Biomedical subjects

H Spies

Publications and source records attributed to H Spies.

At least 19 recordsLinked to original sources

PubMed2004

Synthesis and biological evaluation of silylated mixed-ligand 99mTc complexes with the [PNS/S] donor atom set.

New oxotechnetium complexes of general formula [99mTc(O)(PNS)(S(CH2)nOSiR3)] (4-6) were synthesized by direct reduction of [99mTcO4]- with stannous chloride, in the presence of the tridentate heterofunctionalized phosphine H2PNS and of the monodentate silylated thiols [HS(CH2)nOSiR3] (n = 2, R = Ph (1); n = 3, R = Ph (2); n = 3, R = Et (3)). The mixed-ligand rhenium and technetium complexes of general formula [M(O)(PNS)(S(CH2)nOH)] (n = 2: M = 99mTc, (7), M = Re, (7a); n = 3: M = 99mTc, (8), M = Re, (8a)) were also prepared. All the 99mTc complexes were obtained with high radiochemical purity (> 95%), after purification by HPLC, and were characterized by comparison of their HPLC profiles with the ones obtained for the corresponding Re compounds. The silylated compounds 4-6 are stable in phosphate saline buffer (PBS) pH 7.4, rat plasma, human serum and whole blood, and do not bind to plasmatic proteins, and also do not challenge with glutathione. The biological behavior of [99mTc(O)(PNS)(S(CH2)nOH)] (7, 8) and [99mTc(O)(PNS)(S(CH2)nOSiR3)] (4-6) was studied. The effect of the pH on the cleavage of the O-Si bond in complexes 4-6 was also evaluated.

Animals↗

PubMed2003

Novel tumortropic ester derivatives of 99mTc(V) mesodimercapto succinic acid with low affinity for bone tissue.

Starting from our previous finding that 99mTc(V) dimercaptosuccinic acid (99mTc(V)-DMSA), a useful agent for the localization of osteosarcoma and bone metastases, loses its bone affinity when one ester group is introduced into the complex we studied the impact of esterification in more detail. This paper reports on the evaluation of various ester complexes of 99mTc(V)-DMSA in rats and tumour-bearing nude mice with regard to their tumour retention and improvement of the tumour to tissue ratios. The distribution patterns of the complexes [99mTcO(DMSA)2]- (A), [99mTcO(DMSA/DMSEt)]- (B) and [99mTcO(DMSEt)2]- (C) are gradually changed with the number of ester groups in the anionic complex. However, the asymmetric diester complex [99mTcO(DMSA/DMSEt2)]- (D) is very slowly cleared, especially from the blood of nude mice. Moreover, this complex differs significantly from the symmetrical complex C in its elimination behaviour from the liver and kidneys. The tumour uptake is maintained with complexes that contain one or two non-hydrolysable ester functions. Preliminary biodistribution studies of the monoethyl and diethyl ester complexes B, C and D in comparison with A in tumour-bearing nude mice showed similar uptake into the human squamous cell carcinoma (FaDu) as well as into the human colonic cell carcinoma (HT29) of nude mice. The low bone accumulation of B, C and D results in excellent tumour-to-bone ratios, e.g., approx. 3:1 for the ester complex B compared to approx. 1:2 for complex A. Differences were observed in the accumulation and elimination behaviour of the complexes A and B in various bone structures of rats. The age-dependent uptake of A and B was compared in long bone (femur) and in cranial bone of rats. The results suggest that 99mTc(V)-DMSA complexes that contain a functional ester, and their 188Re analogues, may be superior to 99mTc(V)/188Re(V)-DMSA in diagnostic and therapeutic nuclear medicine.

Aging↗

PubMed2002

Tc and Re chelates of 8alpha-amino-6-methyl-ergoline: synthesis and affinity to the dopamine D2 receptor.

The influence of structural changes at the 8alpha-amino position of 8alpha-amino-6-methyl-ergoline on the lipophilicity and affinity to the D2 receptor was studied. 8alpha-amino-6-methyl-ergoline (1) was converted into the derivatives (2a-f) by mercaptoacetylation of the amino group to make it possible to prepare the rhenium and technetium complexes (3, 4a,b). Binding tests on cloned human dopamine D2 receptors show that the affinities of the coordination compounds (IC50 values between 50 and 240 nM) are less than those of the derivatives 2a-f (IC50=3-50 nM) but more than those of the parent compound 1. Biodistribution studies of the Tc complexes 4a,b performed on Wistar rats show a slow blood clearance with substantial accumulation and retention in the liver and kidneys and low brain uptake.

Animals↗

PubMed2002

Synthesis and biological evaluation of technetium(III) mixed-ligand complexes with high affinity for the cerebral 5-HT(1A) receptor and the alpha1-adrenergic receptor.

Tc(III) and Re(III) complexes [M(NS(3))(CNR)] (M = Re, 99mTc, NS(3) = 2,2',2"-nitrilotris(ethanethiol), CNR = functionalized isocyanide bearing a derivative of WAY 100635) have been synthesized and characterized. Re was used as Tc surrogate for chemical characterization and in vitro receptor-binding studies. For two representatives subnanomolar affinities for the 5-HT(1A) as well as for the alpha1-adrenergic receptor were reached. Biodistribution studies in rats of the 99mTc complexes showed brain uptakes between 0.3 and 0.5% ID/organ (5 min p.i.). In vitro autoradiography of one 99mTc representative in sections of post mortem human brain indicate its accumulation in 5-HT(1A) receptor-rich brain regions. However, addition of the specific 5-HT(1A) receptor agonist 8-OH-DPAT as well as the alpha1-adrenoceptor antagonist prazosin could not substantially block this tracer accumulation. A preliminary SPET study in a monkey showed negligible brain uptake.

Animals↗

PubMed2002

Spatio-temporal dynamics of expansion growth in roots: automatic quantification of diurnal course and temperature response by digital image sequence processing.

A newly developed technique based on image sequence analysis allows automatic and precise quantification of the dynamics of the growth velocity of the root tip, the distribution of expansion growth rates along the entire growth zone and the oscillation frequencies of the root tip during growth without the need of artificial landmarks. These three major parameters characterizing expansion growth of primary roots can be analysed over several days with high spatial (20 microm) and temporal resolution (several minutes) as the camera follows the growing root by an image-controlled root tracking device. In combination with a rhizotron set up for hydroponic plant cultivation the impact of rapid changes of environmental factors can be assessed. First applications of this new system proved the absence of diurnal variation of root growth in Zea mays under constant temperature conditions. The distribution profile of relative elemental growth rate (REGR) showed two maxima under constant and varying growth conditions. Lateral oscillatory movements of growing root tips were present even under constant environmental conditions. Dynamic changes in velocity- and REGR-distribution within 1 h could be quantified after a step change in temperature from 21 degrees C to 26 degrees C. Most prominent growth responses were found in the zone of maximal root elongation.

Circadian Rhythm↗

PubMed2001

Synthesis and characterization of novel trigonal bipyramidal technetium(III) mixed-ligand complexes with SES/S/P coordination (E = O, N(CH3), S).

Five-coordinate oxotechnetium(V) mixed-ligand complexes [TcO(SES)(S-p-C6H4-OMe)], where SES is a tridentate dithiolato fragment of the type -S(CH2)2E(CH2)2S- (E = O, 1; E = S, 2; E = NMe, 3) are converted via reduction-substitution reactions in the presence of PMe2Ph into the corresponding five-coordinate Tc(III) complexes [Tc(SES)(S-p-C6H4-OMe)(PMe2Ph)] (E = O, 4; E = S, 5; E = NMe, 6). Rearrangement of the original square pyramidal "3 + 1" oxo species to the trigonal bipyramidal "3 + 1 + 1" Tc(III) complexes occurs by placing the three thiolate donors on the basal plane, the phosphine phosphorus, and the heteroatom of the tridentate ligand at the apexes of the bipyramid. These Tc(III) complexes are diamagnetic species, thereby allowing multinuclear NMR characterization in solution, which confirm their structures to be identical to those observed in the solid state via X-ray determinations.

Crystallography, X-Ray↗

PubMed2001

Ligand-exchange reaction of labile "3 + 1"99mTc(V) complexes with SH group-containing proteins.

The reactivity of labile 3 + 1 mixed-ligand 99mTc complexes of the type [99mTcO(SES)(RS)] with SES being a tridentate dithiol ligand and glutathione or dimethylcysteamine as monodentate ligands RSH towards proteins was investigated in vitro and in vivo. It was found that the complexes undergo reversible transchelation reactions with SH group-containing components of blood such as albumin or haemoglobin. High labelling yields were obtained when 3 + 1 complexes with the tridentate SSS ligand were used. The biodistribution of blood proteins labelled by ligand-exchange reaction with the [99TcO(SSS)] or [99mTcO(SNMeS)] core was studied and compared with the in vivo distribution of the labile 3 + 1 complexes containing glutathione as monodentate ligand.

Animals↗

PubMed2001

Patent foramen ovale closure in patients with transient ischemia attack/stroke.

Paradoxical embolism through a patent foramen ovale (PFO) has been recognized as a potential cause of transient ischemia attack (TIA) and stroke especially in younger patients. The therapeutic options are medical treatment (antiaggregation or anticoagulation) with an annual recurrence rate of 3% to 4% for stroke or TIA, surgical PFO closure, or catheter closure. Randomized studies are ongoing; however, the results will not be available soon. Since August 1994, we have attempted catheter closure of a PFO in 281 patients (age 17 to 79 years, mean 46.8 +/- 13.2) with paradoxical embolism. Of these, 184 patients had at least one embolic stroke, 112 patients at least one TIA, and 15 patients at least one peripheral embolism. The diameter of the PFO, measured with a balloon catheter, ranged from 3 mm to 24 mm with a mean of 10 +/- 3.5 mm. Implantation of the occluder was technically successful in all patients (two attempts in four patients). Seven different devices were used: 26 Sideris buttoned, 11 ASDOS, 19 Angel Wings, 98 PFO-Star, 37 Cardioseal-Starflex, 57 Amplatzer and, 33 Helex devices. One patient suffered from septicemia and subsequently died. In 2 patients, device embolization occurred during or after the procedure (1 Sideris, 1 PFO-Star; catheter retrieval successful). Thirty-seven patients had other minor complications without long-term sequelae: atrial fibrillation within the first weeks after implantation in five patients, asymptomatic thrombus on the device at routine transesophageal echocardiogram (TEE) in 7 patients (1 Angel Wings, 1 ASDOS, 1 CardioSeal, 4 PFO-Star), and device frame fracture in 25 patients (2 Sideris, 4 ASDOS, 1 Angel Wings, 1 CardioSeal, 17 PFO-Star). No complications occurred with the newer devices (Amplatzer and Helex). A residual shunt after 6 months was found in 5.5% of the patients who had completed their 6-month TEE follow-up. In two patients, a second occluder was implanted because of a residual shunt. During a follow-up period of 1 month to 71 months (mean 12 +/- 16 months, 268 patient years), a recurrence of an embolic event (seven TIA, two stroke) occurred in eight patients. None of these occurred with the newer devices (Amplatzer, Helex). Freedom from recurrence of the combined end point of TIA, ischemic stroke, and peripheral embolism was 95.7% (95% CI: 89.0%-98.4%) at 1 year and 94.1% (95% CI: 80.1-98.4%) at 3 years. Catheter PFO closure is a technically simple procedure. With the newer devices and increasing experience, the success rate has improved and the complication rate has decreased. The advantage of the procedure is that closing the defect means a causal treatment. However, catheter closure of PFO despite a very low morbidity has inherent potential risks like any other interventional procedure. Furthermore, selection of patients who definitely have PFO as the cause of their cerebral event has not been defined. For these reasons, further studies are warranted.

Adolescent↗

PubMed2000

pH-controlled inclusion and release of oxyanions by dendrimers bearing methyl orange moieties.

We report the synthesis of POPAM dendrimers, bearing up to 64 chromophores at their periphery. For these dendrimers, a radiotracer technique was used to study the liquid-liquid partition of pertechnetate and (14)C-labeled nucleotides in trichloromethane-aqueous systems. Inclusion and release of guest molecules can be controlled by changing the pH. The extraction efficacy increases with rising generation number.

Azo Compounds↗

PubMed2000

'3+1' mixed-ligand oxotechnetium(V) complexes with affinity for melanoma: synthesis and evaluation in vitro and in vivo.

'3+1' Mixed-ligand [(99m)Tc]oxotechnetium complexes with affinity for melanoma were synthesized in a one-pot reaction. Complexation of technetium-99m with a mixture of N-R(3-azapentane-1,5-dithiol) [R = Me, Pr, Bn, Et(2)N(CH(2))(2)] and N-(2-dialkylamino)ethanethiol [alkyl = X = Et, Bu, morpholinyl] using Sn(2+) as the reducing agent resulted in the formation of '3+1' mixed-ligand technetium-99m complexes [TcO(SN(R)S)(SNX(2))] in high radiochemical yield (60-98%). In vitro uptake studies in B16 murine melanoma cells indicated a moderate tumor-cell accumulation (40%) of compound 1 [R = Me, X = Et] and a higher accumulation (69%) of compound 2 [R = Me, X = Bu] after a 60-min incubation. In vivo evaluation of compounds 1-6 in the C57Bl6/B16 mouse melanoma model demonstrated tumor localization. Compound 2 displayed the highest accumulation with up to 5% ID/g at 60 min after injection. In vivo, 2 also showed a low blood-pool activity and high melanoma/spleen (4.3) and melanoma/lung (1.9) ratios at 1 h. These results suggest that small technetium-99m complexes could be useful as potential melanoma-imaging agents.

Animals↗

PubMed2000

[The treatment of iatrogenic spurious aneurysm of the femoral artery by direct thrombin injection].

BACKGROUND AND OBJECTIVE: After percutaneous catheter introduction a false aneurysm occasionally develops at the site of puncture. This has been treated either surgically or, more recently, by ultrasound-guided compression. A new method has been tried in which the false aneurysm is thrombosed by injecting thrombin into it. PATIENTS AND METHODS: In 29 patients thrombin was injected directly into the false aneurysm of the femoral artery, caused by catheter introduction into the vessel. Puncture of the aneurysm and injection of the thrombin solution was performed with continuous duplex-sonographic monitoring. The patients' age ranged from 42 to 88 years (mean 71 +/- 12 years). The false aneurysm had occurred after diagnostic catheterization (n = 5), balloon dilatation of peripheral vessels (n = 5) or balloon catheter dilatation of the coronary arteries (n = 19) with catheters size 5 F (n = 4), 6 F (n = 6), 8 F (n = 16) or 9-13 F (n = 3). The catheterization had been done 1-30 days previously (mean 5.3 +/- 6.9 days). The diameter of the aneurysm ranged from 2.1 to 5 cm (mean 3.5 +/- 0.9 cm). RESULTS: The aneurysms thrombosed within seconds after injection of 0.075 to 1.5 ml (mean 0.4 +/- 0.4 ml). All interventions were successful and without complications. Any resulting haematoma regressed within a few days to a few weeks and none recurred. In two patients a persisting haematoma had later to be removed surgically, and in another patient a second aneurysm was removed surgically without prior thrombin injection. CONCLUSION: A false aneurysm of the femoral artery caused by percutaneous catheterization can be successfully thrombosed by direct thrombin injection.

Adult↗

PubMed2000

Stability studies on (99m)technetium(III) complexes with tridentate/monodentate thiol ligands and phosphine ('3 + 1 + 1' complexes).

The preparation and characterisation of 3 + 1 + 1 technetium complexes of the general formula [Tc(SES)(RS)(PMe2Ph)] (SES = tridentate dithiol ligand, E = S, O, NMe; RSH = monothiol ligand) at the n.c.a. level is described. The Tc(III) complexes are prepared in a one-step procedure starting from pertechnetate in yields of 85-95% of radiochemical purity. A comparison of their chromatographic data with the fully characterised 99Tc complexes indicate the identity of the investigated compounds. Stability studies show that the 99mTc complexes undergo some alteration in solution. They are oxidised to the 3 + 1 oxotechnetium (V) complexes and/or decompose in aqueous solution. In challenge experiments performed with glutathione, exchange of the monothiolato ligand occurs in the same manner as known for the 3 + 1 complexes.

Chromatography, High Pressure Liquid↗

PubMed2000

Radiochemical synthesis and tissue distribution of Tc-99m-labeled 7alpha-substituted estradiol complexes.

The diagnosis and staging of breast cancer could be improved by the development of radiopharmaceutical imaging agents that provide a noninvasive determination of the estrogen receptor (ER) status of tumor cells. Agents labeled with (99m)Tc would be especially valuable in this regard. In attempting to achieve this goal, we synthesized four (99m)Tc-labeled 7alpha-substituted estradiol complexes. One complex utilizes the "3+1" mixed ligand design to introduce the Tc metal, whereas the other three took advantage of the cyclopentadienyltricarbonylmetal (CpTM) design. The Tc moieties were attached to the 7alpha position of estradiol with a hexyl tether, a monoether tether, or a polyether tether. The corresponding rhenium compounds have binding affinities for the ER of 20-45% compared with estradiol. Radiochemical yields of the (99m)Tc-labeled compounds ranged from approximately 15% for the CpT-Tc complexes to 95% for the 3 + 1 inorganic complex. Tissue distribution studies in immature female rats showed low nonreceptor-mediated uptake in the target organs and high uptake in nontarget organs such as the liver and fat. These complexes represent the first time that estradiol has been labeled at the 7alpha position with (99m)Tc and provide a further refinement of our understanding of ligand structure-binding affinity correlations for the ER.

Animals↗

PubMed2000

Permeation studies in vitro and in vivo of potential radiopharmaceuticals with affinity to neuro receptors.

PURPOSE: To check the influence of structural characteristics on their permeation through the blood-brain barrier (BBB), a set of radioactive [99mTc]chelates bearing amine groups was synthesized and tested in vitro as well as in vivo. METHODS: Compounds with different log P and pKa values were obtained by complex forming reactions of [99mTc]pertechnetate with varying substituents. Transport was studied in rats and mice, as well as in an ECV304 cell culture model. RESULTS: In vitro higher permeation was found for compounds with electron attracting substituents in beta-position to the amine group (pKa values 7.4 to 8.3) than for those with more basic amine groups (pKa values > 8.9) even for similar log DH 7.4. In vivo brain uptake between 0.8 and 4.8% of the injected dose (ID) per organ was found for the former, whereas <0.4% ID were present for the latter. CONCLUSIONS: Three structurally diverse classes of [99mTc]chelates showed distinct patterns with regard to brain uptake in vivo and BBB permeability in vitro which could not be predicted by their lipophilicity alone. The close correlation between the data from rats and mice and those obtained with cell cultures render the ECV304 cells an attractive model for the screening of new compounds.

Animals↗

PubMed1999

[Primary stent implantation in the internal carotid artery].

BACKGROUND AND OBJECTIVE: Advances in interventional catheter technology have made it possible to dilate stenoses also in the internal carotid artery (ICA). This may cause cerebral emboli, but primary stent implantation may fixate atherosclerotic material on the vessel wall and thus prevent embolization. PATIENTS AND METHODS: Marked stenosis in the ICA was treated by balloon dilatation in 71 consecutive patients aged between 40 and 85 years (mean 69 +/- 9 years). If possible, a stent was implanted before the first balloon dilatation. RESULTS: A stent was placed before dilatation in 53 of 76 procedures. Dilatation with a small balloon to allow stent placement was necessary in 23. Thus stent implantation before definitive dilatation was successful in all instances. The degree of stenosis was reduced from 79 +/- 11 to 9 +/- 14%. In all procedures the stenosis was reduced to less than 50%. One patient had a severe and two had a mild stroke. One patient died of a myocardial infarction 2 days after the procedure. Thus the neurological complication rate was 3.9% and the death rate 1.3%. Follow-up examination revealed an asymptomatic occlusion of the ICA after two weeks in one patient, a recurrent stenosis after 6 months in two of 46 patients. In all other patients the degree of stenosis was less than 50% at 6 months. CONCLUSION: Primary stent placement before balloon dilatation in ICA stenosis was possible in the majority of patients. This procedure would thus seem to reduce the risk of thromboembolic complications.

Adult↗

PubMed1999

Stent or angioplasty after recanalization of chronic coronary occlusions? (The SARECCO Trial).

This study tests whether stent implantation without anticoagulation after catheter recanalization of coronary occlusions can improve outcome compared with balloon angioplasty alone. One hundred ten patients were randomly assigned to angioplasty alone (no stent group) or stent implantation (stent group) after successful recanalization and balloon angioplasty. The type of stent and angioplasty technique utilized were decided by the operator. The acute procedural success in both groups was 100%. The acute minimal lumen diameter (MLD) was 1.85 +/- 0.44 mm in the no stent group versus 2.54 +/- 0.53 mm in the stent group (p <0.01). The diameter stenosis was 21 +/- 13% versus 3 +/- 14% (p <0.01). This was achieved not only by the stent implantation itself but primarily by a larger maximum balloon diameter in the stent group after stent implantation (3.32 +/- 0.55 mm vs 2.86 +/- 0.4 mm, p <0.05). After 4 months, the MLD was 1.15 +/- 0.73 mm in the no stent group versus 1.81 +/- 0.9 mm in the stent group (p <0.01). The diameter stenosis was 56 +/- 29% versus 34 +/- 28% (p <0.01). After 2 years, event-free survival was 26% in the no stent group and 52% in the stent group (p <0.05). Thus, acute and long-term procedural and angiographic success of stent implantation without anticoagulation after recanalization of total coronary occlusions is superior to that of balloon angioplasty alone. This beneficial effect is mainly the result of the larger balloon diameters, which may be used after stent implantation.

Angioplasty, Balloon↗

PubMed1999

Crystal and solution structure of oxo rhenium(V) complexes with cysteine and cysteine methyl ester.

The monooxo rhenium(V) complexes of cysteine (complex 1) and cysteine methyl ester (complex 2) were synthesised via a ligand exchange reaction starting from gluconatooxorhenium(V). Unexpectedly, the obtained oxorhenium(V) complex with cysteine methyl ester (2) was partially saponified. Both complexes were characterised by common analytical techniques in their solid state. Thus, an octahedral complex structure with 2(NH2,S) co-ordination in the equatorial plane and one carboxyl group bound trans to the oxo group is proven for complex 2 by X-ray diffraction. Furthermore, the existence of a dioxo species at higher pH was proven for the first time with this type of ligand by determining the nearest co-ordination sphere of the rhenium centre in solution at a pH of 12 using extended X-ray absorption fine structure spectroscopy.

Crystallization↗

PubMed1999

Synthesis of novel progestin-rhenium conjugates as potential ligands for the progesterone receptor.

To assist in the development of technetium-based radiopharmaceuticals that are useful for the diagnostic imaging of steroid receptor-positive breast tumors, we have synthesized a series of small-sized metal chelates according to 'n + 1' mixed-ligand, thioether-carbonyl and organometallic designs. In these preliminary investigations, rhenium was used as a model for the radioactive technetium. The metal chelates contain the rhenium metal in several oxidation states, being + 5, + 3, and + 1, and they were attached to 21-substituted progesterone derivatives. A competitive receptor-binding assay (rat uterine cytosol, 0 degrees C) was used to determine the binding affinity of these conjugates for the progesterone receptor. The highest affinity of 9% (RU5020 = 100%) was obtained with a '3 + 1' mixed-ligand complex, containing a NMe group as the central donor atom in the tridentate ligand part. This value reflects a relative binding affinity of 75% compared with the parent steroid progesterone.

Crystallography, X-Ray↗