ß -[18F]Fluoro Azomycin Arabinoside (ß -[18F]FAZA): Synthesis, Radiofluorination and Preliminary PET Imaging of Murine A431 Tumors.

BACKGROUND: 1-α-D-(5-Deoxy-5-[18F]fluoroarabinofuranosyl)-2-nitroimidazole([18F] FAZA) is a PET radiotracer that demonstrates excellent potential in imaging regional hypoxia, and is clinically used in diagnosing a wide range of solid tumors in cancer patients. [18F]FAZA, however, is radiofluorinated in only moderate recovered radiochemical yield (rRCY, ~12%). It is postulated that the relative stability of the C1' ß-anomeric bond at C5' will make 1-ß-D-(5-fluoro-5-deoxyarabinofuranosyl)-2-nitroimidazole (ß-FAZA), the ß-conformer of FAZA, an attractive candidate for clinical hypoxia imaging. OBJECTIVES: The principle goals were to synthesize ß-FAZA and ß-Ac2TsAZA, the radiofluorination precursor, to establish the radiofluorination chemistry leading to ß-[18F]FAZA, and to investigate the biodistribution of ß-[18F]FAZA in an animal tumor-bearing model using PET imaging. METHODS: The appropriately-protected furanose sugar was coupled with 2-nitroimidazole to afford 1-ß-D-(2,3-di-O-acetylarabinofuranosyl)-2-nitroimidazole (ß-Ac2AZA). Fluorination of ß-Ac2AZA with DAST, followed by alkaline hydrolysis, afforded ß-FAZA (21%). The radiolabeling synthon, 1-ß-D-(5-O-toluenesulfonyl-2,3-di-O-acetylarabinofuranosyl)-2-nitroimidazole (ß-Ac2TsAZA), on radiofluorination using the 18F/K222 complex under various reaction conditions, followed by base-catalyzed deacetylation, afforded ß-[18F]FAZA. ß-[18F]FAZA was radiochemically stable for at least 8 h when stored in aqueous ethanol (8%) at 22 °C. A preliminary PET imaging-based biodistribution study of ß-[18F]FAZA was performed in A431 tumor-bearing nude mice. RESULTS: ß-FAZA and ß-Ac2TsAZA were synthesized in satisfactory yield. Radiochemistry of [18F]FAZA was established. PET images showed strong uptake in hypoxic regions of the tumor. CONCLUSION: The synthesis of ß-FAZA and ß-[18F]FAZA are reported. Radiofluorination of ß-Ac2TsAZA and the deprotection of ß-Ac2[18F]FAZA were facile, but led to a more complex mixture of radiofluorinated by-products than observed with the corresponding precursor of α-[18F]FAZA. PET images were indicative of hypoxia-selective accumulation of ß-[18F]FAZA in tumor.

3'-Deoxy-3'-[(18)F]fluorothymidine (FLT) uptake in breast cancer cells as a measure of proliferation after doxorubicin and docetaxel treatment.

INTRODUCTION: The nucleoside analogue [(18)F]fluorothymidine (FLT) has been designed as a marker of cell proliferation that can be imaged in vivo by positron emission tomography. Clinical pilot studies have demonstrated decreasing FLT uptake following antiproliferative chemotherapy of breast cancer. However, the significance of posttreatment FLT uptake has not been evaluated at the cell level. The aim of this study was to investigate whether FLT uptake detects proliferation inhibition induced by docetaxel or doxorubicin treatment in an in vitro breast cancer model. METHODS: Breast cancer cells (MCF-7) were treated with docetaxel or doxorubicin for 24 h at drug doses inducing 25-99% inhibition of clonogenic survival (IC(25) to IC(99)). Cellular FLT uptake was estimated at 4 h and at 1, 3 and 5 days interval from chemotherapy. [(3)H]Thymidine incorporation and S-phase fraction were measured for comparison. Analysis of variance and the Bland-Altman difference plot were employed for statistical analysis. RESULTS: After treatment, FLT uptake was declined in dependence of the proliferation inhibition mediated by both chemotherapeutic agents (all P<.0001). The decrease of FLT was greater after doxorubicin treatment than after the corresponding docetaxel dose. With doxorubicin (IC(99)), FLT accumulation was reduced by 70% as early as 4 h after treatment. FLT uptake was closely correlated to [(3)H]thymidine incorporation and S-phase fraction (r=.84 to .93). CONCLUSIONS: Right after docetaxel or doxorubicin treatment, FLT uptake corresponds to the reduction of tumor cell proliferation induced. [(18)F]FLT appears promising for monitoring chemosensitivity in breast cancer.

Hypoxia imaging with FAZA-PET and theoretical considerations with regard to dose painting for individualization of radiotherapy in patients with head and neck cancer.

PURPOSE: To evaluate the role of hypoxia positron emission tomography (PET) using [18F]fluoroazomycin-arabinoside (FAZA) in head and neck cancer for radiation treatment planning using intensity-modulated radiotherapy and dose painting. METHODS AND MATERIALS: Eighteen patients with advanced squamous cell head and neck cancer were included. Both FAZA-PET and axial CT were performed using mask fixation. The data were coregistered using software based on mutual information. Contours of tumor (primary gross tumor volume, GTV/CT-P) and lymph node metastases (GTV/CT-N) were outlined manually, and FAZA standardized uptake values (SUVs) were calculated automatically. The hypoxic subvolume (GTV/PET-FAZA) having at least 50% more FAZA uptake than background (mean SUV) neck muscle tissue was contoured automatically within GTV/CT-P (GTV/PET-FAZA-P) and GTV/CT-N (GTV/PET-FAZA-N). RESULTS: The median GTV/PET-FAZA-P was 4.6 mL, representing 10.8% (range, 0.7-52%) of the GTV/CT-P. The GTV/PET-FAZA-P failed to correlate significantly with the GTV/CT-P (p = 0.06). The median GTV/PET-FAZA-N was 4.1 mL, representing 8.3% (range, 2.2-51.3%) of the GTV/CT-N. It was significantly correlated with the GTV/PET-N (p = 0.006). The GTV/PET-FAZA-P was located in a single confluent area in 11 of 18 patients (61%) and was diffusely dispersed in the whole GTV/CT-P in 4 of 18 patients (22%), whereas no hypoxic areas were identified in 3 of 18 patients (17%). The GTV/PET-FAZA-N was outlined as a single confluent region in 7 of 18 patients (39%), in multiple diffuse hypoxic regions in 4 of 18 patients (22%), and was not delineated in 7 of 18 patients (39%). CONCLUSION: This study demonstrates that FAZA-PET imaging could be used for a hypoxia-directed intensity-modulated radiotherapy approach in head and neck cancer.

[11C]Vinblastine syntheses and preliminary imaging in cancer patients.

PURPOSE: The primary aim of this work was to establish a radiolabeling procedure of vinblastine, a vinca alkaloid widely used in chemotherapy, with the positron-emitter carbon-11 for application in positron-emission-tomography (PET) studies in cancer patients. The optimized reaction conditions were transferred to an automated radiosynthesizer system for the preparation of [11C]vinblastine under GMP conditions for human use. We report about the whole body activity distribution after injection of [11C]vinblastine as well as the pharmacokinetic behavior in selected organs and the tumor in two patients that were investigated with [11C]vinblastine PET before chemotherapy. METHODS: For carbon-11 labeling of vinblastine the reaction conditions were determined with respect to the two possible labeling precursors (i.e. [11C]methyl iodide and [11C]diazomethane), solvent, reaction temperature and reaction time. Both, [11C]diazomethane and [11C]methyl iodide were tested as labeling precursors with the corresponding demethyl compound of vinblastine, i.e. the vinblastine acid and the potassium salt of vinblastine acid. Two patients with renal carcinoma underwent [11C]vinblastine PET before chemotherapy. One patient underwent a second scan during infusion of unlabeled vinblastine at a therapeutic dose. RESULTS: Best results for the labeling procedure were found when methylation was carried out at 100 degrees C within 20 min using 2 mg/mL of the potassium salt of vinblastine acid in DMSO and [11C]methyl iodide as labeling precursor. Based on [11C]methyl iodide starting activity a radiochemical yield of up 53 % [11C]vinblastine was achieved. In addition, the synthesis was transferred to a remotely controlled module for routine GMP conform production for human use. In large scale production runs up to 1 GBq of [11C]vinblastine was obtained ready for injection within 45 min after EOB. In one patient, whole body PET scans 40 min after injection of 112 MBq [11C]vinblastine showed a focally increased [11C]vinblastine uptake and [11C]vinblastine metabolite uptake, respectively in the known metastases, along with a slow but continuous washout during the measurement interval (0-60 min p.i.). Another patient showed no focally increased [11C]vinblastine uptake and [11C]vinblastine metabolite uptake in the tumor, where radioactivity concentration was comparable to that in the blood. In this patient, a second PET scan during infusion of unlabeled vinblastine revealed similar kinetics with a trend towards delayed hepatic metabolism and higher blood and tumor concentrations. Whereas this patient showed a partial response to chemotherapy, the first patient did not, hypothetically due to the observed vinblastine washout from the tumor. CONCLUSIONS: The carbon-11 labeling of vinblastine using [11C]methyl iodide is superior to the method using [11C]diazomethane. A well working automated radiosynthesis was established for the production of [11C]vinblastine for PET-investigations in cancer patients. The individual pharmacokinetic behavior of the chemo-therapeutic agent to the tumor can be assessed with PET, thus, can be considered to be a realistic approach for individualized chemotherapy.

Dopamine transporter positron emission tomography in spinocerebellar ataxias type 1, 2, 3, and 6.

BACKGROUND: The spinocerebellar ataxias (SCAs) are a genetically heterogeneous group of autosomal dominant ataxias: some mutations, including SCA1, SCA2, and SCA3, are multisystemic disorders characterized by a variety of noncerebellar symptoms while others, like SCA6, give rise to a pure cerebellar syndrome. OBJECTIVE: To identify impairments of the dopaminergic system and regional changes of glucose metabolism in SCA1, SCA2, SCA3, and SCA6. METHODS: We used [11C]d-threo-methylphenidate and [18F]fluorodeoxyglucose positron emission tomography to identify cerebral dopamine terminal loss and specific regional metabolic patterns in SCA1, SCA2, SCA3, and SCA6. RESULTS: The binding potential of [11C]d-threo-methylphenidate was reduced in the striatum in SCA2 and SCA3; in contrast to patients with Parkinson disease, no increased susceptibility of the putamen was evident. Decreased regional cerebral glucose metabolism was found in the cerebellum of all patients with SCA, the brainstem of SCA1, SCA2, SCA3, the thalamus and putamen of SCA3, and the parietal cortex of patients with SCA2. A trend toward increased regional cerebral glucose metabolism was found in the temporal cortex of all patients with SCA, pronounced in SCA6. CONCLUSIONS: Specific biochemical patterns point to different mechanisms of neuronal dysfunction in SCA1, SCA2, SCA3, and SCA6; dopamine terminal loss is severe in SCA2 but distinct from Parkinson disease.

Prognostic impact of hypoxia imaging with 18F-misonidazole PET in non-small cell lung cancer and head and neck cancer before radiotherapy.

UNLABELLED: In radiotherapy of head and neck cancer (HNC) and non-small cell lung cancer (NSCLC), hypoxia is known to be an important prognostic factor for long-term survival and local tumor control. The PET tracer (18)F-fluoromisonidazole (FMISO) allows noninvasive assessment of tumor hypoxia. This study analyzed whether FMISO PET could predict tumor recurrence after radiotherapy. METHODS: Forty patients with advanced HNC (n = 26) or NSCLC (n = 14) were studied before curative radiotherapy. Dynamic (0-15 min) and static PET scans were acquired up to 4 h after injection of 400 MBq of FMISO. Standardized uptake values (SUVs) and ratios to reference tissues (mediastinum or muscle) were calculated. In addition, time-activity curves up to 14 min after injection were classified visually. PET data were correlated with clinical follow-up data (presence or absence of local recurrence within 1 y), which were available for 21 patients. RESULTS: For HNC, patients with local recurrence could be separated from disease-free patients by SUV 4 h after injection (all recurrences had an SUV > 2). For NSCLC, no such correlation was observed. The tumor-to-muscle ratios (T/Mu) and tumor-to-mediastinum ratios (T/Me) at 4 h after injection correlated with the risk of relapse in both tumor entities: All patients with a T/Me greater than 2.0 (NSCLC, n = 5) or with a T/Mu greater than 1.6 (HNC, n = 5) presented with tumor recurrence, whereas only 3 of the remaining 11 patients experienced recurrence (27%). Qualitative analysis of time-activity curves for 37 patients revealed 3 curve types (rapid washout, n = 9; intermediate [delayed washout], n = 12; and accumulation, n = 16). Eighteen patients categorized by curve type could be followed up: In 5 of 6 patients with an accumulation curve, disease recurred locally within 1 y, compared with 5 of 8 patients with a delayed-washout curve and 0 of 4 with a rapid-washout curve. CONCLUSION: Our results indicate that outcome after radiotherapy can be predicted on the basis of kinetic behavior of FMISO in tumor tissue. An accumulation-type curve, high SUV, and high T/Mu and T/Me at 4 h after injection are highly suggestive of an incomplete response to treatment and might be used to select patients for intensified therapy protocols.

PET with [18F]fluorothymidine for imaging of primary breast cancer: a pilot study.

The aim of this study was to evaluate the use of [(18)F]fluorothymidine (FLT) as a positron emission tomography (PET) tracer for the diagnosis of breast cancer. To this end, 12 patients with 14 primary breast cancer lesions (T2-T4) were studied by FLT-PET. For comparison, [(18)F]fluorodeoxyglucose (FDG) PET scans were performed in six patients. Thirteen of the 14 primary tumours demonstrated focally increased FLT uptake (SUV(mean)=3.4+/-1.1). Seven out of eight patients with histologically proven axillary lymph node metastases showed focally increased FLT uptake in the corresponding areas (SUV(mean)=2.4+/-1.2). The lowest SUV (mean =0.7) was observed in one of two inflammatory cancers. The contrast between primary tumours or metastases and surrounding tissue was high in most cases. In direct comparison to FDG-PET, the SUVs of primary tumours (5/6) and axillary lymph node metastases (3/4) were lower in FLT-PET (SUV(FLT): 3.2 vs SUV(FDG): 4.7 in primary tumours and SUV(FLT): 2.9 vs SUV(FDG): 4.6 in lymph node metastases). Since FLT uptake in surrounding breast tissue was also lower, tumour contrast was comparable to that with FDG. It is of note that normal FLT uptake was very low in the mediastinum, resulting in a higher tumour-to-mediastinum ratio as compared to FDG ( P=0.03). FLT-PET is suitable for the diagnosis of primary breast cancer and locoregional metastases. High image contrast may facilitate the detection of small foci, especially in the mediastinum.

[18F]FLT PET for diagnosis and staging of thoracic tumours.

The nucleoside analogue 3'-deoxy-3'-[18F]fluorothymidine (FLT) has been introduced for imaging of tumour cell proliferation by positron emission tomography (PET). This study evaluated the use of FLT in patients with thoracic tumours prior to treatment. Whole-body FLT PET was performed in 16 patients with 18 tumours [17 thoracic tumours (nine non-small cell lung cancers, five oesophageal carcinomas, two sarcomas, one Hodgkin's lymphoma) and one renal carcinoma] before treatment. Fluorine-18 fluorodeoxyglucose (FDG) PET was performed for comparison except in those patients with oesophageal carcinoma. For semi-quantitative analysis, the average and maximum standardised uptake values (avgSUV and maxSUV, respectively) (FLT, 114+/-20 min p.i.; FDG, 87+/-8 min p.i.; 50% isocontour region of interest) was calculated. All 17 thoracic tumours and 19/20 metastases revealed significant FLT accumulation, resulting in easy delineation from surrounding tissue. The additional small grade 1 renal carcinoma was not detected with either FLT or FDG. In most lung tumours (avgSUV 1.5-8.2) and metastases, FLT showed intense uptake. However, one of two spinal bone metastases was missed owing to the high physiological FLT uptake in the surrounding bone marrow. Oesophageal carcinoma primaries (avgSUV 2.7-10.0) and occasional metastases showed particularly favourable tumour/non-tumour contrast. Compared with FDG, tumour uptake of FLT was lower (avgSUV, P=0.0006; maxSUV, P=0.0001), with a significant linear correlation (avgSUV, r2=0.45; maxSUV, r2=0.49) between FLT and FDG. It is concluded that FLT PET accurately visualises thoracic tumour lesions. In the liver and the bone marrow, high physiological FLT uptake hampers detection of metastases. On the other hand, FLT may be favourable for imaging of brain metastases owing to the low physiological uptake.