, as the underlying mechanism for TGA in this case, consistent with the emerging involvement of the prefrontal cortex in strategies or control of memory traces retrieval. Thus, in analogy with permanent amnesia, TGA may be a core syndrome with several possible foci of dysfunction along the neuronal networks that subserve explicit memory. In the future, combined PET neuropsychological assessment in the acute stage of TGA may prove useful in defining distinct neuropsychological—topographical subtypes of this intriguing clinical entity.

The drug MDL 72222, a selective 5-HT3 receptor antagonist, was labelled with 11C and evaluated for distribution kinetics in brain and in vivo binding to 5-HT3 receptors using cold MDL 72222 challenge and positron emission tomography (PET), in three anaesthetized baboons. After tracer doses of [11C]MDL 72222 (i.v. bolus), 11C radioactivity was equally partitioned between plasma and blood cells and readily crossed the blood-brain barrier; it was distributed heterogeneously into 17 different structures of the brain. The kinetic curves for 11C in tissue showed a rapid initial uptake, followed by a slower ascending phase, up to about the twentieth minute and by a plateau, until the end of experiment (90 min). The plateau values indicated marked uptake in brain which, however, varied according to the region considered. In inhibition studies with cold MDL 72222 (1 mg·kg−1) as pretreatment, co-injection or displacement, no clear-cut effects on the kinetics of [11C]MDL 72222 in brain were detected in any region, including those known to be rich in 5-HT3 receptors. These observations suggest that specific binding to 5-HT3 receptors was not detectable in brain in vivo, because of the high lipophilicity (thus a great capacity for non-specific binding) of MDL 72222. These negative findings may also result from both the possible suboptimal affinity of MDL 72222 for 5-HT3 receptors in vivo and the relatively low density of 5-HT3 receptors present only in selected areas of the mammalian brain. This study is a step in the search of selective 5-HT3 receptor radioligands, adequate for in vivo applications. Slow clearance of[11C]MDL 72222 from brain tissue in baboons, should be accounted for in clinical pharmacokinetic investigations for optimal posology considerations.

Studies of central benzodiazepine receptors in the human brain in vivo are now possible using positron emission tomography (PET) and [11C]flumazenil. With the aim of measuring Bmax and Kd in brain regions, we used a two-injection [11C]flumazenil (at high and low specific radioactivity, respectively) pseudo-equilibrium paradigm to evaluate, in seven unmedicated healthy volunteers, the relative merits of three 'reference' structures (pons, hemispheric white matter and corpus callosum) in which the free radioligand concentration in brain tissue was estimated 15-40 min after i.v. injection of the radioligand. By means of high-resolution PET, the Bmax and Kd were calculated for each subject in 18 gray matter structures, based on a two-point Scatchard plot. We found that the use of the corpus callosum as reference often resulted in spurious Bmax and Kd values. The pons was the best reference structure because it provided satisfactory Bmax values (closest to in vitro data) and most consistent Kd values, and was the region easiest to sample on PET images. The pattern of regional Bmax was consistent with that expected from in vitro studies, with values highest in the cerebral cortex, intermediate in the cerebellum, and lowest in the striatum and the thalamus. The Kd values were uniform among regions and were consistent with earlier in vitro and in vivo data. This work documents the feasibility of estimating Bmax and Kd of central benzodiazepine receptors in multiple brain regions for clinical research.

In most positron emission tomography (PET) radioligand models, it is assumed, but rarely proven, that nonspecific (NS) binding in the target structure is equal to that in the reference structure. [18F]Setoperone is a well-validated and widely used PET radioligand for the study of neocortical 5HT2A receptor (5HT2A R). Single-experiment modeling to quantitate neocortical 5HT2A R binding potential (or k3/k4) used the cerebellum as reference structure because it is virtually devoid of 5HT2A R. Previous studies supported the use of cerebellum as reference in both the baboon and the human, but a quantitative estimation of NS binding was not carried out. Thus the aim of this study was to estimate NS binding directly in both species. Four young healthy volunteers were studied before and after 2 weeks of daily doses of an atypical neuroleptic possessing strong 5HT2A R antagonist activity. Presaturation PET experiments were carried out in three baboons 10 min after injection of a large amount of cold setoperone. In both species, visual inspection of the time-activity curves (TACs) indicated full saturation of specific binding in the neocortex without effect on the cerebellum, but neocortical TACs fell below cerebellum TACs after ~ 20 min in humans. Cerebellum TACs were fitted (3-Cpt model), providing the k5/k6 ratio and the f2 fraction. The control neocortical TACs were fitted (4-Cpt model) assuming NS binding similar to cerebellum, providing k3, k4, and the k3/k4 ratio, whereas treated neocortical TACs could be fitted only with a 3-Cpt model (i.e., k3/k4 = 0). NS binding for the neocortex in the treated condition, expressed as the f2 fraction, was significantly larger (i.e., NS binding was smaller) than that estimated for the cerebellum in human but not in baboon studies. Modeling of control human studies showed that the use of the cerebellum as reference would result in significant underestimations of the neocortical k3/k4 ratio by about 30%. This study suggests that NS binding is uniform in baboons, but is lower in the neocortex compared to the cerebellum in humans. Based on these data however, a systematic correction factor may be applied in future human studies as a convenient way to correct for this uneven distribution in NS binding.

A dissociation in the central processes of spelling, with preferentially lexical over phonological impairment, frequently affects patients with early Alzheimer's disease. The aim of this work was to test whether dissociations in the language domain in Alzheimer's disease can be exploited with PET to assess the neural basis of cognition. To this end, we studied the functional neuroanatomy of writing impairment in Alzheimer's disease by means of PET measurements of the local cerebral glucose utilization and neuropsychological tests specially designed to assess the phonological and lexical components of writing. We analysed the performance in written spelling of irregular words and non-words of 11 right-handed patients with mild-to-moderate Alzheimer's disease. For each patient, we calculated a residual phonological score and a residual lexical score, based on a cognitive interpretation of the errors according to the item category. In each of these 11 patients, using PET, we measured the resting-state utilization of glucose in the left supramarginal gyrus and the left angular gyrus, two cortical regions selected a priori because of their presumed role in the central processes for spelling, and identified on CT scans obtained according to stereotaxic references and coregistered with PET. To assess the relationships between the neuropsychological scores and the metabolic data, we used th e ‘ratio paradigm’, the sensitivity of which has been previously documented in cognitive-metabolic correlative PET studies of Alzheimer's disease that were less focused than the present study in both cognitive and anatomical terms. We found a highly significant positive correlation between phonological score: lexical score neuropsychological ratios and corresponding supramarginal gyrus: angular gyrus metabolic ratios. These findings further support the role of these two left-sided temporo-parietal regions in the central processes of writing and show that the neuropsychological dissociations in early Alzheimer's diseases can be exploited to further our understanding of the functional neuroanatomy of cognitive operations. The role of focal, as compared with more diffuse, brain damage in the development of impaired written language of central origin in Alzheimer's disease is also discussed.