The synthesis of [26,27-11C]dihydroxyvitamin D(3), a tracer for positron emission tomography (PET).

1Alpha,25-dihydroxyvitamin D(3), an endogenous ligand with the highest affinity for the vitamin D receptor (VDR), was labeled with 11C for use in biological experiments. The radionuclide was incorporated via the reaction of [11C]methyllithium on a methyl ketone precursor in tetrahydrofuran at -10 degrees C. Deprotection of the labeled intermediate yielded 2.5-3 GBq [26,27-11C]1alpha,25-dihydroxyvitamin D(3) [11C-1,25(OH)(2) D(3)] with specific radioactivity averaging 100 GBq/micromol at the end of synthesis and HPLC purification. The entire process took 48 min from the end of radionuclide production. In vitro binding experiments in rachitic chick purified VDR demonstrated the high affinity binding of this novel tracer. Thus; 11C-1,25(OH)(2) D(3) is available for in vivo distribution studies and may be suitable for the positron emission tomography (PET) determination of VDR levels and occupancy in animals and humans.

In vivo positron emission tomography studies on the novel nicotinic receptor agonist [11C]MPA compared with [11C]ABT-418 and (S)(-)[11C]nicotine in rhesus monkeys.

The novel 11C-labeled nicotinic agonist (R,S)-1-[11C]methyl-2(3-pyridyl)azetidine ([11C]MPA) was evaluated as a positron emission tomography (PET) ligand for in vivo characterization of nicotinic acetylcholine receptors in the brain of Rhesus monkeys in comparison with the nicotinic ligands (S)-3-methyl-5-(1-[11C]methyl-2-pyrrolidinyl)isoxazol ([11C]ABT-418) and (S)(-)[11C]nicotine. The nicotinic receptor agonist [11C]MPA demonstrated rapid uptake into the brain to a similar extent as (S)(-) [11C]nicotine and [11C]ABT-418. When unlabeled (S)(-)nicotine (0.02 mg/kg) was administered 5 min before the radioactive tracers, the uptake of [11C]MPA was decreased by 25% in the thalamus, 19% in the temporal cortex, and 11% in the cerebellum, whereas an increase was found for the uptake of (S)(-)[11C]nicotine and [11C]ABT-418. This finding indicates specific binding of [11C]MPA to nicotinic receptors in the brain in a simple classical displacement study. [11C]MPA seems to be a more promising radiotracer than (S)(-)[11C]nicotine or [11C]ABT-418 for PET studies to characterize nicotinic receptors in the brain.

A novel subtype of prostacyclin receptor in the central nervous system.

Recently, in the course of our search for the prostacyclin receptor in the brain, we found a novel subtype, designated as IP2, which was finely discriminated by use of the specific ligand (15R)-16-m-tolyl-17,18,19,20-tetranorisocarbacyclin (15R-TIC) and specifically localized in the rostral part of the brain. In the present study, the tritiated compound 15R-[15-(3)H]TIC was synthesized and utilized for more specific research on IP2. The specificity of binding to rat brain regions was confirmed by use of several prostacyclin derivatives including 15S-TIC. Mapping of 15R- and 15S-[3H]TIC binding in adjacent pairs of frozen sections of rat brain demonstrated a quite similar pattern of distribution in almost all rostral brain regions, indicating that the regions may contain only the IP2 subtype. On the other hand, 15R-[3H]TIC binding was very faint as compared with 15S-[3H]TIC binding in the caudal medullary region. High densities of 15R-[3H]TIC binding sites were shown in the dorsal part of the lateral septal nucleus, thalamic nuclei, limbic structures, and some of the cortical regions. Scatchard plot analysis showed two components of high-affinity 15R-[3H]TIC binding in the rostral regions, one with a K(D) value at approximately 1 nM and the other with approximately 30 nM. These results strengthen our previous finding that a different subtype of prostacyclin receptor is expressed in the CNS, and the map with 15R-[3H]TIC obtained here could guide further studies on the molecular and functional properties of the IP2.

[PET as a tool in pharmacologic development]. / PET som hjälpmedel i läkemedelsutveckling.

Positron emission tomography (PET) allows the in vivo recording of tracer compounds with respect to anatomical distribution, time course and absolute concentration. These features has proven of great value in drug development, especially in the phase of early clinical trials. PET can be used to assess the tissue kinetics of a new drug, or to evaluate a drugs interaction with a target system and thereby aid in decisions regarding dosing regimes.

Functional neuroanatomical correlates of electrodermal activity: a positron emission tomographic study.

To reveal areas in the central nervous system of importance for electrodermal control, regional cerebral blood flow (rCBF) was correlated to nonspecific skin conductance fluctuations (NSF) during aversive and nonaversive conditions. Participants viewed a TV screen displaying white noise or snake videotapes presented both with and without electric shocks given to the right hand. H2 15 O positron emission tomography was used to measure rCBF, and the constant voltage technique was used to measure NSF from the left hand. Electrodermal activity was positively related to rCBF in the left primary motor cortex (MI, Brodmann's Area 4) and bilaterally in the anterior (Areas 24 and 32) and posterior cingulate cortex (Area 23). Negative relations were observed bilaterally in the secondary visual cortex (Areas 18 and 19) and the right inferior parietal cortex (Area 39), with a tendency also for the right insular cortex (Areas 13, 15, and 16). Because results from lesion and stimulation studies in humans converge with the present imaging results, we conclude that the cingulum and the motor cortex, in addition to the parietal and possibly the insular cortex, form part of one or several distributed neural network(s) involved in electrodermal control. Because these areas also support anticipation, affect, and locomotion, electrodermal responses seem to reflect cognitively or emotionally mediated motor preparation.

Differential effects of levodopa on dopaminergic function in early and advanced Parkinson's disease.

The effect of levodopa on L-[11C]DOPA influx rate was evaluated in patients with early and advanced Parkinson's disease (PD) by using positron emission tomography (PET). The patients were scanned both drug-free and after a subsequent therapeutic levodopa infusion. Regional analysis of striatal L-[11C]DOPA influx rate showed a correlation to the degenerative loss of nerve terminals reported at postmortem analysis in PD. Levodopa induced markedly differential effects on the striatal L-[11C]DOPA influx rate in early and advanced patients. In patients with mild PD, levodopa infusion decreased L-[11C]DOPA influx, whereas in patients with advanced PD, levodopa induced significant upregulation of L-[11C]DOPA influx. These changes were confined to the putamen and were, in both patient categories, most prominent in the dorsal part of the region. The present investigation demonstrates a marked shift in the modulatory action of levodopa with the advancement of PD and suggests the induction of positive feedback in advanced PD. These findings could help explain the less graded clinical response to levodopa in advanced PD and would thus have importance for the understanding of the pathogenesis underlying motor fluctuations.

Effect of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin and infusion of L-tyrosine on the in vivo L-[beta-11C] DOPA disposition in the monkey brain.

The effect of 6R-L-erythro-5,6,7,8-tetrahydrobiopterin (6R-BH4) and L-tyrosine infusion on [11C]dopamine synthesis was analyzed in the striatum of Rhesus using positron emission tomography (PET). The rate for decarboxylation from L-[beta-11C]DOPA to [11C]dopamine was calculated using a graphical method with cerebellum as a reference region. Although the peripheral administration of 6R-BH4 at low dose (2 mg/kg) did not provide a significant increase in the rate of dopamine biosynthesis, a high dose of 6R-BH4 (20 mg/kg) induced an elevation of the rate. This 6R-BH4-induced elevation of the dopamine synthesis rate was further dose-dependently enhanced by the continuous infusion of L-tyrosine (0.2 and 1.0 mumol/min/kg). L-Tyrosine infusion with a rate of 1.0 mumol/min/kg caused an enhancement of the rate even during low dose administration of 6R-BH4 (2 mg/kg). L-Tyrosine infusion alone did not induce any elevation of the dopamine biosynthesis rate. The analysis of plasma indicated that the metabolic ratios of L-[beta-11C]DOPA to each metabolite were not affected by 6R-BH4 and/or L-tyrosine infusion. The results suggest that the low dose loading of tyrosine facilitates the activity of 6R-BH4 on the presynaptic dopamine biosynthesis, and also that the combined effects can be monitored by PET using L-[beta-11C]DOPA as a biochemical probe.

Positron emission tomography with 11C-methionine in hyperparathyroidism.

BACKGROUND: Positron emission tomography (PET) has not been evaluated for preoperative localization and functional characterization of the parathyroid tissue in hyperparathyroidism. METHODS: Images of the neck and upper mediastinum of 23 patients with hyperparathyroidism were obtained by PET after intravenous administration of 400 to 800 MBq L-[methyl-11C]-methionine. The investigation was repeated in six patients after Na2-ethylenediamine tetraacetic acid infusion, whereby stable 65% to 157% rise in intact serum parathyroid hormone values was attained. RESULTS: Parathyroid surgical procedure revealed single (21 patients) or two enlarged parathyroid glands (two patients) that were characterized as chief cell adenoma (n = 13), hyperplasia (n = 10), or carcinoma (n = 2) and weighed 80 to 6000 mg. Twenty (80%) of these glands were localized by PET. The remaining examinations (20%) were false negative and mainly encompassed small parathyroids in juxtathyroid position. Among 15 patients undergoing parathyroid reoperation true-positive localizations were obtained for 87% of the glands. The images displayed lower tracer uptake in residual thyroid lobes (n = 40), esophagus, and cervical vertebrae. Na2-ethylenediamine tetraacetic acid infusion failed to enhance parathyroid uptake values. Ultrasonography, computed tomography, technetium-thallium scintigraphy, and venous sampling revealed 25% to 53% of the pathologic parathyroid tissues of the patients undergoing reoperation and was largely complementary to PET. CONCLUSIONS: The results suggest that PET may provide novel possibilities for the imaging of pathologic parathyroid glands in hyperparathyroidism.

Positron emission tomography and computed tomography in differential diagnosis between recurrent or residual glioma and treatment-induced brain lesions.

In previous studies of supratentorial gliomas with positron emission tomography (PET) and computed tomography (CT), high uptakes of L-methyl-11C-methionine (11C-L-methionine) were found even in astrocytomas without blood-brain barrier defects as judged by CT or 68Ga-EDTA PET. In a number of patients examined after radiation therapy, there were no consistent changes in the high uptake values. In the present investigation PET and CT were compared with regard to their abilities to visualize and delineate recurrent tumors and treatment-induced brain defects and to differentiate between them. The study was undertaken on four patients who were long-term survivors after treatment for high-grade gliomas. For PET, 11C-L-methionine and 68Ga-EDTA were used. In two patients recurrent/residual tumors appeared considerably larger with 11C-L-methionine PET than with CT or 68Ga-EDTA PET. In one patient, no signs of recurrence were seen with any of these three methods, and in a fourth patient, whose condition was clinically stable, the findings at PET with 11C-L-methionine were non-specific. In areas corresponding to the surgical parenchymal defects, the 11C-L-methionine uptake and, except in one case, the local blood volume was markedly reduced. PET with 11C-L-methionine thus has a potential for distinguishing between postoperative brain lesions and tumor recurrence with a higher accuracy than CT.

Monoamine re-uptake sites in the human brain evaluated in vivo by means of 11C-nomifensine and positron emission tomography: the effects of age and Parkinson's disease.

Six patients with Parkinson's disease, selected to cover a range of clinical features, and 7 healthy volunteers aged 24-81 years, were examined by positron emission tomography after i.v. injection of racemic 11C-nomifensine, a catecholamine re-uptake blocking drug. After injection the radiotracer, radioactivity was rapidly distributed to the brain. The highest accumulation of radioactivity was found in areas rich in dopaminergic and noradrenergic innervation, such as the striatum and the thalamus. In regions with negligible dopaminergic and noradrenergic innervation, such as the cerebellum, radioactivity was lower and evenly distributed. In all investigated brain regions a marked age-related decline in 11C-nomifensine-derived radioactivity relative to the cerebellum was observed in the group of healthy volunteers. Parkinsonian patients did not show such a decline with age. In the group of parkinsonian patients with mainly unilateral involvement, the contralateral putamen exhibited the most pronounced decrease. Only the 3 parkinsonian patients aged 63 and younger showed markedly lower 11C-nomifensine binding in striatal areas than age-matched healthy volunteers. 11C-nomifensine seems to be a valuable tool for investigating noradrenergic and dopaminergic re-uptake sites in vivo. Further achievements will most likely be made when the active enantiomer becomes available.