Kurt Hamacher

Efficient routine production of the 18F-labelled amino acid O-(2-[18F]fluoroethyl)-l-tyrosine

A convenient remotely controlled no-carrier-added synthesis of enantiomerically pure O-(2-[18F]fluoroethyl)-L-tyrosine (FET) is described. This allows the distribution of the radiotracer to other laboratories according to the satellite concept. The radiochemical yield obtained within 80 min is about 60%. The FET containing HPLC fraction can be used immediately (after adding sodium chloride) for human application.

Comparison of 18F-FET and 18F-FDG PET in brain tumors

UNLABELLED The purpose of this study was to compare the diagnostic value of positron emission tomography (PET) using [(18)F]-fluorodeoxyglucose ((18)F-FDG) and O-(2-[(18)F]fluoroethyl)-l-tyrosine ((18)F-FET) in patients with brain lesions suspicious of cerebral gliomas. METHODS Fifty-two patients with suspicion of cerebral glioma were included in this study. From 30 to 50 min after injection of 180 MBq (18)F-FET, a first PET scan ((18)F-FET scan) was performed. Thereafter, 240 MBq (18)F-FDG was injected and a second PET scan was acquired from 30 to 60 min after the second injection ((18)F-FET/(18)F-FDG scan). The cerebral accumulation of (18)F-FDG was calculated by decay corrected subtraction of the (18)F-FET scan from the (18)F-FET/(18)F-FDG scan. Tracer uptake was evaluated by visual scoring and by lesion-to-background (L/B) ratios. The imaging results were compared with the histological results and prognosis. RESULTS Histology revealed 24 low-grade gliomas (LGG) of World Health Organization (WHO) Grade II and 19 high-grade gliomas (HGG) of WHO Grade III or IV, as well as nine others, mainly benign histologies. The gliomas showed increased (18)F-FET uptake (>normal brain) in 86% and increased (18)F-FDG uptake (>white matter) in 35%. (18)F-FET PET provided diagnostically useful delineation of tumor extent while this was impractical with (18)F-FDG due to high tracer uptake in the gray matter. A local maximum in the tumor area for biopsy guidance could be identified with (18)F-FET in 76% and with (18)F-FDG in 28%. The L/B ratios showed significant differences between LGG and HGG for both tracers but considerable overlap so that reliable preoperative grading was not possible. A significant correlation of tracer uptake with overall survival was found with (18)F-FDG only. In some benign lesions like abscesses, increased uptake was observed for both tracers indicating a limited specificity of both techniques. CONCLUSIONS (18)F-FET PET is superior to (18)F-FDG for biopsy guidance and treatment planning of cerebral gliomas. The uptake of (18)F-FDG is associated with prognosis, but the predictive value is limited and a histological evaluation of tumor tissue remains necessary. Therefore, amino acids like (18)F-FET are the preferred PET tracers for the clinical management of cerebral gliomas.

Comparison of fluorotyrosines and methionine uptake in F98 rat gliomas

The transport mechanisms of O-(2-[(18)F]fluoroethyl)-L-tyrosine (FET) and 2-[(18)F]fluoro-L-tyrosine (FTyr) were compared to those of [(3)H]-Methyl-L-methionine (MET) in F98 rat glioma cells in vitro and by tumor imaging by ex vivo dual tracer autoradiography in F98 rat gliomas. Both, FET and FTyr exhibited similar transport characteristics in F98 glioma cells compared to MET, i.e. mainly a sodium dependent transport similar to system B(0,+) and sodium independent transport via system L. Radioactivity of FET in the acid precipitable fraction was <1% after 120 min incubation time while FTyr and MET exhibited a 15-18% incorporation into proteins. Comparison of FET and FTyr with MET uptake in F98 rat gliomas demonstrated a significant correlation of tumor to brain ratios and a similar intratumoral tracer distribution pattern.

pO(2) Polarography versus positron emission tomography ([(18)F] fluoromisonidazole, [(18)F]-2-fluoro-2'-deoxyglucose). An appraisal of radiotherapeutically relevant hypoxia.

Background and Purpose:The aim of the present study was to validate ([18F] fluoromisonidazole (FMISO) and [18F]-2-fluoro-2’-deoxyglucose (FDG) positron emission tomography (PET) for determination of radiotherapeutically relevant hypoxia by the gold standard for measuring tissue oxygenation in human tumors, the computerized polarographic needle electrode system (pO2 histography).Patients and Methods:Up to now, a total of 16 patients with a metastatic neck lymph node from a primary squamous carcinoma of the head and neck underwent pO2 and PET measurements. Tumor tissue pO2 was measured with polarographic needle electrodes using a pO2 histograph (Eppendorf®). Under CT control, the needle electrode was placed in the tumor without general or local anesthesia. To assess the biological and clinical relevance of oxygenation measurement, the relative frequency of pO2 readings, with values ≤ 2.5, ≤ 5.0, and ≤ 10.0 mmHg, as well as mean and median pO2 were recorded.All PET studies were carried out using an ECAT EXACT 922/47® scanner with an axial field of view of 16.2 cm. FMISO PET consisted of one static scan of the relevant region, performed 120 min after intravenous administration. The acquisition and reconstruction parameters were as follows: 15-min emission scanning and 4-min transmission scanning with 68Ge rod sources. FDG PET of the lymph node metastasis was performed 68 ± 11 min after intravenous administration, applying the whole-body tool with 8-min emission scanning and 4-min transmission scanning per bed position.Results:In order to detect possible relations between the different relevant polarographically measured parameters of tumor hypoxia and FMISO PET data-based oxygenation values, the Pearson correlation coefficient was calculated. Average (r > 0.5) to high correlation (r > 0.7) was found between tumor-to-muscle ratio of FMISO after 2 h and parameters of hypoxic fraction (pO2 readings with values ≤ 2.5, ≤ 5.0, and ≤ 10.0 mmHg as well as mean and median). No correlations could be shown between FDG PET parameters and polarographically determined tumor oxygenation status.Conclusion:Summarizing the FMISO uptake represents a global value for macroscopic tumor parts. As a noninvasive measurement this method seems highly feasible to evaluate the state of oxygenation in subjacent tumors.Hintergrund und Ziel:Ziel dieser Untersuchung war die Validierung von [18F]-Fluormisonidazol-(FMISO-) und [18F]-Fluordeoxyglucose-( FDG-)Positronenemissionstomographie (PET) zur Erfassung der strahlentherapeutisch relevanten Hypoxie durch das computergestützte polarographische Nadelelektrodensystem (pO2-Histographie), das den Goldstandard zur Festlegung der Gewebeoxygenierung in menschlichen Tumoren darstellt.Patienten und Methodik:Bis jetzt wurden bei insgesamt 16 Patienten mit metastatisch befallenen Halslymphknoten eines Plattenepithelkarzinoms der Kopf-Hals-Region pO2- und PET-Messungen durchgeführt. Der pO2 des Tumorgewebes wurde mit Hilfe polarographischer Feinnadelelektroden eines pO2-Histographen (Eppendorf®) gemessen. Die Nadelelektrode wurde CT-gesteuert ohne Lokalanästhesie positioniert. Als Grad für die biologische und klinische Relevanz wurden die relative Häufigkeit der pO2-Messwerte ≤ 2,5, ≤ 5,0 und ≤ 10,0 mmHg sowie der Mittelwert und der Median dokumentiert.Die PET-Untersuchungen wurden an einem Vollring-Tomographen (ECAT EXACT 922/47®; Siemens/CTI) durchgeführt. Die FMISO-PET erfolgte als statische Aufnahme der relevanten Region 120 min p.i. Folgende Akquisitions- und Rekonstruktionsparameter wurden verwendet: 15-minütige Emissionsmessung und 4-minütige Transmissionsmessung mit Hilfe von 68Ge-Stabquellen. Die FDG-PET der metastatisch befallenen Halslymphknoten wurde 68 ± 11 min p.i. unter Verwendung eines Ganzkörperprotokolls mit einer Emissionsmessung von 8 min und einer Transmissionsmessung von 4 min pro Bettposition durchgeführt.Ergebnisse:Um mögliche Korrelationen zwischen den verschiedenen relevanten, polarographisch gemessenen Parametern der Tumorhypoxie und den mittels FMISO-PET gewonnenen Messdaten zu detektieren, wurde der Pearson-Korrelationskoeffizient berechnet. Es zeigte sich eine mittlere (r > 0,5) bis hohe Korrelation (r > 0,7) zwischen dem Tumor/Muskel-Quotienten der FMISO-Aufnahme 2 h p. i. und den verschiedenen Hypoxieparametern (pO2-Messwerte ≤ 2,5, ≤ 5,0, ≤ 10,0 mmHg sowie Mittelwert und Median der pO2-Messwerte). Keine Korrelation konnte zwischen den FDG-PET-Parametern und dem polarographisch bestimmten Tumoroxygenierungsstatus aufgezeigt werden.Schlussfolgerung:Die mit PET gemessene FMISO-Aufnahme gibt einen globalisierten Messwert für makroskopische Anteile des Tumors wieder. Aufgrund des nichtinvasiven Charakters scheint diese Methode besonders geeignet, den Oxygenierungsstatus bei tiefer liegenden Tumoren zu erfassen.

Prognostic Value of 18F-Fluoroethyl-l-Tyrosine PET and MRI in Small Nonspecific Incidental Brain Lesions

Nonspecific incidental brain lesions (NILs) are being detected more frequently because of an increasing number of screening or research MRI scans of the brain, and their natural course is uncertain. Methods: In a prospective cohort study starting in 1999, we determined the outcomes of patients with incidental, nonenhancing, supratentorial, lobar, and small-volume (<10 mL) lesions, depending on the findings of MRI and PET with the 18F-labeled amino acid fluoroethyl-l-tyrosine (18F-FET). Patients with seizures, focal neurologic deficits, signs of local or systemic infection or inflammation, known brain disease, or any kind of previous cerebral treatment were excluded. Finally, 21 patients were eligible. MRI was performed in 19 of these patients because of nonspecific symptoms (such as headaches, dizziness, or sudden deafness), whereas 2 patients were healthy volunteers in MRI studies. Clinical follow-up and MRI scans were obtained at 4- to 6-mo intervals, and follow-up ranged from 3 to 8.5 y. Mean lesion-to-brain (L/B) ratios of ≥1.6 on 18F-FET PET were rated as positive. Results: Four different outcome groups were identified. In group A, 5 NILs regressed or vanished completely. All of these lesions were circumscribed on MRI, and 18F-FET uptake was negative, with an L/B ratio of 1.2 ± 0.2 (mean ± SD). In group B, 10 NILs were stable, without growth. All of these lesions were circumscribed on MRI, and 18F-FET uptake was negative (L/B ratio: 1.0 ± 0.1). In group C, 2 NILs grew slowly over years, and an astrocytoma of World Health Organization (WHO) grade II was diagnosed after resection in each case. The lesions were circumscribed on MRI, and 18F-FET uptake was negative (L/B ratios: 0.7 and 1.0). In group D, 4 NILs showed sudden and rapid growth, with clinical deterioration, and a high-grade glioma of WHO grade III or IV was diagnosed after resection in all cases. The lesions were diffuse on MRI, and 18F-FET uptake was significantly increased (L/B ratio: 2.0 ± 0.4) (P < 0.01 for group D vs. group A or group B). Conclusion: For NILs, a circumscribed growth pattern on MRI and normal or low 18F-FET uptake on PET are strong predictors for a benign course, with the eventual development of a low-grade glioma. In contrast, NILs with a diffuse growth pattern on MRI and increased 18F-FET uptake indicate a high risk for the development of a high-grade glioma.

Computer-aided synthesis (CAS) of no-carrier-added 2-[18F]Fluoro-2-deoxy-d-glucose: an efficient automated system for the aminopolyether-supported nucleophilic fluorination

A microcomputer-controlled automated synthesis of 2-[18F]fluoro-2-deoxy-d-glucose (2-[18F]FDG) is described. The modular setup of the apparatus permits reliable and facile routine synthesis of 18F-labelled radiopharmaceuticals based on aminopolyether (APE)-mediated nucleophilic fluorination. The uncorrected radiochemical yield is in the range of 40–55%. Batches up to 600 mCi of 2-[18F]FDG are prepared from 1.1 Ci [18F]fluoride in <1 h. The apparatus can also be used for other APE-supported nucleophilic fluorination procedures.

Preparation of fluorine-18 labelled sugars and derivatives and their application as tracer for positron-emission-tomography

The usefulness of 18F-labelled carbohydrates, especially 2-deoxy-2-[18F]fluoro-D-glucose, to study pathophysiological processes in man non-invasively using positron-emission-tomography (PET) led to a widespread investigation of different 18F-labelled sugars and sugar derivatives. In consideration of the short half-life of fluorine-18 (T(1/2) = 110 min) synthetic strategies concerning precursor design, labelling conditions and deprotection of the intermediate compounds were developed to guarantee an efficient high radiochemical yield synthesis for diagnostic purposes. Besides some aspects of medical application of 2-deoxy-2-[18F]fluoro-D-glucose, a few synthetic strategies are described reflecting development work on promising 18F-labelled sugars for diagnostic purposes during the last two decades.

Differential Uptake of O-(2-18F-Fluoroethyl)-l-Tyrosine, l-3H-Methionine, and 3H-Deoxyglucose in Brain Abscesses

The amino acid O-(2-18F-fluoroethyl)-l-tyrosine (18F-FET) has been shown to be a useful tracer for brain tumor imaging. Experimental studies demonstrated no uptake of 18F-FET in inflammatory cells but increased uptake has been reported in single cases of human brain abscesses. To explore this inconsistency, we investigated the uptake of 18F-FET in comparison with that of l-[methyl-3H]methionine (3H-MET) and d-3H-deoxyglucose (3H-DG) in brain and calf abscesses in rats. Methods: Abscesses were induced in the brain (n = 9) and calf (n = 5) of Fisher CDF rats after inoculation of Staphylococcus aureus. Five days later, 18F-FET and 3H-MET (n = 10) or 18F-FET and 3H-DG (n = 4) were injected intravenously. One hour after injection the rats were sacrificed, and the brain or calf muscle was investigated using dual-tracer autoradiography. Lesion-to-background ratios (L/B) and standardized uptake values (SUVs) were calculated. The autoradiograms were compared with histology and immunostaining for glial fibrillary acidic protein (GFAP), CD68 for macrophages, and CD11b for microglia. Results: 18F-FET uptake in the area of macrophage infiltration and activated microglia at the rim of the brain abscesses was low (L/B, 1.5 ± 0.4). In contrast, high uptake was observed for 3H-MET as well as for 3H-DG (L/B, 4.1 ± 1.1 for 3H-MET vs. 3.1 ± 1.5 for 3H-DG; P < 0.01 vs. 18F-FET). Results for calf abscesses were similar. In the vicinity of the brain abscesses, slightly increased uptake was noted for 18F-FET (L/B, 1.8 ± 0.3) and 3H-MET (L/B, 1.8 ± 0.4), whereas 3H-DG distribution was normal (L/B, 1.2 ± 0.2). Anti-GFAP immunofluorescence showed a diffuse astrocytosis in those areas. Conclusion: Our results demonstrate that there is no accumulation of 18F-FET in macrophages and activated microglia in experimental brain abscesses, whereas 3H-MET and 3H-DG exhibit high uptake in these cells. Thus, the specificity of 18F-FET for gliomas may be superior to that 3H-MET and 3H-DG. Increased 18F-FET uptake in human brain abscesses appears to be related to reactive astrocytosis.

Electrochemical cell for separation of [18F]fluoride from irradiated 18O-water and subsequent no carrier added nucleophilic fluorination.

An electrochemical cell was designed allowing the anodic deposition of n.c.a. [18F]fluoride solubilized in an 18O-water target and subsequent n.c.a. nucleophilic 18F-fluorination. The recovery of the deposited [18F]fluoride can be achieved in the presence of an aprotic solvent containing a phase-transfer catalyst (PTC). The radioisotope adsorbed electrochemically at the cylindrical surface of a glassy carbon electrode can be dried easily by washing the cell twice with dry aprotic solvents while maintaining a low electric field. This simple washing step makes an azeotropic drying process obsolete. Accordingly, less basic cryptates like [K within 2.2.2.]oxalate or triflate can be used for nucleophilic 18F-fluorination because loss of activity as a consequence of azeotropic drying under conditions of low basicity does not occur. The usefulness of this technique is exemplified for the n.c.a. synthesis of various 18F-labelled compounds. The radiotracers were synthesized with higher radiochemical yields and under much easier conditions than the conventional 18F-fluorination procedure which includes an additional drying step of the PTC.

Positron emission tomography with (18F)methylspiperone demonstrates D2 dopamine receptor binding differences of clozapine and haloperidol

Four schizophrenic patients were investigated with dynamic positron emission tomography (PET) using (18F)fluorodeoxyglucose (FDG) and (18F)methylspiperone (MSP) as tracers. Two schizophrenics were on haloperidol therapy at the time of MSP PET. The other two schizophrenics were treated with clozapine, in one of them MSP PET was carried out twice with different daily doses (100 mg and 450 mg respectively). Neuroleptic serum levels were measured in all patients. Results were compared with MSP PET of two drug-free male control subjects and with a previous fluoroethylspiperone (FESP) study of normals. Three hours after tracer injection specific binding of MSP was observed in the striatum in all cases. The striatum to cerebellum ratio was used to estimate the degree of neuroleptic-caused striatal D2 dopamine receptor occupancy. In the haloperidol treated patients MSP binding was significantly decreased, whereas in the clozapine treated patients striatum to cerebellum ratio was normal. Even the increase of clozapine dose in the same patient had no influence on this ratio. Despite the smaller number of patients the study shows for the first time in humans that striatal MSP binding reflects the different D2 dopamine receptor affinities of clozapine and haloperidol.