Imaging of the brain serotonin transporters (SERT) with 18F-labelled fluoromethyl-McN5652 and PET in humans.

PURPOSE: [(11)C]DASB is currently the most frequently used highly selective radiotracer for visualization and quantification of central SERT. Its use, however, is hampered by the short half-life of (11)C, the moderate cortical test-retest reliability, and the lack of quantifying endogenous serotonin. Labelling with (18)F allows in principle longer acquisition times for kinetic analysis in brain tissue and may provide higher sensitivity. The aim of our study was to firstly use the new highly SERT-selective (18)F-labelled fluoromethyl analogue of (+)-McN5652 ((+)-[(18)F]FMe-McN5652) in humans and to evaluate its potential for SERT quantification. METHODS: The PET data from five healthy volunteers (three men, two women, age 39 ± 10 years) coregistered with individual MRI scans were semiquantitatively assessed by volume-of-interest analysis using the software package PMOD. Rate constants and total distribution volumes (V (T)) were calculated using a two-tissue compartment model and arterial input function measurements were corrected for metabolite/plasma data. Standardized uptake region-to-cerebellum ratios as a measure of specific radiotracer accumulation were compared with those of a [(11)C]DASB PET dataset from 21 healthy subjects (10 men, 11 women, age 38 ± 8 years). RESULTS: The two-tissue compartment model provided adequate fits to the data. Estimates of total distribution volume (V (T)) demonstrated good identifiability based on the coefficients of variation (COV) for the volumes of interest in SERT-rich and cortical areas (COV V (T) <10%). Compared with [(11)C]DASB PET, there was a tendency to lower mean uptake values in (+)-[(18)F]FMe-McN5652 PET; however, the standard deviation was also somewhat lower. Altogether, cerebral (+)-[(18)F]FMe-McN5652 uptake corresponded well with the known SERT distribution in humans. CONCLUSION: The results showed that (+)-[(18)F]FMe-McN5652 is also suitable for in vivo quantification of SERT with PET. Because of the long half-life of (18)F, the widespread use within a satellite concept seems feasible.

Convenient recycling and reuse of bombarded [¹8O]H2O for the production and the application of [¹8F]F⁻.

The limited availability and the increasing demands of [(18)O]H2O force the reuse of bombarded [(18)O]H2O for the production of [(18)F]F(-) at least for the purposes of research. Therefore, inorganic and organic contaminants have to be removed from the [(18)O]H2O after bombardment. We present a simple, effective, easy-handling and reliable method of [(18)O]H2O purification including oxidation and distillation. The obtained recycled [(18)O]H2O had comparable quality to commercially distributed [(18)O]water. This was confirmed by a detailed comparison of produced radionuclides and their activities and the application of [(18)F]F(-) for the automated synthesis of [(18)F]fluspidine.

Age-dependent effects of severe traumatic brain injury on cerebral dopaminergic activity in newborn and juvenile pigs.

There is evidence that the dopaminergic system is sensitive to traumatic brain injury (TBI). However, the age-dependency of this sensitivity has not been studied together with brain oxidative metabolism. We postulate that the acute effects of severe TBI on brain dopamine turnover are age-dependent. Therefore 18F-labelled 6-fluoro-L-3,4-dihydroxyphenylalanine (FDOPA) together with Positron-Emission-Tomography (PET) was used to estimate the activity of the aromatic amino acid decarboxylase (AADC) in the brain of 11 newborn piglets (7-10 days old) and nine juvenile pigs (6-7 weeks old). Six newborn and five juvenile animals were subjected to a severe fluid-percussion (FP) induced TBI. The remaining animals were used as sham operated untreated control groups. Simultaneously, the regional cerebral blood flow (CBF) was measured with colored microspheres and the cerebral metabolic rates of oxygen and glucose were determined. At 1 h after FP-TBI, [18F]FDOPA was infused and PET scanning was performed for 2 h. At 2 h after FP-TBI administration, a second series of measurements of physiological values including CBF and brain oxidative metabolism data had been obtained. Severe FP-TBI elicited a marked increase in the rate constant for fluorodopamine production (k3FDOPA) in all brain regions of newborn piglets studied by between 97% (mesencephalon) and 143% (frontal cortex) (p < 0.05). In contrast, brain hemodynamics and cerebral oxidative metabolism remained unaltered after TBI. Furthermore, the permeability-surface area product of FDOPA (PSFDOPA) was unchanged. In addition, regional blood flow differences between corresponding ipsi- and contralateral brain regions did not occur after TBI. Thus, it is suggested that severe FP-TBI induces an upregulation of AADC activity of newborn piglets that is not related to alterations in brain oxidative metabolism.

Effect of hypoxia/hypercapnia on metabolism of 6-[(18)F]fluoro-L-DOPA in newborn piglets.

There is evidence that the dopaminergic system is sensitive to altered p(O(2)) in the immature brain. However, the respective enzyme activities have not been measured in the living neonatal brain together with brain oxidative metabolism. Therefore 18F-labelled 6-fluoro-L-3,4-dihydroxyphenylalanine (FDOPA) together with positron emission tomography (PET) was used to estimate the activity of the aromatic amino acid decarboxylase (AADC) in the brain of fifteen newborn piglets (2-5 days old). Two PET scans were performed in each piglet. Eleven animals underwent a period of normoxia and moderate hypoxia/hypercapnia (H/H). The remaining four animals were used as an untreated control group. Simultaneously, the brain tissue p(O(2)) was recorded, the regional cerebral blood flow (CBF) was measured with colored microspheres and the cerebral metabolic rate of oxygen (CMRO(2)) was determined. In addition, in four untreated and six H/H treated piglets the relative amounts of fluorodopamine and the respective metabolites were determined in brain tissue samples using HPLC analysis. H/H conditions were induced by lowering the inspired fraction of oxygen from 0.35 to 0.10 and adding CO(2) to the inspired gas resulting in an arterial p(CO(2)) between 74 and 79 mmHg. H/H elicited a more than 3-fold increase of the CBF (P<0.05) so that the CMRO(2) remained unchanged throughout the H/H period. Despite this, the brain tissue p(O(2)) was reduced from 19+/-4 to 6+/-3 mmHg (P<0.05). The permeability-surface area product of FDOPA (PS(FDOPA)) was unchanged. However, the transfer rate of FDOPA (k(3)(FDOPA)) of the nigrostriatal dopaminergic system and the relative amounts of fluorodopamine and the respective metabolites were significantly increased (P<0.05). It is suggested that H/H induces an increase of AADC activity. However, an H/H-induced CBF increase maintains bulk O(2) delivery and preserves CMRO(2).

The influx of neutral amino acids into the porcine brain during development: a positron emission tomography study.

Pigs of three different age groups (newborns, 1 week old, 6 weeks old) were used to study the transport of the large neutral amino acids 6-[18F]fluoro-L-DOPA ([18F]FDOPA) and 3-O-methyl-6-[18F]fluoro-L-DOPA ([18F]OMFD) across the blood-brain barrier (BBB) with positron emission tomography (PET). Compartmental modeling of PET data was used to calculate the blood-brain clearance (K1) and the rate constant for the brain-blood transfer (k2) of [18F]FDOPA and [18F]OMFD after i.v. injection. A 40-70% decrease of K1(OMFD), K1(FDOPA) and k2(OMFD) from newborns to juvenile pigs was found whereas k2(FDOPA) did not change. Generally, K1(OMFD) and k2(OMFD) are lower than K1(FDOPA) and k2(FDOPA) in all regions and age groups. The changes cannot be explained by differences in brain perfusion because the measured regional cerebral blood flow did not show major changes during the first 6 weeks after birth. In addition, alterations in plasma amino acids cannot account for the described transport changes. In newborn and juvenile pigs, HPLC measurements were performed. Despite significant changes of single amino acids (decrease: Met, Val, Leu; increase: Tyr), the sum of large neutral amino acids transported by LAT1 remained unchanged. Furthermore, treatment with a selective inhibitor of the LAT1 transporter (BCH) reduced the blood-brain transport of [18F]FDOPA and [18F]OMFD by 35% and 32%, respectively. Additional in-vitro studies using human LAT1 reveal a much lower affinity of FDOPA compared to OMFD or L-DOPA. The data indicate that the transport system(s) for neutral amino acids underlie(s) developmental changes after birth causing a decrease of the blood-brain barrier permeability for those amino acids during brain development. It is suggested that there is no tight coupling between brain amino acid supply and the demands of protein synthesis in the brain tissue.

Developmental changes in the activities of aromatic amino acid decarboxylase and catechol-O-methyl transferase in the porcine brain: a positron emission tomography study.

Newborn (7-10 days old) and young (6-8 weeks old) pigs were used to study the metabolism of 6-[18F]fluoro-L-DOPA (FDOPA) in various brain regions with positron emission tomography (PET). Compartmental modeling of PET data was used to calculate the rate constants for the decarboxylation of FDOPA (k3) and for the metabolism of the resulting [18F]fluoro-dopamine (kcl). Whereas general physiological parameters such as cerebral blood flow, cerebral oxygen uptake, arterial blood gases and glucose concentration remained unchanged in young pigs as compared to newborns, a 50-200% increase of k3 in frontal cortex, striatum and mesencephalon was found. Also a 60% enhancement of kcl in the frontal cortex was measured, which is related to changes of the catechol-O-methyl-transferase (COMT) activity and implies a special function of this enzyme in the development of this brain region. In addition, measurement of plasma metabolites of FDOPA with HPLC was performed. The metabolism of FDOPA in young pigs was significantly faster than in newborns. Calculation of the rate constant for O-methylation of FDOPA by COMT revealed a significant elevation of this enzyme activity in young pigs compared to newborns. The increase of AADC and COMT activity with brain development is considered to be associated with special stages of neuronal maturation and tissue differentiation.

Impact of asymmetric intrauterine growth restriction on organ function in newborn piglets.

Fetal malnutrition may induce asymmetric intrauterine growth restriction (aIUGR) with long-lasting consequences. Understanding the organ-specific structural and functional effects aIUGR may have on the newborn, and understanding the potential impact on the neonatal response to compromising conditions, appears to be essential for adequate treatment. Therefore, a survey is given of some organ-specific alterations in newborns, which have suffered from aIUGR. We studied these effects in a model of asymmetric intrauterine growth restriction based on the spontaneous occurrence of runting in pigs. We wish to demonstrate that experimental studies in animal models are necessary and helpful to elucidate pathogenetic mechanisms. aIUGR seems to have both beneficial and detrimental effects on the newborn. The development of skeletal muscles (conversion to oxidative type I fibers) and of their vascular supply as well as of the brain dopaminergic activity is accelerated. Also, aIUGR apparently improves the ability to withstand critical periods of gradual oxygen deficit as shown by the maintenance of renal blood flow during severe systemic hypoxia, and by improved cerebrovascular autoregulation in hemorrhagic hypotension. On the other hand, aIUGR leads to the reduction of the number of nephrons and to impaired renal excretory functions with arterial hypertension and chronic renal failure.

Visualization of the focus in congenital hyperinsulinism by intraoperative sonography.

In surgery for focal congenital hyperinsulinism (CHI), the identification and complete resection of the focus without collateral damage is of utmost importance. In a pilot study we applied intra-abdominal high-frequency sonography during surgery for focal CHI in 2 infants. The focus could be identified, its relation to the pancreatic and common bile duct could be shown, and the typical octopus-like tentacles could be demonstrated. In one case the resection was successful; in the other it was not. These preliminary results suggest that intraoperative sonography could be a valuable tool in the surgical therapy of focal CHI and warrants further evaluation in a clinical study.

Effect of moderate hypercapnic hypoxia on cerebral dopaminergic activity and brain O2 uptake in intrauterine growth-restricted newborn piglets.

There is evidence that intrauterine growth restriction (IUGR) is associated with altered dopaminergic function in the immature brain. Compelling evidence exists that in the newborn brain, specific structures are especially vulnerable to O2 deprivation. The dopaminergic system is shown to be sensitive to O2 deprivation in the immature brain. However, the respective enzyme activities have not been measured in the living neonatal brain after IUGR under hypercapnic hypoxia (H/H). Therefore, 18F-labeled 6-fluoro-L-3,4-dihydroxyphenylalanine (FDOPA) together with positron emission tomography was used to estimate the aromatic amino acid decarboxylase activity of the brain of seven normal weight (body weight 2078 +/- 434 g) and seven IUGR newborn piglets (body weight 893 +/- 109 g). Two positron emission tomography scans were performed in each piglet. All animals underwent a period of normoxia and moderate H/H. Simultaneously, cerebral blood flow was measured with colored microspheres and cerebral metabolic rate of O2 was determined. In newborn normal-weight piglets, the rate constant for FDOPA decarboxylation was markedly increased in mesostriatal regions during H/H, whereas brain oxidative metabolism remained unaltered. In contrast, moderate H/H induced in IUGR piglets a marked reduction of clearance rates for FDOPA metabolites (p <0.05), which was accompanied by a tendency of lowering the rate constant for FDOPA conversion. Furthermore, IUGR piglets maintained cerebral O2 uptake in the early period of H/H, but during the late period of H/H, a significantly reduced cerebral metabolic rate of O2 occurred (p <0.05). Thus, IUGR is accompanied by a missing activation of dopaminergic activity and attenuated brain oxidative metabolism during moderate H/H. This may indicate endogenous brain protection against O2 deprivation.