[Show abstract][Hide abstract] ABSTRACT: Introduction
Radioimmunotherapy (RIT) with <sup>90</sup>Y-labeled anti-CD66 antibody is used to selectively irradiate the red marrow (RM) before blood stem cell transplantation of acute leukemia patients. To calculate the activity to administer, time-integrated activity coefficients are required. These are estimated prior to therapy using gamma camera and serum measurements after injection of <sup>111</sup>In labeled anti-CD66 antibody. Equal pre-therapeutic and therapeutic biodistributions are usually assumed to calculate the coefficients. However, additional measurements during therapy had shown that this assumption had to be abandoned. A physiologically based pharmacokinetic (PBPK) model was developed to allow the prediction of therapeutic time-integrated activity coefficients in eight patients.
The aims of the study were to demonstrate using a larger patient group 1) the need to perform patient-specific dosimetr
PLoS ONE 05/2015; 10:e0127934. DOI:10.1371/journal.pone.0127934 · 3.23 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Functional nanoparticles are highly interesting imaging agents for positron emission tomography (PET) due to the possibility of multiple incorporation of positron emitting radionuclides thus increasing the signal strength. Furthermore, long-term nanoparticle biodistribution tests with increased signal-to-noise ratio can be achieved with nanoparticles carrying long-lived isotopes. Mesoporous silica nanoparticles, MSNs, have recently attracted a lot of interest as both imaging agents and carriers for drugs in vitro and in vivo. Here we present results related to the synthesis of PET imageable MSNs carrying the long-lived (89)Zr isotope (half-life of 78.4 hours). Here, (89)Zr(4+) was immobilized through covalent attachment of the complexing agent p-isothiocyanatobenzyldesferrioxamine (DFO-NCS) to large-pore MSNs. Due to the presence of the high DFO content on the MSNs, quantitative (89)Zr(4+) labeling was achieved within just a few minutes, and no subsequent purification step was needed in order to remove non-complexed (89)Zr(4+). The stability of the (89)Zr-labeled MSNs against leaching of (89)Zr(4+) was verified for 24 hours. The high signal strength of the (89)Zr-DFO-MSNs was evidenced by successful PET imaging using a mouse model at particle loadings one order of magnitude lower than those previously applied in PET-MSN studies. The biodistribution followed the same trends as previously observed for MSNs of different sizes and surface functionalities. Taken together, our results suggest that (89)Zr-DFO-MSNs are promising PET imaging agents for long-term in vivo imaging.
[Show abstract][Hide abstract] ABSTRACT: Die molekulare Bildgebung mit FDG-PET/CT stellt ein wertvolles Instrument zur Tumorlokalisation, Ausbreitungsdiagnostik und Therapiekontrolle dar. International ist ein breites Indikationsspektrum etabliert, während das deutsche Gesundheitssystem eine deutlich restriktivere Position vertritt. Die Translation innovativer Bildgebungsansätze in die klinische Medizin ist ohne geeignete Förder und Evaluationsinstrumente problematisch.
best practice onkologie 06/2013; 8(3). DOI:10.1007/s11654-013-0073-x
[Show abstract][Hide abstract] ABSTRACT: [11C]Choline-positron emission tomography in combination with computer tomography ([11C]Choline-PET/CT) is a promising imaging approach for localizing relapsing prostate cancer. We therefore studied performance of [11C]Choline-PET/CT in patients relapsing from prostate cancer after radical prostatectomy (RP) and scheduled for salvage radiation therapy (SRT) in terms of relapse localization and relationship to outcome after SRT.
In a prospective pilot study we examined 27 patients with [11C]Coline-PET/CT before SRT. All patients had biochemical relapse after RP and were treated with SRT. [11C]Choline-PET/CT was done within 14 days before SRT.
Eleven of 27 patients had at follow up of 76.5±5.7 months a favorable long-term response to SRT and needed no specific further prostate cancer related treatment. In 16/27 patients, rising serum PSA concentrations were observed 34.2±20.1 months after SRT, qualifying them as treatment failures. Tumor stage, risk profile and PSA before SRT were not different in long term responders and failures. [11C]Choline-PET/CT showed local relapse in about 50% of both long-term responders failures, locoregional nodal relapse in 4/16 failures and a singular bone metastasis in 1/16 failures.
[11C]Choline-PET/CT showed in roughly 50% of patients evidence of local relapse within the prostatic fossa. Roughly 30% of treatment failures had evidence of locoregional nodal or distant metastatic disease outside the radiation ports possibly related to treatment failures after SRT. Kaplan-Meier analysis suggested that [11C]Choline-PET/CT positive patients do worse at follow-up in terms of freedom from biochemical recurrence.
The quarterly journal of nuclear medicine and molecular imaging: official publication of the Italian Association of Nuclear Medicine (AIMN) [and] the International Association of Radiopharmacology (IAR), [and] Section of the Society of.. 10/2012; 56(5):430-9. · 1.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A simple and efficient synthesis of 3,4-dihydroxy-6-[11C]methyl-l-phenylalanine ([11C]MeDOPA) is described by use of Stille cross-coupling reaction between the corresponding tin precursor and [11C]CH3I. The reaction conditions were determined with respect to reaction time and temperature. The best radiochemical yields were obtained at a temperature of 60 °C and a reaction time of 5 min. Deprotection of the 11C-labeled intermediate was carried out by using 9 M HCl at 140 °C for 10 min to afford 6-[11C]methyl-l-DOPA. The overall yield was 63 ± 2.7% with a radiochemical purity >99%. The overall preparation time including hydrolysis, HPLC purification and formulation was 40 min. For reference, 6-methyl-d,l-DOPA was prepared in a four step synthesis and analytically characterized. As a new 11C-labeled amino acid, [11C]MeDOPA exhibits an important alternative to [18F]FDOPA for PET studies of tumors such as the neuroendocrine ones.
Journal of Radioanalytical and Nuclear Chemistry 08/2012; 293(2). DOI:10.1007/s10967-012-1685-2 · 1.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Fluorodeoxyglucose-positron emission tomography (FDG-PET)/computed tomography (CT) is able to localize persistent or recurrent disease in differentiated thyroid carcinoma (DTC). The aim of the study was to correlate PET/CT results with precise intraoperative localization of persistent or recurrent papillary and follicular thyroid carcinoma. Patients with differentiated thyroid carcinoma who received FDG-PET scans were prospectively documented. The PET/CT results were correlated with other localization studies (neck ultrasound, 131I whole-body scan) and accurately compared to intraoperative findings and histopathological examinations. FDG-PET/CT scans were performed in 18 patients, between 16 and 84 years of age, from December 2008 to June 2011. Fourteen patients had papillary thyroid carcinomas and 4 had follicular thyroid carcinomas. All patients had a previous thyroidectomy and radioiodine ablation. Before cervical re-exploration, FDG-PET/CT-positive findings were reported in 14 individuals, whereas 4 PET scans provided no evidence of disease. Intraoperatively, 13 of 14 FDG-PET/CT-positive localizations of recurrent or persistent thyroid carcinomas were verified and confirmed by histopathology (sensitivity 93%). In another patient lymph node metastases of lung cancer were detected intraoperatively. However, FDG-PET/CT underestimated the number of lesions in 5 of 6 patients undergoing systematic lymphadenectomy. No lymph node or soft tissue metastases were found intraoperatively in 3 of the 4 patients with negative FDG-PET scans. A solitary cystic lymph node metastasis was found in the fourth patient but was not detected by FDG-PET/CT (specificity 75%). FDG-PET/CT has high sensitivity and specificity for the detection of persistent or recurrent differentiated thyroid carcinoma. FDG-PET/CT helps to select patients who might benefit from surgery because it provides precise anatomical details.
Hormone and Metabolic Research 07/2012; 44(12). DOI:10.1055/s-0032-1316351 · 2.04 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: A rapid and efficient n.c.a. radiosynthesis of 6-[(11)C]methyldopamine ([(11)C]MeDA) using the Stille cross-coupling reaction as a key step was developed. The labeling conditions for the formation of the intermediate compound (protected [(11)C]MeDA, [(11)C]7) were determined with respect to reaction temperature and time. The radiochemical yield 89 ± 1.4% (decay-corrected) of the protected intermediate [(11)C]7 was obtained at a reaction temperature of 60°C and a reaction time of 5 min using Pd(2)(dba)(3)/P(o-tolyl)(3) and CsF/CuBr as a co-catalyst system. The overall yield after deprotection with 45% HBr at 140°C for 10 min was 64 ± 3.9% (decay-corrected) within a total preparation time of 40 min, including hydrolysis, HPLC purification and formulation.
Applied radiation and isotopes: including data, instrumentation and methods for use in agriculture, industry and medicine 05/2012; 70(8):1475-9. DOI:10.1016/j.apradiso.2012.04.021 · 1.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: An efficient radiosynthesis of [18F]FEt-Tyr-urea-Glu ([18F]FEtTUG) as a new ligand for prostate specific membrane antigen (PSMA) was developed by use of [18F]fluoroethyltosylate as labeling precursor. The corresponding fluoroethyl-tyrosine-urea-glutamate peptide was prepared as reference standard for HPLC control and identified and characterized by standard procedures (MS, NMR). The labeling conditions were optimized with respect to reaction time, reaction temperature, base and solvent. The maximal radiochemical yield of [18F]FEtTUG (77 ± 0.8 %) was obtained within a reaction time of 15 min at a reaction temperature of 80 °C using 10 M NaOH (18 equiv. related to precursor) in 80 % aqueous acetonitrile. The total preparation time including radiosynthesis, hydrolysis, HPLC purification and formulation was 70 min (EOB). The radiochemical purity was ≥98 %.
Journal of Radioanalytical and Nuclear Chemistry 03/2012; 295(3). DOI:10.1007/s10967-012-2293-x · 1.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dosimetry is important in the development of radioactive pharmaceuticals, especially for optimizing radionuclide therapy with respect to risk-benefit analysis. To calculate the applied absorbed doses in the target and risk organs standard phantom masses are frequently used. However, deviations to the true organ mass can lead to suboptimal decisions in dose finding studies. To estimate the magnitude of deviations introduced when using standard phantom masses instead of individual organ masses, we investigated 10 patients treated with radioimmunotherapy using (90)Y labelled anti-CD66 antibody. The use of standard phantom masses instead of individually measured organ masses results in mean deviations for liver, spleen and kidneys of 2% (Min. -22%, Max. 34%), -3% (Min. -34, Max. 100%) und -8% (Min. -37, Max. 38%), respectively. For the administered therapeutic activity differences of -16% (Min. -45%, Max. 4%) were observed depending on the used organ mass. These results demonstrate that using standard phantom masses for dosimetry before radionuclide therapy is not adequate.
[Show abstract][Hide abstract] ABSTRACT: For experimental studies by animal PET [11C]-labeled 15-(4-methylphenyl)pentadecanoic acid (MePPA) is an attractive alternative to the radioiodinated 15-(4-iodophenyl)pentadecanoic
acid (IPPA) which has widely been used for imaging of fatty acid metabolism. The important physiological aspect is that the
iodine atom and the methyl substituent have similar steric and lipophilic properties. For preparation of [11C]MePPA, Stille cross-coupling reaction was applied since the same tin precursor as for the radiosynthesis of IPPA and readily
available [11C]CH3I can be used. Unsaturated tris(dibenzylideneacetone)dipalladium(0)/tri(o-tolyl)phosphine [Pd2(dba)3/P(o-tolyl)3] was taken as the catalytic system. The reaction conditions were optimized with respect to temperature, time, solvent and
amount of precursor. The best radiochemical yields of 73 ± 2.8% (decay corr.) were obtained using 0.525 mg tin precursor in
DMF at 80 °C already after a reaction time of 10 min. The labeled methyl ester was hydrolyzed by 1 M NaOH/EtOH at 80 °C within 3 min to give [11C]IPPA in a RCY of 62 ± 3.0%. The radiochemical purity of the product assured by HPLC was >99% and the overall preparation
time including HPLC purification and formulation was 40 min.
Journal of Radioanalytical and Nuclear Chemistry 06/2011; 288(3):881-886. DOI:10.1007/s10967-011-1022-1 · 1.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: No. 1654 Objectives: For quality control of radiopharmaceuticals, thin layer chromatography (TLC) is the widely used analytical tool. For β-counting Geiger-Müller-detectors (Geiger et al., 1928) and open/closed window proportional gas flow counters (Schulze et al., 1962) are suitable for TLC scanning. For -radiation, scintillating crystals [NaI(Tl); BGO] are in use. However, all detectors suffer from drawbacks as the need of effective collimators for BGO, an appropriate counting gas for proportional counters, limited counting speed for GM tubes and laborious evaluation of a phosphor-imager (PI). Plastic scintillators have high sensitivity to β-, low sensitivity to -radiation and quite short response time. Methods: PPSD comprises of plastic scintillator, 0.5mm thick, mounted on a photomultiplier. [18F]FDG was used for determination of resolution, dynamics and efficiency. Dilutions by a factor up to 10-100 were made. Silica gel plates were used as stationary phase. Aliquots ranging from 0.5µL to 5µL were spotted at distances (2-20mm) from each other on TLCs. Measurements were performed by BGO, GM, PI and PPSD. All experiments were repeated (n=2).
Journal of Nuclear Medicine 01/2011; 52(Supplement 1):1654. · 5.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: No. 1640 Objectives: For metabolic studies of tracers labeled with PET radionuclides and "classic" radionuclides such as C-14 and tritium, on-line detection of β+/β-particles in radio-HPLC is essential.Since special Li-glasses (GS1) are available as internal solid scintillators, we evaluated the applicability of such a detector for metabolites labeled with N-13, C-14 and tritium, F-18, C-11 as well as in dual isotope studies. Methods: HPLC system was used with a Ramona as β-detector (raytest, Germany) in line. For calibration, 13NH3, [18F]FDG (140MBq/0.1mL), [11C]choline (108MBq/0.1mL), [3H]acetic acid (185MBq/mL), and [14C]aspartic acid (3.7MBq/mL),were used. Dilutions by a factor up to 10-100,000 were made. For analysis of 14C-labeled and 3H-labeled amino acids, SCX Partisil column was used. The system was also utilized for assessing the purity of commercially available [14C]proline, [14C]glutamic acid, [14C]aspartic acid, [14C]glutamine, [14C]alanine, [14C]urea (37MBq/mL), [3H]glutamic acid, and [3H]alanine. For dual isotope studies, a mixture of 13N-and 14C-amino acids was analysed by same HPLC conditions. Similar system was used for analysis of 13N-labeled amino acids in animal experiments.
Journal of Nuclear Medicine 01/2011; 52(Supplement 1):1640. · 5.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: No. 1669 Objectives: There are significant metabolic differences between normal tissue and tumors, such as the glutamine metabolism is comparatively higher in tumor cells and essential for biosynthesis of amino acids and nucleotides. For the reactions of the glutamine metabolism ammonia plays a crucial role and is therefore further investigated in the present study. Methods: The turnover of N-13-ammonia into glutamine and further products like urea was studied in SCID mouse xenografts of various cell lines (LNCaP C4-2, PC-3 and TRAMP). The animals were treated with intravenously administered N-13-ammonia for varying times and the tumors were dissected and homogenized afterwards. Insoluble cell fragments were separated and the supernatants were analyzed for N-13-metabolites via radio-HPLC. Blood samples were treated and analyzed similarly. The HPLC-peaks of the N-13 metabolites urea, glutamine and ammonia were collected for additional assay of radioactivity using a -counter. Results: Analysis of xenograft models after incubation with N-13 ammonia revealed radio-labeled metabolites like urea and glutamine as well as ammonia itself. Traces of additional radio-labeled amino acids could also be detected by radio-HPLC. Already 2 min after administration 3.3 ± 5.6 % of the radioactivity within the tumor was verifiable as glutamine increasing to 58.2 ± 14.1 % after 10 min. Also the amount of radio-labeled urea increased from 10.6 ± 6.0 % (2 min) to 28.7 ± 15.2 % (10 min). Correspondingly, the values for N-13-ammonia decreased from 42.8 ± 0.3 % (2 min) to 8.4 ± 6.6 % (10 min). In blood the amount of N-13-glutamine and N-13-urea remained constant over time whereas the level of N-13-ammonia decreased.
Journal of Nuclear Medicine 01/2011; 52(Supplement 1):1669. · 5.56 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: FDG-PET/CT is increasingly used in staging of lung cancer as single "one stop shop" method. AIM, PATIENTS, METHODS: We prospectively included 104 neurological asymptomatic patients (65 years, 26% women) with primary diagnosis of lung cancer. In all patients PET/CT including cerebral imaging and cerebral MRI were performed.
Diagnosis of brain metastases (BM) was made by PET/CT in 8 patients only (7.7%), by MRI in 22 (21.2%). In 80 patients both PET/CT and MRI showed no BM. In 6 patients (5.8%) BM were detectable on PET/CT as well as on MRI. Exclusive diagnosis of BM by MRI with negative finding on PET/CT was present in 16 patients (15.4%). 2 patients (1.9%) had findings typical for BM on PET/CT but were negative on MRI. With MRI overall 100 BM were detected, with PET/CT only 17 BM (p < 0.01). For the diagnosis of BM PET/CT showed a sensitivity of 27.3%, specificity of 97.6%, positive predictive value of 75% and negative predictive value of 83.3%. BM diameter on PET/CT and MRI were consistent in 43%, in 57% BM were measured larger on MRI.
Compared to the gold standard of MRI for cerebral staging a considerable number of patients are falsely diagnosed as free from BM by PET/CT. MRI is more accurate than PET/CT for detecting multiple and smaller BM.
In patients with a curative option MRI should be performed additionally to PET/CT for definitive exclusion of brain metastases.
[Show abstract][Hide abstract] ABSTRACT: A rapid method for the preparation of the radioiodinated 15-(4-iodophenyl)pentadecanoic acid (p-IPPA) was developed. 131I-p-IPPA was obtained from the corresponding tin precursor and 131I-iodide using Chloramine-T as an oxidant in a radiochemical yield of 90 ± 1.4% with a radiochemical purity > 99% when performing the labeling at room temperature within a reaction time of 3 min. The study of dependences on temperature (0, 20 and 80 °C) and reaction time (1, 3, 5, 10 and 30 min) showed no yield increase with higher temperatures and prolonged reaction times but the formation of side products.
Journal of Radioanalytical and Nuclear Chemistry 10/2010; 286(1). DOI:10.1007/s10967-010-0643-0 · 1.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Amyloid aggregates play a major role in the development of Alzheimer's disease. Targeting these aggregates by PET probes enables non-invasively the detection and quantification of amyloid deposit distribution in human brains. Based on benzothiazole core structure a series of amyloid imaging agents were developed. Currently [(11)C]2-(4'-(methylamino)phenyl)-6-hydroxybenzothiazole (Pittsburgh Compound-B (PIB) is the most specific and widely used amyloid imaging ligand. But due to the short half life of (11)C, longer lived (18)F-labeled derivatives offer logistic advantages and higher contrast images. In this work, three different [(18)F]fluoroethoxy-substituted benzothiazole derivatives ([(18)F]2-(4'-(methylamino)phenyl)-6-(2-fluoroethoxy)benzothiazole, [(18)F]2-((2'-(2-fluoroethoxy)-4'-amino)phenyl)benzothiazole and [(18)F]2-(3'-((2-fluoroethoxy)-4'-amino)phenyl)benzothiazole) were synthesized via [(18)F]fluoroethylation. The latter two derivatives with fluoroethoxy-substitution on the aromatic amino group showed very low binding affinity for amyloid aggregates. In contrast [(18)F]2-(4'-(methylamino)phenyl)-6-(2-fluoroethoxy)benzothiazole with [(18)F]fluoroethoxy-substitution in 6-position showed excellent amyloid imaging properties with respect to lipophilicity, brain entry and brain clearance in normal SCID mice, amyloid plaque binding affinity and specificity.
Applied radiation and isotopes: including data, instrumentation and methods for use in agriculture, industry and medicine 06/2010; 68(6):1066-72. DOI:10.1016/j.apradiso.2009.12.044 · 1.06 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Myotonic dystrophy type 1 and 2 (DM1/DM2) are multisystemic diseases with common cognitive deficits beside the cardinal muscular symptoms. We performed a comprehensive analysis of cerebral abnormalities to compare the neuropsychological defects with findings in different imaging methods in the same cohort of patients.
Neuropsychological investigations, structural cerebral MRI including brain parenchymal fraction (BPF) and voxel-based morphometry (VBM), and (18)F-deoxy-glucose PET (FDG-PET) were performed in patients (20 DM1 and 9 DM2) and matched healthy controls, and analyzed using statistical parametric mapping (SPM2).
DM1 and DM2 patients showed typical neuropsychological deficits with a pronounced impairment of nonverbal episodic memory. Both patient groups showed a reduction of the global gray matter (measured by BPF), which could be localized to the frontal and parietal lobes by VBM. Interestingly, VBM revealed a bilateral hippocampal volume reduction that was correlated specifically to both a clinical score and episodic memory deficits. VBM also revealed a pronounced change of thalamic gray matter. White matter lesions were found in >50% of patients and their extent was correlated to psychomotor speed. FDG-PET revealed a frontotemporal hypometabolism, independent of the decrease in cortical gray matter. All abnormalities were similar in both patient groups but more pronounced for DM1.
Our results suggest that 1) some of the characteristic cognitive deficits of these patients are linked to specific structural cerebral changes, 2) decreases in gray matter and metabolism are independent processes, and 3) the widespread brain abnormalities are more pronounced in DM1.
[Show abstract][Hide abstract] ABSTRACT: In radioimmunotherapy (RIT) preloading is a common strategy to improve biodistribution. The amount of unlabeled antibody is
usually administered relative to the body surface area. However, studies have shown a considerably large interpatient variation
of the biodistribution for the same preload. In this work, as a prerequisite for individualizing RIT, a physiologically based
pharmacokinetic (PBPK) model for RIT using anti-CD20 antibody is developed and simulations are conducted based on physiological
parameter values taken from the literature. The influence of different amounts of preloads for varying lymphoma transcapillary
recirculation rates is determined. It is shown that – depending on the convection of antibody across the transvascular wall
– an optimal preload amount does exist. For slow transport across the capillaries higher amounts of antibody as a preload
are needed to sustain the flow into the interstitium (100 – 600 mg). For more rapid transport across the microvascular wall
less unlabeled antibody is required (7.5 – 12 mg) to achieve the optimal lymphoma uptake. Thus, identifying the optimal dose
for each patient or lymphoma, i.e., personalizing RIT, could considerably improve the biodistribution while saving antibody