Michael Herz

O-(2-[18F]fluoroethyl)-L-tyrosine and L-[methyl-11C]methionine uptake in brain tumours: initial results of a comparative study.

Abstract.O-(2-[18F]Fluoroethyl)-l-tyrosine (FET) is a recently described amino acid analogue that has shown high accumulation in animal tumours. The aim of this study was to compare the uptake of FET with that of l-[methyl-11C]methionine (MET) in patients with suspected primary or recurrent intracerebral tumours. Sixteen consecutive patients with intracerebral lesions were studied on the same day by positron emission tomography (PET) using MET and FET. Uptake of FET and MET was quantified by standardized uptake values. Tracer kinetics for normal brain and intracerebral lesions were compared. On the basis of the MET-PET studies, viable tumour tissue was found in 13 patients. All tumours showed rapid uptake of FET and were visualized with high contrast. Mean uptake of FET for normal grey matter, white matter and tumour tissue was 1.1±0.2, 0.8±0.2 and 2.7±0.8 SUV, respectively. In all three tissues, uptake of MET was slightly higher (1.4±0.2, 0.9±0.1 and 3.3±1.0 SUV; P<0.01). However, contrast between tumour and normal tissues was not significantly different between MET and FET. Uptake of FET in non-neoplastic lesions (1.0±0.1 SUV) was significantly lower than in tumour tissue (P=0.007). For all lesions there was a close correlation (r=0.98) between MET and FET uptake. In conclusion, in PET studies of human brain tumours, the uptake and image contrast of FET appear to be very similar to those of MET. The specificity of FET for tumour tissue is promising but has to be addressed in a larger series of patients with non-neoplastic lesions.

Metabolic characterization of breast tumors with positron emission tomography using F-18 fluorodeoxyglucose.

PURPOSEnTo evaluate the diagnostic value of position emission tomographic (PET) imaging with F-18 fluorodeoxyglucose (FDG) in differentiating between benign and malignant breast tumors.nnnPATIENTS AND METHODSnFifty-one patients, with suspicious breast lesions newly discovered either by physical examination or by mammography, underwent PET imaging before exploratory surgery. FDG-PET images of the breast were analyzed visually and quantitatively for objective assessment of regional tracer uptake.nnnRESULTSnPrimary breast cancer was identified visually with a sensitivity of 68% to 94% and a specificity of 84% to 97% depending on criteria used for image interpretation. Quantitative analysis of FDG uptake in tumors using standardized uptake values (SUV) showed a significant difference between benign (1.4 +/- 0.5) and malignant (3.3 +/- 1.8) breast tumors (P < .01). Receiver operating characteristic (ROC) curve analysis exhibited a sensitivity of 75% and a specificity of 100% at a threshold SUV value of 2.5. Sensitivity increased to 92% with a corresponding specificity of 97% when partial volume correction of FDG uptake was performed based on independent anatomic information.nnnCONCLUSIONnPET imaging allowed accurate differentiation between benign and malignant breast tumors providing a high specificity. Sensitivity for detection of small breast cancer ( < 1 cm) was limited due to partial volume effects. Quantitative image analysis combined with partial volume correction may be necessary to exploit fully the diagnostic accuracy. PET imaging may be helpful as a complimentary method in a subgroup of patients with indeterminate results of conventional breast imaging.

PET imaging of somatostatin receptors: design, synthesis and preclinical evaluation of a novel 18F-labelled, carbohydrated analogue of octreotide

Abstract. Because of the excellent nuclear properties of fluorine-18 and the growing interest in somatostatin receptor (sst) scintigraphy with PET, a novel carbohydrated 18F-labelled sst ligand was developed and preclinically evaluated. Synthesis of Nα-(1-deoxy-D-fructosyl)-Nε-(2-[18F]fluoropropionyl)-Lys0-Tyr3-octreotate ([18F]FP-Gluc-TOCA) was completed in ~3xa0h (20%–30% yield). [19F]FP-Gluc-TOCA showed no affinity to hsst1 and hsst3, moderate affinity to hsst4 (IC50: 437±84xa0nM) and hsst5 (IC50: 123±8.8xa0nM) and very high affinity to hsst2 (IC50: 2.8±0.4xa0nM). As a result of carbohydration, lipophilicity of [18F]FP-Gluc-TOCA was found to be low (lg POW=–1.70±0.02). In mice, the tracer was rapidly cleared via renal excretion (kidneys: 8.69%±1.09%ID/g) and showed low uptake in liver (0.72%±0.14%ID/g) and intestine (1.88%±0.52%ID/g) and high tumour uptake (13.54%±1.47%ID/g) (all data at 1xa0h p.i.). Tumour to non-tumour ratios at 60xa0min p.i. reached 25, 19, 7, 1.6 and 56 for blood, liver, intestine, kidney and muscle, respectively. A similar biodistribution pattern was observed in pancreatic tumour-bearing rats. Tumour uptake in rats was reduced to 36% and 18% of control (30 and 60xa0min) by co-injection of 500xa0µg Tyr3-octreotide, demonstrating sst-specific uptake. In a first [18F]FP-Gluc-TOCA-PET study of a patient with a metastatic carcinoid in the liver the tracer showed superior pharmacokinetics, e.g. rapid urinary excretion and low uptake in liver, kidney and spleen. Multiple liver lesions (SUVs ranging from 21.4 to 38.0) and previously unknown focal uptake in the abdomen (SUV 10.0) were clearly visible. This is the first report on PET imaging using an 18F-labelled sst binding peptide; it indicates that [18F]FP-Gluc-TOCA offers excellent imaging characteristics and allows sst imaging with high tumour to non-tumour contrast.

Differential diagnosis of CNS lesions in AIDS patients by FDG-PET

Objective The aim of this study was to evaluate the potential of FDG-PET in the differential diagnosis of CNS lesions in patients with AIDS, particularly to differentiate between toxoplasmosis and lymphoma. Materials and Methods We examined 11 AIDS patients, 6 with toxoplasmosis, I with a tuberculoma, and 4 with a primary CNS lymphoma. The FDG uptake within the lesion was compared with the uptake in a contralateral brain area [standardized uptake value (SUV)]. Results In all subjects with cerebral infections (toxoplasmosis, tuberculoma), the SUV ratio was significantly (p < 0.05) lower than the SUV ratio in patients with lymphoma (range of 0.3–0.7 vs. 1.7–3.1) with no overlap of the uptake values. Conclusion In conclusion, FDG-PET may help to characterize these lesions metabotically and play an important role in the clinical management of AIDS patients with CNS involvement.

First 18F-Labeled Tracer Suitable for Routine Clinical Imaging of sst Receptor-Expressing Tumors Using Positron Emission Tomography

Purpose: Despite excellent radionuclide characteristics, no 18F-labeled peptides are available for quantitative peptide receptor mapping using positron emission tomography (PET) so far, mainly due to time-consuming multistep radiosyntheses with limited overall yields. A newly developed two-step chemoselective conjugation method allows rapid and high-yield [18F]fluorination of peptides via oxime formation and was applied for the synthesis of new 18F-labeled carbohydrated Tyr3-octreotate (TOCA) analogs with optimized pharmacokinetics suitable for clinical routine somatostatin-receptor (sst) imaging. Experimental Design:18F-labeled glucose (Gluc-S-) and cellobiose (Cel-S-) derivatives of aminooxy-functionalized TOCA were synthesized via oxime formation with 4-[18F]fluorobenzaldehyde ([18F]FBOA-peptides). Both the in vitro internalization profile of Gluc-S-Dpr([18F]FBOA)TOCA and Cel-S-Dpr([18F]FBOA)TOCA in hsst2-expressing Chinese hamster ovary cells (dual tracer protocol) and their biodistribution in AR42J tumor-bearing mice were investigated and compared with two [18F]fluoropropionylated ([18F]FP) analogs, Gluc-Lys([18F]FP)TOCA and Gluc-S-Dpr([18F]FP)TOCA. Results: In contrast to [18F]FP-labeling (3 h), chemo-selective [18F]FBOA-formation (50 min) afforded the respective radiopeptides in high yields (65–85%). In vitro, Gluc-S-Dpr([18F]FBOA)TOCA and Cel-S-Dpr([18F]FBOA)-TOCA showed high internalization (139 ± 2 and 163 ± 8 of the reference [125I]Tyr3-octreotide, respectively), which was reflected by high tumor accumulation in vivo [21.8 ± 1.4 and 24.0 ± 2.5% of injected dose/g (1 h), respectively]. How-ever, only Cel-S-Dpr([18F]FBOA)TOCA and Gluc-S-Dpr([18F]FP)TOCA (tumor: 15.1 ± 1.5% of injected dose/g) with its very low accumulation in all of the nontarget organs showed improved tumor:organ ratios compared with Gluc-Lys([18F]FP)TOCA. For Cel-S-Dpr([18F]FBOA)TOCA,tumor:organ ratios (1 h) were 42:1, 27:1, 15:1, 3:1, and 208:1 for blood, liver, intestine, kidney, and muscle, respectively. Conclusion: Due to the fast and high-yield chemoselective radiofluorination strategy and to its excellent pharmacokinetics, Cel-S-Dpr([18F]FBOA)TOCA represents the first tracer suitable for routine clinical application in PET somatostatin receptor imaging.

Chemoselective pre-conjugate radiohalogenation of unprotected mono- and multimeric peptides via oxime formation

Abstract As part of our ongoing efforts in the development of new 18F-labeled peptides for clinical PET imaging, a new two-step 18F-labeling methodology based on the chemoselective oxime formation between an unprotected aminooxy-functionalized peptide and a 18F-labeled aldehyde was investigated and optimized. 4-[18F]Fluorobenzaldehyde ([18F]FB-CHO) was prepared by direct n.c.a. fluorination of 4-formyl-N,N,N-trimethylanilinium triflate and purified by radio-HPLC or a strong-cation-exchange/reverse phase cartridge system. The aminooxyacetic acid (Aoa) modified model peptide LEF-NH2 (Leu-Glu-Phe-NH2) and monomeric, dimeric and tetrameric RGD-containing cyclopeptides were synthesized by solid phase peptide synthesis. Radiochemical yields of N-(4-[18F]fluorobenzylidene)-oxime-formation ([18F]FBOA) with the Aoa-modified unprotected peptides were investigated. Optimized reaction conditions (60 °C, 0.5 mM peptide, 15 min, aqueous solution, pH 2.5) resulted in 70%-90% conjugation yields for all unprotected peptides studied. Chemoselectivity was demonstrated in competition experiments with amino acid mixtures. Biodistribution in M21 melanoma bearing mice showed improved tumor uptake and excretion behaviour in the series c(RGDfE)HEG-Dpr-[18F]FBOA < (c(RGDfE)HEG)2K-Dpr-[18F]FBOA < ((c(RGDfE)HEG)2K)2K-Dpr-[18F]FBOA. Two hours p.i. the fraction of intact c(RGDfE)HEG-K-Dpr-[18F]FBOA in blood, liver, kidney and tumor was >90%, indicating high in vivo stability of the oxime linkage. Initial PET studies with ((c(RGDfE)HEG)2-K)2-K-Dpr-[18F]FBOA showed excellent imaging of M21-melanomas in mice. In conclusion, the new two-step chemoselective 18F-labeling fulfills all requirements for large scale syntheses of peptides in clinical routine. This methodology is also adaptable to other radioisotopes (e.g. radiohalogenation in general) and will thus offer a broad field of application.

Differentiation of tumour and inflammation: characterisation of [methyl-3H]methionine (MET) and O-(2-[18F]fluoroethyl)-L-tyrosine (FET) uptake in human tumour and inflammatory cells.

PurposePrevious studies suggest that radiolabelled amino acids could be superior to FDG in differentiating tumour and inflammation. Therefore the aim of this study was to investigate the uptake of FET and MET in human tumour and inflammatory cells and to investigate their uptake kinetics.MethodsFor uptake studies, cells were incubated with 370xa0kBq FET or 3.7xa0kBq MET for 15xa0min. Kinetic studies were performed at variable concentrations of FET and MET. Competitive inhibition studies were done with BCH, MeAIB and L-serine.ResultsAll inflammatory cells incorporated more MET than the tumour cells. The uptake of FET, in contrast, was significantly lower in all inflammatory cells than in the tumour cells. In tumour cells the uptake of MET was about five times the uptake of FET. The competitive inhibitors reduced uptake of both tracers to 20–40% in tumour cells and to 70% in inflammatory cells. Kinetic studies showed that MET and FET transport was saturable in all cells except macrophages and followed a Michaelis-Menten kinetic. Highest capacity (Vmax) and affinity (Km) for the uptake of MET was observed in granulocytes. Capacity and affinity for FET uptake were highest in the DHL-4 cells.ConclusionIn contrast to MET, FET accumulated to a significantly greater extent in tumour cells than in inflammatory cells. The marked differences between tumour and inflammatory cells concerning FET and MET uptake suggest that FET and MET are substrates of different subtypes of the L system.

Preclinical evaluation of 4-[18F]fluoroprolines: diastereomeric effect on metabolism and uptake in mice

The aim of this study was to evaluate the diastereomeric effect on uptake and metabolic behavior of (2S,4R)-4-[18F]fluoro-L-proline (trans-[18F]FPro) and (2S,4S)-4-[18F]fluoro-L-proline (cis-[18F]FPro) in view of their potential suitability as tracers for abnormal collagen synthesis. No-carrier-added 4-[18F]fluoro-L-prolines were prepared according to the literature in about 150 min (50-60% radiochemical yield). Both compounds exhibited high in vivo stability. The tumor uptake of cis-[18F]FPro in osteosarcomas of mice was high and at 240 min postinjection reached 11.8 +/- 2.2 %ID/g compared with 7.07 +/- 1.68 %ID/g for trans-[18F]FPro. In contrat to trans-[18F]FPro, which showed fast and complete renal clearance, the cis isomer was accumulated in the pancreas, and showed hepatic clearance and renal reuptake. Speciation studies on tissue homogenates revealed protein incorporation only for cis-[18F]FPro. However, due to the relatively slow protein incorporation rate of cis-[18F]FPro, the tumor uptake of both compounds in colon carcinomas, mammary carcinomas, and osteosarcomas 1 h postinjection predominantly reflect amino acid transport.

Evaluation of 18F-Fluoride PET/MR and PET/CT in Patients with Foot Pain of Unclear Cause

Our objective was to compare the quality and diagnostic performance of 18F-fluoride PET/MR imaging with that of 18F-fluoride PET/CT imaging in patients with foot pain of unclear cause. Methods: Twenty-two patients (9 men, 13 women; mean age, 48 ± 18 y; range, 20–78 y) were prospectively included in this study and underwent a single-injection dual-imaging protocol with 18F-fluoride PET/CT and PET/MR. At a minimum, the PET/MR protocol included T1-weighted spin echo and proton-density fat-saturated sequences in 2 planes each with simultaneous acquisition of PET over 20 min. PET/CT included a native isotropic (0.6 mm) diagnostic CT scan (80 kV, 165 mAs) and a subsequent PET scan (2 min per bed position). By consensus, 2 masked interpreters randomly assessed both PET datasets for image quality (3-point scale) and for the presence of focal lesions with increased 18F-fluoride uptake (maximum of 4 lesions). For each dataset (PET/CT vs. PET/MR), the diagnoses were defined using both PET and a morphologic dataset. Standardized uptake values (SUVs) from the 2 devices were compared using linear correlation and Bland–Altman plots. Moreover, we estimated the potential for dose reduction for PET/MR compared with PET/CT considering the longer acquisition time of PET/MR analyzing count rate statistics. Results: Image quality was rated diagnostic for both PET datasets. However, with a mean rating of 3.0/3 for PET/MR and 2.3/3 for PET/CT, image quality was significantly superior for PET/MR (P < 0.0001). The sensitivity of the PET datasets in PET/MR and PET/CT was equivalent, with the same 42 lesions showing focal 18F-fluoride uptake. In PET/MR, the mean SUVmean was 10.4 (range, 2.0–67.7) and the mean SUVmax was 15.6 (range, 2.9–94.1). In PET/CT, the corresponding mean SUVmean of PET/CT was 10.2 (range, 1.8–55.6) and the mean SUVmax was 16.3 (range, 2.5–117.5), resulting in a high linear correlation coefficient (r = 0.96, P < 0.0001, for SUVmean and for SUVmax). A final consensus interpretation revealed the most frequent main diagnoses to be osteoarthritis, stress fracture, and bone marrow edema. PET/CT was more precise in visualizing osteoarthritis, whereas PET/MR was more specific in nondegenerative pathologies because of the higher soft-tissue and bone marrow contrast. The longer acquisition time of MR compared with CT would potentially allow 18F-fluoride dose reduction using hybrid 18F-fluoride PET/MR imaging of at least 50% according to the counting rate analysis. Conclusion: In patients with foot pain of unclear cause, 18F-fluoride PET/MR is technically feasible and is more robust in terms of image quality and SUV quantification than 18F-fluoride PET/CT. In most patients, 18F-fluoride PET/MR provided more diagnostic information at a higher diagnostic certainty than did PET/CT. Thus, PET/MR combines the high sensitivity of 18F-fluoride PET to pinpoint areas with the dominant disease activity and the specificity of MR imaging for the final diagnosis with the potential for a substantial dose reduction compared with PET/CT.

Comparison of 18F-Labeled Fluoroalkylphosphonium Cations with 13N-NH3 for PET Myocardial Perfusion Imaging

Despite substantial advances in the diagnosis of cardiovascular disease, there is a need for 18F-labeled myocardial perfusion agents for the diagnosis of ischemic heart disease because current PET tracers for myocardial perfusion imaging have a short half-life that limits their widespread clinical use in PET. Thus, 18F-labeled fluoroalkylphosphonium derivatives (18F-FATPs), including (5-18F-fluoropentyl)triphenylphosphonium cation (18F-FPTP), (6-18F-fluorohexyl)triphenylphosphonium cation (18F-FHTP), and (2-(2-18F-fluoroethoxy)ethyl)triphenylphosphonium cation (18F-FETP), were synthesized. The myocardial extraction and image quality of the 18F-FATPs were compared with those of 13N-NH3 in rat models. Methods: The first-pass extraction fraction (EF) values of the 18F-FATPs (18F-FPTP, 18F-FHTP, 18F-FETP) and 13N-NH3 were measured in isolated rat hearts perfused with the Langendorff method (flow velocities, 0.5, 4.0, 8.0, and 16.0 mL/min). Normal and myocardial infarction rats were imaged with small-animal PET after intravenous injection of 37 MBq of 18F-FATPs and 13N-NH3. To determine pharmacokinetics, a region of interest was drawn around the heart, and time–activity curves of the 18F-FATPs and 13N-NH3 were generated to obtain the counts per pixel per second. Defect size was analyzed on the basis of polar map images of 18F-FATPs and 13N-NH3. Results: The EF values of 18F-FATPs and 13N-NH3 were comparable at low flow velocity (0.5 mL/min), whereas at higher flows EF values of 18F-FATPs were significantly higher than those of 13N-NH3 (4.0, 8.0, and 16.0 mL/min, P < 0.05). Myocardium-to-liver ratios of 18F-FPTP, 18F-FHTP, 18F-FETP, and 13N-NH3 were 2.10 ± 0.30, 4.36 ± 0.20, 3.88 ± 1.03, and 0.70 ± 0.09, respectively, 10 min after injection, whereas myocardium-to-lung ratios were 5.00 ± 0.25, 4.33 ± 0.20, 7.98 ± 1.23, and 2.26 ± 0.14, respectively. Although 18F-FATPs and 13N-NH3 sharply delineated myocardial perfusion defects, defect size on the 13N-NH3 images was significantly smaller than on the 18F-FATP images soon after tracer injection (0–10 min, P = 0.027). Conclusion: 18F-FATPs exhibit higher EF values and more rapid clearance from the liver and lung than 13N-NH3 in normal rats, which led to excellent image quality in a rat model of coronary occlusion. Therefore, 18F-FATPs are promising new PET radiopharmaceuticals for myocardial perfusion imaging.