Radionuclide impurities in [¹8F]F⁻ and [¹8F]FDG for positron emission tomography.

The paper describes radionuclide impurities (γ-emitters and (3)H) in proton irradiated (18)O enriched water from an Nb target vessel with Nb entrance window, their distribution in different synthesis steps and finally in the PET radiopharmaceuticals [(18)F]Fluoride and [(18)F]FDG.

Intraoperative sonography: a technique for localizing focal forms of congenital hyperinsulinism in the pancreas.

Congenital hyperinsulinism (CHI), syn. nesidioblastosis, is the most frequent cause of persistent, recurrent hypoglycemia in infancy. One third of patients show a single circumscribed focus. Enucleation of the focus and the removal of all affected ß-cells with preservation of healthy tissue is the treatment of choice. The intrapancreatic choledochus as well as the ductus pancreaticus major must remain intact. The diagnostic gold standard is 18F-DOPA-PET/CT. Intraoperative sonography is carried out to correctly visualize the focus preoperatively localized by PET/CT in situ during the operation. The enucleation of the focus was carried out 3 - 20 days after PET/CT in 5 patients at an age of 3.5 - 14 months. Intraoperative ultrasound was carried out with high-capacity devices of different manufacturers under use of broadband probes (9 - 14 MHz). The localization by intraoperative ultrasound was accurate in all 5 patients with focal CHI, with regard to the intraoperative localization as previously described by PET/CT and histology. D. choledochus and D. pancreaticus major were separated intraoperatively by ultrasound. 3 of 5 patients were cured by complete enucleation of the focus. Nevertheless, the entire intraoperative identification of the segmented focus is still problematic. Characteristic sonographic features of a CHI focus are: hypoechogenicity, variable homogeneous and inhomogenous texture, blurred, irregular limitation without capsule, filiform, lobular processes, and insular dispersal into the surrounding tissue. Intraoperative high-resolution sonography helps the pediatric surgeon to determine size, configuration and topography of a CHI focus.

Radiation treatment planning in brain tumours: potential impact of 3-O-methyl-6-[(18)F]fluoro-L-DOPA and PET.

AIM: Amino acid PET has become an important diagnostic tool for brain tumour imaging. In this data analysis, the potential impact of amino acid PET with 3-O-methyl-6-[(18)F]fluoro-L-DOPA ([(18)F]OMFD) on radiation treatment planning is addressed by the following questions: 1. Was tumour tissue identified with OMFD-PET which was not covered by the conventionally derived planning target volume (PTV)? 2. Would the PTV have been changed incorporating OMFD-PET? PATIENTS, METHODS: OMFD-PET of 25 patients after subtotal resection of malignant glioma was evaluated. The region of elevated tracer uptake of PET and of contrast enhancing masses on MRI were outlined as separate gross tumour volumes (GTV(MRI) and GTV(OMFD)) and reconstructed in the planning CT for comparison with the conventionally drawn GTV(conv). A PTV(new) based on GTV(conv+MRI) was calculated. Pairwise differential volumes were calculated to estimate overlap and differential volumes delineation by each image modality and the PTV(conv) and PTV(new) respectively. RESULTS: Differential volume analysis showed > 10 cm(3) of GTV(OMFD) outside GTV(conv) and GTV(MRI) in 5/25 patients respectively. From GTV(MRI) > 10 cm(3) were found outside GTV(OMFD) in 8/25 patients. Although all tumour areas indicated by [(18)F]OMFD were covered by the conventionally derived PTV, based on a GTV(OMFD+MRI), the PTV(new) would have been enlarged >20% in seven patients. In seven patients the PTV(new) would have been reduced. CONCLUSION: OMFD-PET indicated tumour tissue outside the tumour region identified with MRI, adding valuable information for the delineation of the GTV in radiation treatment planning. OMFD-PET contains the potential to tailor the high dose radiation to the appropriate tumour volume, especially if dose escalation is desired.

[18F]-DOPA positron emission tomography for preoperative localization in congenital hyperinsulinism.

In recent years, considerable progress has been made in the biochemical, morphological and molecular genetic differentiation of congenital hyperinsulinism (CHI). Fluorine-18 L-3,4-dihydroxyphenylalanine positron emission tomography ((18)F-DOPA-PET) has been introduced for differentiation between focal and diffuse CHI. The ability to take up L-DOPA and convert it into dopamine is correlated with the activity of the aromatic amino acid decarboxylase and increased in the hyperfunctional affected pancreatic area in comparison to normally functioning pancreas. The high sensitivity of this method allows the surgeon to perform a curative limited resection of a focus without the risk of long-term diabetes. The exact preoperative planning by (18)F-DOPA-PET/CT computer tomography allows laparoscopic operation in selected cases with the focus in the tail and limits necessity to open the pancreatic duct in cases with focus in the head. Patients with persistent CHI should be managed within a strong network of diagnostic, treatment, and research institutions.

Factors affecting the specific activity of [18F]fluoride from a [18O]water target.

AIM: Characterisation of the influence of different polymeric tube materials of a water target system, used for the production of 18F activity, on the specific activity of radiotracers. MATERIAL, METHODS: Target water samples taken from different locations of the 18F water target system of a Cyclone 18/9 cyclotron, equipped with Teflon (PTFE) or polypropylene (PP) tubes, were analyzed for non-radioactive [19F]fluoride content. [19F]Fluoride content was measured by ion chromatography (IC20, Dinoex) with suppressed conductivity detection. Both the ion chromatographic results and the amount of 18F activity produced were used for the calculation of the specific activity (SA) of [18F]fluoride at the start of the labelling synthesis. To check these results, the SA of the labelled receptor ligand [18F]ZK811460 was also determined by using the different tubing materials. RESULTS: Dose-exposed PTFE tubes of the target dispensing (loading) system were identified to be a major source of [19F]fluoride contamination. CONCLUSION: By replacing PTFE tubes of the target dispensing system with PP tubes, the content of 19F was reduced considerably resulting in an increase of SA of the radiotracer [18F]ZK811460 by factor of two.

Aspects of 6-[18F]fluoro-L-DOPA preparation. Deuterochloroform as a substitute solvent for Freon 11.

AIM: Replacement of the ecologically harmful solvent Freon 11 (CFCl(3)) by chloroform for the module-assisted preparation of 6-[(18)F]fluoro-L-DOPA based on the electrophilic radiofluorodestannylation of the precursor N-formyl-3,4-di-tert-butoxycarbonyloxy-6-(trimethylstannyl)-L-phenylalanine ethyl ester. MATERIALS, METHODS: The TRACERlab Fx FDOPA module (GE Medical Systems) was used for the preparation of 6-[(18)F]fluoro-L-DOPA. Cyclotron-produced [(18)F]F(2) gas (5 GBq) was passed through a cooled solution (5 degrees C) of the stannyl precursor (45 mg) in CDCl(3) (10 ml). After the [(18)F]fluorination step, HCl (2 ml, 6 mol/l) was added to the solution. Then the reaction mixture was heated at 80 degrees C for 5 min under vacuum to evaporate the chloroform. The hydrolysis to remove the protecting groups was completed by heating the closed reactor at 130 degrees C for 8 min. After cooling to 20 degrees C the reaction mixture was purified by HPLC with two polymer-based RP columns (PRP-1, 7 microm, 10 x 250 mm, Hamilton) using a solution of AcOH/AcONa (pH 4.7) as eluent. The 6-[(18)F]fluoro-L-DOPA fraction was collected and sterile filtrated. RESULTS: Three types of stabilised chloroform were tested for the radiofluorination of the precursor. Only by use of deuterochloroform stabilised with silver no significant losses of radioactivity were observed. Thus, 6-[(18)F]fluoro-L-DOPA purified by HPLC was obtained in decay-corrected radiochemical yields of 25+/-3%, ready for human use. CONCLUSION: CDCl(3) has proved to be a convenient solvent for the module-assisted preparation of 6-[(18)F]fluoro-L-DOPA. In this way the use of the polluting Freon 11 can be avoided.

Module-assisted synthesis of the bifunctional labelling agent N-succinimidyl 4-[(18)F]fluorobenzoate ([(18)F]SFB).

The three-step radiosynthesis of N-succinimidyl 4-[(18)F]fluorobenzoate ([(18)F]SFB) was adapted to a remotely controlled synthesis module. After optimization of the reaction conditions, the final [(18)F]SFB was obtained in decay-corrected radiochemical yields of 34-38% (related to [(18)F]fluoride; n=12) within a synthesis time of 68 min. The radiochemical purity was in the range of 93-96%.

Changes in brain metabolism associated with remission in unipolar major depression.

OBJECTIVE: Functional brain correlates of remission in patients with major depressive disorder (MDD) are measured with positron emission tomography (PET) and 18F-fluorodeoxyglucose. METHOD: Glucose metabolism was measured in patients (n = 41) with moderate to severe MDD during acute depression and in the remitted state defined as a period of asymptomatic condition over 12 weeks. Data analyses used a region-of-interest (ROI) approach and statistical parametric mapping (SPM). RESULTS: There were significant decreases in metabolism upon remission with respect to the baseline scan in left prefrontal, anterior temporal and anterior cingulate cortex and bilateral thalamus (SPM analysis) and bilateral putamen and cerebellum (SPM and ROI analyses). There was a significant asymmetry in prefrontal and anterior cingulate cortex metabolism with lower metabolism in the left hemisphere that persisted despite clinical remission. CONCLUSION: These findings support the hypothesis that selective monoamine reuptake inhibition leads to an attenuation of a brain circuit that mediates depressive symptomatology.

3-O-methyl-6-[18F]fluoro-L-DOPA and its evaluation in brain tumour imaging.

3-O-Methyl-6-[(18)F]fluoro-L-DOPA (OMFD) is a major metabolite of 6-[(18)F]fluoro-L-DOPA. Although synthesis of OFMD was primarily established to study the dopaminergic system, as it is an amino acid analogue, uptake in experimental tumours has been found. The aim of this study was to evaluate the applicability of OMFD for brain tumour imaging and to obtain initial estimates of whole-body biodistribution and radiation dosimetry in humans. Nineteen patients with suspected or confirmed brain tumours were investigated with OMFD and dynamic brain PET, complemented by whole-body PET in seven patients. Tracer kinetics were compared for normal brain and intracerebral lesions. Tissue accumulation was quantified with standardised uptake values (SUVs). Whole-body distribution in combination with tracer kinetics from animal experiments was used for the calculation of radiation dosimetry data. On the basis of OMFD PET, viable brain tumour was suspected in 16 patients with SUVs of 3.0+/-0.8 and a tumour to non-tumour ratio of 1.9+/-0.5. Highest tumour and normal brain uptake occurred between 15 and 30 min, with a subsequent slow decrease. Late whole-body tracer distribution was uniform without specific organ accumulation. Elimination occurred via urine. The mean radiation dose to the whole body was estimated at 0.016 mSv/MBq, with the kidneys as dose-critical organ (0.033 mGy/MBq). In conclusion, OMFD enables the visualisation of brain tumours with SUVs similar to other fluorinated amino acids. The whole-body radiation exposure from OMFD is comparable to that from FDG imaging.

Efficient synthesis of the 18F-labelled 3-O-methyl-6-[18F]fluoro-L-DOPA.

The 18F-labelled amino acid derivative 3-O-methyl-6-[18F]fluoro-L-DOPA ([18F]OMFD) is a potential radiotracer for imaging tumour tissue using positron emission tomography. The precursor N-formyl-3-O-methyl-4-O-boc-6-trimethyl-stannyl-L-DOPA-ethyl ester enables direct electrophilic radiofluorination by stereoselective destannylation. After partial hydrolysis, optimized HPLC purification and sterile filtration, the [18F]OMFD obtained with high radiochemical purity and ready for use. The total synthesis time is about 50 min and the radiochemical yield achieved is 20-25% (decay corrected, related to [18F]F(2)). It was demonstrated that [18F]OMFD could be produced routinely and reliably for clinical use. [18F]FDOPA-preparation devices can be used with minor modifications.

Distribution of 16alpha-[18F]fluoro-estradiol-3,17beta-disulfamate in rats, tumour-bearing mice and piglets.

Based on a high affinity to the enzyme estrone sulfatase (ES), 16alpha-[18F]fluoroestradiol-3,17beta-disulfamate ([18F]FESDS) has been suggested as a potential PET radiotracer for imaging steroid-dependent breast tumours. The distribution of [18F]FESDS was studied in rats, tumour-bearing nude mice and piglets. In all species evidence for binding to a second target, the enzyme carbonic anhydrase (CA), was obtained. ES and CA inhibitors significantly reduced the radiotracer uptake in various organs but not in tumours. It is concluded that [18F]FESDS binds to ES and CA in vivo but this binding is not strong enough to allow tumour imaging with positron emission tomography (PET).

Distribution of estrone sulfatase in rat brain determined by in vitro autoradiography with 16alpha-[18F]fluoroestradiol-3,17beta-disulfamate.

16Alpha-fluoroestradiol-3,17beta-disulfamate (FESDS) strongly inhibits estrone sulfatase (ES), an enzyme which is also present in the brain. The enzyme is probably involved in important regulatory functions of neurosteroids which may be disturbed in certain brain diseases. In the present study, [18F]FESDS was used to measure the amount of ES in various rat brain regions using quantitative in vitro autoradiography. The obtained values vary between 0.29 pmol (mg protein)(-1) (pons) and 11.5 pmol (mg protein)(-1) (striatum). They are positively correlated with the enzyme activity measured in homogenates of the corresponding regions. Because this radiotracer binds also to carbonic anhydrase in the brain it is only of limited use for in vivo imaging studies.

Aspects of 6-[18F]fluoro-L-DOPA preparation: precursor synthesis, preparative HPLC purification and determination of radiochemical purity.

A modified method for the synthesis of the intermediate product N-Boc-3,4-di(Boc-O)-6-iodo-L-phenylalanine ethyl ester of the [18F]FDOPA precursor preparation was developed. With the application of bis-(trifluoroacetoxy)-iodobenzene for the iodination step with elemental iodine the yield of the intermediate can be increased from 12% to 50-60%. By replacing silica-gel-based RP HPLC column by a polymer-based column for semi-preparative purification of [18F]FDOPA from the reaction mixture the radiochemical purity of the final product can be increased up to >99%. For the determination of the radiochemical impurity [18F]fluoride a HPLC method using a column with polymer-based RP material was introduced.

Automated synthesis of 16alpha-[18F]fluoroestradiol-3,17beta-disulphamate.

After 16alpha-[15F]fluoroestradiol ([18F]FES) has been successfully prepared in an automated module, the synthesis of 16alpha-[18F]fluoroestradiol-3,17beta-disulphamate ([18F]FESDS) is described as a module-assisted one-pot procedure which can provide 10GBq [18F]FESDS with a radiochemical purity better than 99%. The procedure is reliable and reproducible and requires a time of about 90 min. Because of its high sulphatase-inhibitory effect [15F]FESDS is thought to be a new PET tracer to image sites of high sulphatase activity.

Intrauterine growth restriction induces up-regulation of cerebral aromatic amino acid decarboxylase activity in newborn piglets: [18F]fluorodopa positron emission tomographis study.

There is evidence that intrauterine growth restriction (IUGR) is associated with altered dopaminergic function in the immature brain. However, the relevant enzyme activities have not been measured in the living neonatal brain together with brain oxidative metabolism. Therefore, fluorine-18-labeled 6-fluoro-L-3,4-dihydroxyphenylalanine (FDOPA) was used together with positron emission tomography to estimate the activity of the aromatic amino acid decarboxylase in the brain of 10 newborn IUGR piglets (2 to 5 d old; body weight, 908 +/- 109 g) and in 10 normal-weight (3 to 5 d old; body weight, 2142 +/- 373 g) newborn piglets. The regional transport of FDOPA to the brain and the clearance rate of labeled metabolites from brain tissue were broadly similar in the two groups. However, the regional rate constant for back flux from the brain was markedly increased in IUGR piglets for striatum (72%) and frontal cortex (83%) (p < 0.05). Furthermore, the rate constant for conversion of FDOPA to fluorodopamine was markedly increased (between 48% in cerebellum and 91% in mesencephalon, p < 0.05) in all brain regions of IUGR piglets studied. Thus, it is suggested that IUGR induces an up-regulation of aromatic amino acid decarboxylase activity that is not related to alterations in brain oxidative metabolism.

Relation between brain tissue pO2 and dopamine synthesis of basal ganglia--a 18FDOPA-PET study in newborn piglets.

Perinatal hypoxic-ischemic cerebral injury is a major determinant of neurologic morbidity and mortality in the neonatal period and later in childhood. There is evidence that the dopaminergic system is sensitive to oxygen deprivation. However, the respective enzyme activities have yet not been measured in the living neonatal brain. In this study, we have used 18F-labelled 6-fluoro-L-3,4-dihydroxyphenylalanine (FDOPA) together with positron emission tomography (PET) to estimate the activity of the aromatic amino acid decarboxylase (AADC), the ultimate enzyme in the synthesis of dopamine, in the brain of newborn piglets under normoxic and moderate asphyxial conditions. The study was performed on 8 newborn piglets (2-5 days old). In each piglet PET studies were performed under control conditions and during 2-hour asphyxia. Simultaneously, brain tissue pO2 was recorded, cerebral blood flow (CBF) was measured with colored microspheres and cerebral metabolic rate of oxygen (CMRO2) was determined. Asphyxia was induced by lowering the inspired fraction of oxygen from 0.35 to 0.10 and adding about 6% CO2 to the inspired gas. Asphyxia elicited a more than 3-fold increase of the CBF (p < 0.01) so that CMRO2 remained unchanged throughout the asphyxial period. Despite this, brain tissue pO2 was reduced from 19 +/- 4 mm Hg to 6 +/- 3 mm Hg (p < 0.01). Blood-brain transfer of FDOPA as well as permeability-surface area product (PS) from striatum were unchanged. Striatal synthesis rate of fluoro-dopamine from FDOPA (k3) was, however, significantly increased (p < 0.01). This increase of the AADC activity is associated with reduced brain tissue pO2. Asphyxia-induced CBF increase impedes an alteration of brain oxidative metabolism.

Long-distance transport of radionuclides between PET cyclotron and PET radiochemistry.

At the Rossendorf PET Centre the PET cyclotron and the radiochemical laboratories are 500 m away from each other. The distance is bridged by a radionuclide transport system (RATS) whose details such as layout, technical parameters, control system and radiation protection are described along with our experience in long-distance transport of radionuclides.

Upregulation of the aromatic amino acid decarboxylase under neonatal asphyxia.

Perinatal hypoxic-ischemic cerebral injury is a major determinant of neurologic morbidity and mortality in the neonatal period and later in childhood. There is evidence that the dopaminergic system is sensitive to asphyxia. However, the respective enzyme activities have not yet been measured in the living neonatal brain. In this study, we have used 18F-labeled 6-fluoro-L-3,4-dihydroxyphenylalanine (FDOPA) together with positron-emission tomography (PET) to estimate the activity of the aromatic amino acid decarboxylase (AADC), the ultimate enzyme in the synthesis of dopamine (DA), in the brain of newborn piglets. Simultaneously, the cerebral blood flow (CBF) was measured with colored microspheres. Asphyxia elicited an up to threefold increase of the CBF. Despite this, the blood-brain transfer of FDOPA as well as the clearance rate constants from brain were unchanged. However, the synthesis rate of FDA from FDOPA was significantly increased in frontal cortex, striatum, and midbrain. This increase of the AADC activity and the decrease of monoamine oxidase activity may contribute to the increase of extracellular DA during asphyxia which is expected to be involved in severe disturbances of neuronal metabolism, e.g., by generating free radicals.

Simultaneous measurement of [18F]FDOPA metabolism and cerebral blood flow in newborn piglets.

Available information on the dopamine (DA) metabolism of the immature brain is rare. In order to establish a useful animal model we have performed PET experiments in anesthetized neonatal pigs using 6-[18F]-fluoro-L-DOPA (FDOPA) as tracer. In this study, we have simultaneously determined the cerebral blood flow and the rate constant of FDOPA conversion by the aromatic amino acid decarboxylase, the ultimate enzyme in the synthesis of dopamine. The estimated values of FDOPA decarboxylation in the basal ganglia were similar to values calculated in adult animals and humans. However, in contrast to those studies a significant decarboxylation was also found in the frontal cortex and the cerebellum. HPLC analysis of brain samples also revealed extensive and rapid metabolism of FDOPA in the five investigated brain regions. At 8 min after tracer injection about 80% of FDOPA was already converted to FDA and its metabolites. Surprisingly, a rather high fraction (16-21%) of [18F]-fluoro-3-methoxytyramine was found which may indicate a low storage capacity of vesicular DA at this perinatal stage. It is suggested that the findings are related to the ontogenetic development of the dopaminergic system. The knowledge of the regulation of the DA metabolism in the immature brain may have implications for the understanding of neurodevelopmental effects of perinatal oxygen deprivation.