bluuebunny/crossref_metadata_2025_split huggingface dataset:
Characterisation of co‐polymer targeting of doxorubicin and its iodinated conjugate in tumour models
Authors: Klinski E. , Li S. , Zweit J. , Hadfield J. , Bailey J. , Alakhov V. , Ranson M. 
Published: April 2012

AbstractThis study was undertaken towards enabling PET imaging of polymer‐based drug delivery. Iodinated doxorubicin conjugate (DOXIB) was characterised against un‐conjugated DOX within and outside a polymer formulation in tumour cell lines and tumour bearing animal models. The results provide the basis for developing the feasibility of [124I]‐DOXIB PET to assess in vivo pharmacokinetics of drug formulation.
A DNA‐intercalating complex of a pyrene derivative with the 188Re(CO)3‐moiety as a potentially improved radiotherapeutic drug
Authors: Haefliger P. , Ortner K. , Alberto R. 
Published: April 2012

AbstractThe effectiveness of radiotherapy with the 188Re nuclide could be improved by inducing damage selectively to the DNA of the cancerous cells, which is more sensitive to radiations than the rest of the cell. A complex of a 188Re(CO)3 core with a pyrene derivative has been synthesized for further investigation of the proof of principle that DNA localized 188Re can cause DNA strandbreaks at. low activity conc entrations.
The mixed ligand [2+1] approach: An easier way of labeling the [M(CO)3]+ core (M=99,99MTC, RE)?
Authors: Ortner K. , Kündig M. , Mundwiler S. , Alberto R. 
Published: April 2012

AbstractWithin the mixed ligand [2+1] approach several model complexes of the general formula [99mTc(OH2)(L∩L)(CO)3] have been synthesized in one step starting from [TcO4]−. Only one bidentate ligand co‐ordinates to the metal centre allowing the co‐ordination of a monodentate ligand which can easily be connected to a biomolecule. Our labeling experiments of peptides bound to a monodentate ligand show that the [2+1] approach is possibly too slow for a radiopharmaceutical application. A similar approach with the biomolecule bound to a bidentate chelator overcomes these disadvantages but retains advantages of the mixed ligand concept.
99MTc‐C‐Deoxyglucose: Synthesis, cellular uptake, biodistribution and scintigraphic imaging
Authors: Yang D. J. , Azhdarinia A. , Yu D‐F , Kim E. E. , Podoloff D. A. 
Published: April 2012

AbstractThis study was aimed to synthesize 99mTc‐ethylenedicysteine‐deoxyglucose (EC‐DG) and determine in vitro cellular uptake and in vivo biodistribution and imaging feasibility in tumor‐bearing rodents. Experimental: Synthesis of EC‐deoxyglucose (EC‐DG) was carried out by reacting EC with glucosamine using carbodiimide as a coupling agent. After dialysis the chemical yield was 70%. By adding pertechnetate in the presence of tin chloride (0.1 mg) to EC‐DG (20–100 mg), the radiochemical yield was achieved 70–100% as determined by radio‐TLC. Hexokinase assays of EC‐DG were performed at UV wavelength 340 nm. In vitro cellular uptake assay was conducted by using a human lung cancer cell line (A549). Each well containing 80,000 cells was added d‐ and 1‐glucose (1 mg and 2.0 mg) along with 2μCi of 99mTc‐EC‐deoxyglucose and 18F‐FDG. After incubation, the cells were washed. A gamma counter counted the cells. To determine whether blood glucose level could be induced by EC‐DG and suppressed by insulin, normal Fischer 344 rats were fasting overnight prior to the experiments. The baseline of blood glucose level (mg/dl) was measured by a glucose meter. Each rat was administered 1.2 mmol/kg (i.v.) of glucosamine, FDG and EC‐deoxyglucose. In a separate experiment, rats were administered EC‐DG and FDG, and then insulin (5 units) was administered after 30 minutes. Blood samples were collected from tail vein every 30‐min up to 6 hrs post‐administration. For breast tumor‐bearing animal model, female Fischer 344 rats (150±25 g) were inoculated with tumor cells (106 cells/rat, s.c. derived from DMBA‐induced tumor cell line) into the hind legs. For lung tumor‐bearing animal model, each athymic nude mouse (20–25g) was inoculated (s.c.) with 0.1 ml of human lung tumor cells from the A549 tumor cell line suspension into the hind legs. Studies performed 17 to 21 days after implantation when tumors reached approximately 0.6–1.0 cm diameter. Each animal was injected (i.v.) with 10 μCi (per rat) or 1 μCi (per mouse) of 99mTc‐EC, 99mTc‐EC‐DG and FDG (standard) (n=3/time point). The injected mass of 99mTc‐EC‐DG was 1 mg per rodent. Following administration of the radiotracers, the rodents were sacrificed at 0.5–4 hrs and the selected tissues were excised, weighed and counted for radioactivity. Scintigraphic images were obtained 0.5–4 hours after i.v. injection of 100 μCi of the radiotracer. Results: EC‐DG showed positive hexokinase assay. By adding d‐glucose, a decreased uptake of 99mTc‐EC‐DG and 18F‐FDG was observed. Blood glucose level was induced by glucosamine, FDG and EC‐DG. This increased blood glucose level could be suppressed by co‐administration of EC‐DG or FDG and insulin. Compare to 99mTc‐EC and free 99mTc, tumor‐to tissue count density ratios increased as a function of time in 99mTc‐EC‐DG group. Brain and heart uptake was less than FDG. Tumor/brain and tumor/muscle ratios were higher than FDG. Tumor could be visualized well when compared to 99mTc‐EC (control group).
Synthesis of derivatized cyclopentadienyl‐tricarbonyl complexes of 99MTC in water with an in situ co source
Authors: Alberto Roger , Wald Joachim , Ortner Kirstin , Candreia Lukas , Pietzsch H.‐J. 
Published: April 2012

AbstractWe want to present herein an improved and general synthesis of [(R‐Cp)99mTc(CO)3] directly from water, where R represents simple organic substituents like benzoyl or acetyl, but also CNS receptor ligands from i.e. the aryl‐piperazine type (WAY) binding to the serotonergic receptor.
Preraration of a new 99mTc nitrido complex and its biodistribution in mice
Authors: Zhang J. B. , Wang X. B. 
Published: April 2012

AbstractThe complex 99mTcN‐CBDTC(CBDTC: N‐cyclobutyl dithiocarbamato) was synthesized by the reduction of 99mTcO4− into [99mTcN]2+ with stannous chloride in the presence of succinic dihydrazide and propylenediamine tetraacetic acid, followed by the addition of sodium N‐cyclobutyl dithiocarbamate trihydrate. Biodistribution in mice showed that the complex was significantly retained into the brain. The brain uptake(ID%/g) was 3.61, 3.15 and 2.62 and the brain/blood ratio was 1.00, 1.44 and 1.30 at 5, 30 and 60min post‐injection, respectively. The results for the complex suggested that it could be a potential brain‐perfusion imaging agent.
Labeling of anti‐elastin antibody with technetium‐99m
Authors: de Oliveira M. B. N. , da Silva C. R. , Lorena D. E. , Caldeira‐De‐Araújo A. , Porto L. C. M. S. , Souza J. E. Q. , Bernardo‐Filho M. 
Published: April 2012

AbstractElastin is the functional protein component of the elastic fiber and it is related with some diseases such as atherosclerosis and pulmonary emphysema. The present study refers to the preparation of the 99mTc labeled monoclonal anti‐elastin antibody. The monoclonal antibody was incubated. with an excess of 2‐iminothiolane. The radiochemical controls were carried out. Then, it was passed through a Sephadex G50 column. A peak corresponding to the radiolabeled antibody was obtained. The biodistribution pattern of the 99mTc‐anti‐elastin was studied in healthy male Swiss mice and the uptake of this labeled antibody was mainly in liver and kidneys. The results indicate that the labeled technique is simple, produces high labeling yields and has not been found to alter the immunochemical properties of the antibody.
A preliminary comparison of methods for production of 188Re‐C595 antibody for radioimmunotherapy of bladder cancer
Authors: Murray A. , Scholfield D. P. , Schibli R. , Novak I. , Waibel R. , Vincent R. M. , Perkins A. C. 
Published: April 2012

AbstractTwo different methods (reduction mediated and carbonyl labelling) for conjugating 188Re to an anti‐tumour monoclonal antibody are described. The radioimmunoconjugates produced were analysed for stability, immunoreactivity, specificity and homogeneity. This indicated that although the two conjugates were comparable in terms of specificity and homogeneity, the carbonyl labelled preparation was more stable. Tumour localisation of both conjugates was confirmed in an ex vivo model of bladder cancer. It is concluded that although both radioimmunoconjugates have potential for intravesical therapy of bladder cancer, carbonyl labelling may offer a method with increased stability.
Comparison of 99mTc octreotide‐tetramine conjugates with in vitro and in vivo affinity for the somatostatin receptor
Authors: Nikolopoulou A. , Maina T. , Nock B. , Tsipra C. , Poppe M. , Mäcke H. , Chiotellis E. 
Published: April 2012

AbstractGiven that many cancer cells overexpress somatostatin (SMS) receptors on their membrane, several SMS analogs labeled with radionuclides have been developed aiming at the scintigraphic diagnosis and/or radiotherapy of SMS‐positive neoplasms. Thus, a synthetic analog of the peptide hormone somatostatin (SMS) labeled with 111In (OctreoScan® 111) is routinely used for the in vivo localization of SMS‐positive tumors in the clinic. Given that 99mTc remains the gold standard in Diagnostic Nuclear Medicine, we have synthesized two metabolically stabilized SMS analogs, N4‐Bzl‐Glyc‐Tyr3‐octreotide, 1, and N4‐Bzl‐Suc‐octreotide, 2, by covalent coupling of a N4 bifunctional ligand to the N‐terminal of the peptide backbone. The two analogs can be easily labeled with 99mTc under mild conditions leading to a single radiolabeled product in high yields and high specific activities. Both analogs significantly retain their ability to bind to the SMS receptor, as shown by proper competition binding experiments. After their administration in healthy mice both radiolabeled analogs were rapidly excreted from the body into the urine through the kidneys. The accumulation of the radioactivity in the SMS receptor rich organs, like pancreas and adrenals, was found specific by in vivo blocking tests.
Charaterization of Tc‐99m‐tricarbonyl complexes as transport substrates of the multidrug resistance (MDR1) P‐glycoprotein
Authors: Dyszlewski M. , Blake H. , Dahlheimer J. , Piwnica‐Worms D. 
Published: April 2012

AbstractOne of the best characterized mechanisms of drug resistance in human tumors is overexpression of the multidrug resistance (MDR1) P‐glycoprotein (Pgp). Pgp functions as an energy‐dependent extrusion pump that efficiently transports drugs out of tumor cells and has thus been an attractive target for improving cancer therapies (1). Lipophilic cationic radiopharmaceuticals, such as 99mTc‐sestamibi and 99mTc‐tetrofosmin, have been validated as transport substrates for Pgp in a variety of multidrug resistant human and rodent cells and have demonstrated utility for functional imaging of Pgp transport and modulation in both normal human tissues and tumors as well as in FVB mdrla/lb(‐l‐) gene knockout mice (2–7). The aim of this study was to explore the Pgp recognition properties of novel 99mTc(I)‐tricarbonyl complexes containing either methoxyisobutylisonitrile (MIBI) or dimethylmethoxypropylphosphine (DMMPP) ligands that have recently been reported as potential cardiac imaging agents (8).
Synthesis and characterization of [99mTc]metomidate as the tricarbonyl‐conjugate
Authors: Netter M. , Zolle I. , Schibli R. , Hammerschmidt F. , Berger M. , Schubiger P. A. 
Published: April 2012

AbstractFunctionalized metomidate was labelled with the [99mTc]tricarbonyl‐complex in high yield. With carrier amounts of Tc‐99 the analogous [99Tc]tricarbonyl‐BiPy‐MTO‐conjugate was obtained, showing an identical retention time, however, conjugate formation was not quantitative. When the [Re]tribromo‐tricarbonyl‐ligand was reacted with the BiPy‐MTO‐precursor, the reaction parameters had to be optimized for conjugate formation. Based on high adrenocortical binding to adrenal tissue slices, it is expected that the radiotracer will also localize in the adrenal in‐vivo.
Technetium‐99m‐MAG3 as a transport substrate of rat renal organic anion transporter‐1
Authors: Shikano N. , Kawai K. , Ishikawa N. , Kubodera A. 
Published: April 2012

AbstractThe first step of technetium‐99m‐mercaptoacetylglycylglycylglycine (99mTc‐MAG3) secretion by the proximal tubule cells is the extraction of 99mTc‐MAG3 from the peritubular plasma by proximal tubule cells through the basolateral membrane. The evidence for 99mTc‐MAG3 being excreted from renal proximal tubules via rat organic anion transporter 1 (OAT1) by molecular biological experiments with expressed OAT1 in Xenopus laevis oocytes was discussed. Inhibition studies of 99mTc‐MAG3 revealed that OAT1 mediated Na+‐independent 99mTc‐MAG3 uptake, and that this transport was energy‐independent. Accumulated dicarboxylate, such as glutarate, stimulated 99mTc‐MAG3 uptake. Tc‐99m‐MAG3, as well as paminohippurate (PAH), and o‐iodohippurate (OIH), was confirmed to be a transport substrate of OAT1 by the uptake of expressed oocytes.
Preparation and experimental study of a new renal imaging agent: N, N‐BIS (2‐aminoethyl) propane haxaacetic acid labeled with technitium‐99m
Authors: Wang R. F. , Zhang C. L. , Huo L. , He X. K. , Fu Z. L. , Liu G. Z. , Liu F. 
Published: April 2012

AbstractThe purpose of this study is to prepare 99mTc‐diaminoethylpropane diamine haxaacetic acid and clarify its renal excretion mechanism. BPHA obtained from chemical synthesis and characterized by IR and MS was labeled with technitium‐99m. The renal excretion mechanism was determined by probenecid inhibition experiment. The radioactivity remained in the body at different time point postinjection was measured by a γ detector. Renal dynamic imaging of rabbit and human was performed using a γ camera. For all the experiments 99mTc‐DTPA was also examined as contrast. Similar to 99mTc‐DTPA, 99mTc‐BPHA was excreted with a glomerular excretion mechanism. After 24 h, 99mTc‐BPHA remained in the body was very little. Kidney imaging of rabbit and volunteer showed excellent kidney images and fast 99mTc‐BPHA excretion. The results showed that the self‐made 99mTc‐BPHA appeared to be a glomerular filtration imaging agent satisfying clinical requirement and an alternative to 99mTc‐DTPA.
Effect of ginkgo biloba on the in vitro labeling of red blood cells and plasma proteins with technetium‐99M
Authors: Moreno S. R. F. , Feliciano G. D. , Freitas R. S. , Mattos D. M. , Gomes M. L. , Farah M. B. , Laurentino‐Filho G. L. , Rocha E. K. , Filho M. Bernardo 
Published: April 2012

AbstractGinkgo biloba is the phytoterapic most used in popular medicine in the treatment of inflammation, free‐radical with traumatic brain injury and Alzheimer's dementia. Red blood cells (RBC) labeled with technetium‐99m (Tc‐99m) are used for several evaluations in nuclear medicine. This labeling depends on a reducing agent, usually the stannous ion. Any drug which alters the labeling of the tracer could be expected to modify the disposition of the radiopharmaceutical. We have evaluated the influence of the Ginkgo biloba extract on the labeling of RBC and plasma proteins with Tc‐99m. Blood was withdrawn and incubated with Ginkgo biloba extract (0; 0.004; 0.04; 0.4; 4 and 20 mg/mL). Stannous chloride (1.2 μl/mL) was added and, then, Tc‐99m was added. Plasma (P) and blood cells (RBC) were isolated, also precipitated with trichloroacetic acid and soluble (SF) and insoluble fractions (IF) separated. The analysis of the results shows that there is a decrease in the radioactivity (from 97.7 ± 0.7 to 49.5 ± 3.9%) in RBC with the drug (4mg/mL). In the labeling process of RBC with Tc‐99m, the stannous and pertechnetate ions pass though the membrane, so, we suggest that the Ginkgo biloba effect can be explained by (i) an inhibition of the transport of these ions, (ii) damage in membrane, (iii) competition with the cited ions for the same binding sites, or (iv) possible generation of reactive oxygen species that could oxidize the stannous ion.
Effect of the leaf extract from cauliflower (brassica oleracea L. var. botrytis) on the biodistribution of the radiopharmaceutical sodium pertechnetate in mice and on the electrophoretic mobility of plasmid pUC 9.1 DNA
Authors: Lima E. A. C. , Dire G. , Mattos D. M. M. , de Oliveira M. Nunes , Mattos J. C. P. , Dantas F. J. S. , Caldeira‐De‐Araújo A. , Bernardo‐Filho M. 
Published: April 2012

AbstractThere is evidence that the biodistribution of radiopharmaceuticals may be altered by a variety of drugs. If unknown, the drug interaction with radiopharmaceuticals can lead to misdiagnosis or the necessity to repeat the examination, increasing the dose to the patient. Different substances has the ability to modify the electrophoretic mobility of the deoxyribonucleic acid (DNA). Cauliflower has the leaves used in folk medicine. We evaluated the influence of the leaf extract of cauliflower on: (i) the biodistribution of the radiopharmaceutical sodium pertechnetate (99mTcO4Na) and in (ii) the mobility of a plasmid pUC 9.1 through gel electrophoresis analysis. 99mTcO4Na (0.3ml) was administered into female Wistar rats which had drunk or not the extract for 60 days. After 10 min, the animals were sacrificed, the organs isolated, the radioactivity determined in a well counter and the percentages of radioactivity per gram (%ATI/g) in the organs calculated. The %ATI/g was not significantly altered (p>0.05) in the treated animals. The supercoiled form of the plasmid was modified by the cauliflower extract. We suggest that the action of this extract on the DNA might be explained by a direct effect or by the generation of reactive oxygen species (ROS) that could be inducing lesions in the plasmid DNA. However, this lesive effect was not capable to alter the biodistribution of the 99mTcO4Na in the treated animals with the extract.
Synthesis and evaluation of a new bifunctional chelator designed for labeling biomolecules by the technetium‐tricarbonyl technology
Authors: Baidoo Ke , Knight Lc , Romano Je , Gabriel Jl , Maurer Ah 
Published: April 2012

AbstractWe have prepared a new bifunctional chelating agent 6‐(N′‐Pyridin‐2‐ylmethylene‐hydrazino)‐nicotinic acid for use in labeling biomolecules by the technetium‐tricarbonyl technology. The utility of the bifunctional chelate for 99mTc labeling was evaluated using recombinant bitistatin. High yield, high affinity 99mTc labeled bitistatin was obtained. The 99mTc labeled bitistatin has great potential for use in imaging thrombi.
Radiochemical investigations of 177Lu‐DOTA‐8‐Aoc‐BBN[7‐14]NH2: A new gastrin releasing peptide receptor (GRPr) targeting radiopharma ceutical
Authors: Smith Charles J. , Hoffman Timothy J. , Hayes Donald L. , Owen Nellie K. , Sieckman Gary L. , Volkert Wynn A. 
Published: April 2012

AbstractThe new conjugate, 177Lu‐DOTA‐8‐Aoc‐BBN[7–14]NH2, was prepared in high yield (≥95%) upon addition of 177LuCl3 to an aqueous solution (Ammonium Acetate) of DOTA‐8‐Aoc‐BBN[7–14]NH2. The 177Lu‐DOTA‐8‐Aoc‐BBN[7–14]NH2‐conjugate is stable over a wide range of pHs and does not undergo in vitro decomposition for ≤24h. Biodistribution studies of the 177Luconjugate were determined in tumor bearing (PC‐3), SCID mice. Tumor uptake and retention values of 4.22 ± 1.09%ID/g, 3.03 ± 0.91%ID/g, and 1.54 ± 1.14%ID/g were obtained at 1, 4, and 24h, respectively.
Synthesis, antibody conjugation, radiolabeling, and biodistribution of the first diethylene triamine pentahydroxamate (DTPH) bifunctional chelating agent
Authors: Safavy A. , Smith D. C. , Bazooband A. , Buchsbaum D. J. 
Published: April 2012

AbstractSynthesis of a novel pentahydroxamic acid bifunctional chelating agent (BCA) constructed on the diethylene triamine core of diethylene triamine pentaacetic acid (DTPA) is reported. Thus, the Nα, Nζ‐[tetrakis((N‐hydroxy‐N‐methyl)carbonyl)]‐N4‐[((N‐hydroxy‐N‐methyl)carbonyl)]‐4‐(2, 6‐diamino)‐4‐azahexanoic hydrazide (DTPH, 1) was synthesized through a convergent synthetic strategy, in 14 steps and in 8% overall yield. The BCA was conjugated to the monoclonal antibody (MAb) ?CH2HuCC49 and the conjugate was radiolabeled with 177Lu. Results of biodistribution of this labeled conjugate in athymic nude mice are reported.
Production and radioassay of TC‐94M for pet studies
Authors: Szajek L. P. , Der M. , Plascjak P. , Eckelman W. C. 
Published: April 2012

AbstractThe goal of this work was to develop a remote apparatus for the preparation of Tc‐94m pertechnetate, suitable for the injection into a variety of Tc‐99m instant kits, and to develop a dose calibrator radioassay of this radionuclide for use in the radiopharmacy. At the NIH Clinical Center Tc‐94m has been produced utilizing 12.1 ± 0.5 MeV protons in the Mo‐94 (p, n) Tc‐94m nuclear reaction with >92% isotopically enriched Mo‐94 molybdenum oxide pellet external target and NaOH/MEK chemical separation. With a Tc‐94m average production rate of 15 ± 3 mCi/μA‐hr (17 preparations) we have routinely obtained 25 ± 6 mCi of Tc‐94m pertechnetate at 45 minutes past EOB in the first 3 mL of isotopic saline for injection into a Tc‐99m‐sestamibi instant kit.
A research resource in radionuclide research
Authors: Mccarthy D. W. , Bigott H. M. , Perkins T. A. , Voller T. F. , Welch M. J. 
Published: April 2012

AbstractSince September 1999, Washington University has been funded as a Research Resource in Radionuclide Research by the National Cancer Institute. The goals of the Resource include providing novel radionuclides for collaborative research and other applications. In addition, imaging facilities at Washington University, including the microPET (Concorde Microsystems, Knoxville, TN), the first commercial device based on the design of Cherry and colleagues (1), are being made available to collaborators to assist in the evaluation of radiotracers for both diagnosis and therapy.
Preliminary evaluation of radiolabeled bitistatin as a potential agent for targeting integrins in tumor angiogenesis with pet
Authors: Knight L. C. , Mccarthy D. , Romano J. E. , Welch M. J. 
Published: April 2012

AbstractTo determine whether bitistatin could target tumors by integrin receptors in tumor neovasculature for eventual imaging with PET, we tested the biodistribution of radioiodinated bitistatin in mice bearing mammary tumors. High uptake in tumor (up to 12% ID/g) was observed with maximum uptake at 2 hours. Uptake was primarily blockable and therefore receptor‐mediated. These studies suggest that bitistatin, and possibly other disintegrins, have sufficient affinity for αvβ3 to localize in tumors, and that bitistatin labeled with a positron‐emitting radionuclide such as 124I or 64Cu should enable tumor imaging with PET.
L‐[2‐RADIOIODO]‐Tyrosine a potential tumour tracer for spect. Radiosynthesis, in vitro and in vivo evaluation
Authors: Mertens J. , Iterbeke K. , Lahoutte T. , Joos C. , Tourwé D. , Bossuyt A. 
Published: April 2012

AbstractThe pharmacophore L‐2‐Br‐tyrosine (2‐Br‐T) was obtained by a stereospecific synthesis in which benzophenonimine glycinesultame, sodium hexamethyldisilane and O‐(methoxycarbonyl)‐3‐bromo‐4‐bromo ethylphenol are successively coupled followed by hydrolysis.Radioiodination (N.C.A.123/125I) was performed by Cu1+ assisted nucleophilic exchange on 2‐Br‐T with a mean labelling yield of 85%. RPHPLC coupled to C18 Sep‐pak recovery allowed to obtain the radioactive compound with a radiochemical purity of >98%. The in vitro evaluation was carried out on WiDr cells (human colon carcinoma). L‐2‐125I‐ tyrosine (2‐*I‐T) was shown to follow for the larger part the L‐transport system. For times up to 60 minutes the uptake was comparable with that of the reference 3H‐tyr. A considerable amount of the radioactivity uptake was slowly washed out in efflux conditions. In comparison with 3H‐tyr the incorporation in proteins was low. This can point to a retention mechanism which can be favourable for diagnosis. In vivo in rats bearing R1M rabdomyosarcoma tumours, the uptake in the tumour 40 minutes p.i. represented 1% ID/g with a tumour to blood ratio of 1.8. The tracer is fastly cleared from the blood to the bladder.