Ashour Mohammed

Universität Heidelberg, Heidelberg, Baden-Wuerttemberg, Germany

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Publications (21)79.4 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: Preformed (99m)Tc chelates with an activated ester function are useful for the gentle labeling of proteins (precomplexation route). In this context, new heterobifunctional ligands derived from 2,3,5,6-tetrafluorophenyl (TFP) 3,4-diamino-benzoates (OC1, OC3, OC4) were synthesized. Their corresponding (99m)Tc-complexation and protein-conjugation characteristics were elucidated and compared with the results previously reported using 2,3,5,6-tetrafluorophenyl N-(S-benzoylthioacetyl)glycylglycyl-p-aminobenzoate (OC2). The reaction temperatures and the reaction time markedly influenced complexation yields. Compared with OC2, the (99m)Tc-chelate formation with OC1 and OC4 was more effective, showing radiochemical yields of 60% and 70% within 20 min, respectively. Owing to steric hindrance, the complexation of OC3, however, did not exceed 10%. No-carrier-added (99m)Tc complexes were conjugated at pH 10 with the anti-EGF-receptor monoclonal antibody MAb425, resulting in labeling yields of 14% for (99m)Tc-OC1 and 7% for (99m)Tc-OC4 after incubating for 20 min at 30 degrees C. Increasing the temperature to 40 degrees C improved these results by 14% and 3%, respectively. As compared with (99m)Tc-OC2, which provides the chelating substituent at the 4-phenyl position only, the application of 3,4-phenyl substituents proved less appropriate for protein conjugation. However, the 3,4-diaminobenzoate backbone may be attractive for an alternative design of novel (99m)Tc N2S2 or N3S complexes, because they show excellent complexation characteristics.
    Nuclear Medicine and Biology 05/2006; 33(3):381-90. · 2.52 Impact Factor
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    ABSTRACT: After establishing a method for ileal mucosa transplantation in an animal model, the authors investigated the absorptive capacity for oligopeptides of the transplanted mucosa. In 14 beagle dogs the authors transplanted ileal mucosa in a vascularized demucosed segment of the transverse colon. The colonic wall-ileal mucosa complex then was integrated in the ileal continuity. Six animals were lost owing to operative complications. Absorptive capacity for oligopeptides was measured in the remaining 8 animals with the iodine 131 (131I)-marked tripeptide glycine-tyrosine-glycine before and 4 weeks after transplantation. The results were compared and analyzed with the Student's t test for matched pairs. Blood concentrations of the marked tripeptide with P value less than .05 were considered as a significant reduction in the absorptive capacity of the transplanted ileal mucosa. After fixation with glutaraldehyd graft, uptake of the colonic wall-ileal mucosa complex was evaluated histologically in 8 animals. In all 8 animals, a 100% graft uptake was verified in all sections. Fifteen minutes after application of 15 MBc Glycine-131I-Tyrosine-Glycine there was no significant difference in the absorption between normal and transplanted ileal mucosa. After 30 minutes, the absorption of the transplanted ileal mucosa showed a tendency (P < .1) for an impaired uptake of the marked tripeptide. However, 60 minutes after application the difference in the absorptive capacity of the transplanted ileal mucosa was significant (P < .05). Autologous allotopic ileal mucosa transplantation is feasible; however, an impaired absorption of oligopeptides of the transplanted mucosa 4 weeks after transplantation could be observed.
    Journal of Pediatric Surgery 11/2004; 39(10):1553-7. · 1.38 Impact Factor
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    ABSTRACT: Radioiodinated N-(2-(diethylamino)ethyl)benzamides have recently been discovered as selective agents for melanotic melanoma and are used for scintigraphic imaging in nuclear medicine. Owing to the high binding capacity, benzamide derivatives conjugated with alkylating cytostatics were synthesized and tested for their potential for targeted drug delivery. Conjugates of chlorambucil with procainamide (1), diethylaminoethylamine (2) and 2-pyrrolidin-1-yl-ethylamine (3), as well as 4-(bis(2-chloroethyl)amino)- (6,7) and 4-(N,N-diethyltriazeno)-substituted (8-10) benzamides, were synthesized. Cell uptake studies with B16 melanoma cells revealed high uptake of radioiodinated 1 and 2, while radiolabelled chlorambucil was found to lack this characteristic. These results were confirmed by biodistribution studies in a mouse melanoma model. Viability measurements revealed that all chlorambucil-benzamide derivatives showed higher toxicity against B16 melanoma and SK-MEL-28 cells than did the parent chlorambucil itself, and that the triazene derivatives were more potent than dacarbazine, which is currently used as a standard cytostatic drug in melanoma therapy. Of all the compounds tested in this series, the triazenes 9 and 10 showed the most promising targeting effect. The toxicity of these compounds against hepatoma cells (MH3924A) and, to a lesser extent, against mouse fibroblast (NIH 3T3) and cervix carcinoma (HeLa) cells was also enhanced, but they were not as toxic as dacarbazine (HeLa). These findings support the concept of a selective, benzamide-mediated in vivo delivery of cytostatics in melanoma cells, leading to enhanced efficacy.
    Melanoma Research 11/2004; 14(5):353-60. · 2.52 Impact Factor
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    ABSTRACT: Differentiation between tumor progression and radiation necrosis is one of the most difficult tasks in oncologic neuroradiology. Functional imaging of tumor metabolism can help with this task, but the choice of tracer is still controversial. This prospective study following up irradiated low-grade astrocytoma (LGA) was, to our knowledge, the first receiver-operating-characteristic (ROC) analysis that intraindividually evaluated the diagnostic performance of the SPECT tracers 3-[(123)I]iodo-alpha-methyl-L-tyrosine (IMT) and (99m)Tc(I)-hexakis(2-methoxyisobutylisonitrile) (MIBI) and the PET tracer (18)F-FDG. We examined 17 patients, initially with histologically proven LGA and treated by stereotactic radiotherapy, who presented with new gadolinium-diethylenetriaminepentaacetic acid-enhancing lesions (n = 26) on MRI. At that time, MRI could not differentiate between progressive tumor and nonprogressive tumor. This MRI examination was closely followed by (18)F-FDG PET and by (99m)Tc-MIBI and (123)I-IMT SPECT. Lesions were classified as progressive tumor (n = 17) or nonprogressive tumor (n = 9) on the basis of prospective follow-up (through clinical examination, MRI, and proton MR spectroscopy) for 26.6 +/- 6.6 mo after PET or SPECT. (123)I-IMT yielded the best ROC characteristics and was the most accurate for classification, with an area under the ROC curve (A(z)) of 0.991. The A(z) of (18)F-FDG (0.947) was not significantly lower than that of (123)I-IMT. The difference in the A(z) of (99m)Tc-MIBI (0.713) from the A(z) of the other tracers used in our study was highly significant (P </= 0.01). (99m)Tc-MIBI SPECT was of low accuracy and, especially, of poor sensitivity even at modest specificity values. (123)I-IMT SPECT imaging of amino acid transport accurately detects tumor progression in patients with irradiated LGA. In contrast to (123)I-IMT, (18)F-FDG PET was slightly less accurate for classification, and (99m)Tc-MIBI SPECT was of limited value. Imaging of amino acid transport with (123)I-IMT is a valuable additional tool for the follow-up of LGA, allowing early, noninvasive differentiation of lesions with ambiguous morphology after irradiation.
    Journal of Nuclear Medicine 04/2004; 45(4):579-86. · 5.77 Impact Factor
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    ABSTRACT: Derivatives of somatostatin (SST) represent the most important peptides for receptor targeting in oncological applications. Whereas the pharmacophor in somatostatin receptor-affine substances has been thoroughly investigated, the influence of modifications at the N-terminal has not yet been systematically studied. In order to investigate the influence of hydrophilic versus lipophilic modifications at the N-terminal end, a series of homologous derivatives of Tyr3-octreotate modified with oligomers of ethylene glycol or fatty acids were synthesized. For this purpose, Tyr3-octreotate was assembled using solid phase peptide synthesis and the fatty acids or oligomers of ethylene glycol were conjugated to the N-terminal end. The oligomers of ethylene glycol were activated by 4-nitrophenylchloroformate to obtain carbamate-linked hydrophilic compounds. The receptor affinities of these compounds were determined by competition experiments with [125I]Tyr3-octreotide on rat cortex membranes. The hydrophilic derivatives and the short chain lipophilic derivatives revealed IC50 values between 0.66 +/- 0.02 nM and 2.16 +/- 0.31 nM respectively. After labeling with (125)I the organ distribution of selected derivatives was investigated in Lewis rats bearing the rat pancreatic tumor CA20948. All of the compounds showed high tumor uptake. The peptides conjugated to oligomers of ethylene glycol showed low uptake into the liver and kidneys. Increasing the length of the fatty acids resulted in a remarkable decrease in kidney uptake. In conclusion, the systematic modifications at the N-terminal result in a low effect on the receptor affinity but allow the modulation of the pharmacokinetic properties of octreotide derivatives.
    Nuclear Medicine and Biology 02/2004; 31(1):21-30. · 2.52 Impact Factor
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    ABSTRACT: Heterobifunctional (99m)Tc ligands are useful for antibody labeling using the precomplexation route. The aim of this work was to synthesize a ligand, which has sufficient chemical stability to be complexed with (99m)Tc without inactivating the reactive conjugation group. Using 2,3,5,6-tetrafluorophenyl N-(S-benzoylthioacetyl)glycylglycyl-p-aminobenzoate (OC2) >60% of the (99m)Tc complex was obtained at 80 degrees C in 20 min, which was separated from the free ligand and impurities by HPLC. After solvent evaporation, (99m)Tc-OC2 was conjugated with the monoclonal antibody mAb425 in 50% radiochemical yield. In all, the labeling method required about 1 h preparation time. The immunoreactive fraction of the (99m)Tc-OC2 mAb425 conjugate was 81%, indicating preserved binding capability after conjugation. Compared to recently described methods, which need in situ activation of the (99m)Tc complex, the application of OC2 saved time and reduced the number of manipulations with radioactive material.
    Bioconjugate Chemistry 11/2003; 14(6):1209-13. · 4.58 Impact Factor
  • Angewandte Chemie International Edition 05/2003; 42(17):1968-71. · 11.34 Impact Factor
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    ABSTRACT: Myocardial perfusion single-photon emission tomography (SPET) performed with cationic technetium-99m complexes indicates ischaemic areas as cold lesions. By contrast, nitroimidazole derivatives labelled with fluorine-18 or (99m)Tc have recently shown promising results for hot spot imaging of ischaemic myocardium. This study evaluates (99m)TcO(BAT-NI), a new (99m)Tc complex comprising the nitroimidazole ligand, 2,10-dimercapto-2,10-dimethyl-4,8-diaza-6-[4-(2-nitroimidazolyl)butyl]undecane, in a low-flow in vivo model of myocardial ischaemia in thoracotomised rats. To elucidate the influence of the 2-nitroimidazole group on ischaemia-induced uptake, comparisons with ligand derivatives were performed where (a) the 2-nitro group was deleted [(99m)TcO(BAT-I)], (b) the 2-nitroimidazole functionality was replaced by a Br atom [(99m)TcO(BAT-Br)] and (c) the (99m)TcO(BAT) moiety was replaced by an iodine-125 iodophenoxybutyl ligand ((125)IP-NI). The radiolabelled compounds were i.v. injected 15 min after reducing resting myocardial blood flow by 50-60% and the uptake of radioactivity was assessed 90 min post injection. Autoradiography of left ventricular short-axis slices showed median uptake ratios of ischaemic/non-ischaemic myocardium (I/N) of 3.4, 4.5 and 3.4 for (99m)TcO(BAT-NI), (99m)TcO(BAT-I) and (99m)TcO(BAT-Br), respectively. In contrast, (125)IP-NI was not preferentially taken up by ischaemic myocardium. Accumulation of (99m)TcO(BAT-NI) in ischaemic heart regions was comparable to that in the liver. Biodistribution studies showed a median uptake of 0.65% ID/g of (99m)TcO(BAT-NI) in ischaemic tissue and an I/N of 3.3. On planar images of the thorax and upper abdomen the ischaemic hearts were visualised faintly; the median heart to lung count ratio for (99m)TcO(BAT-NI) was 1.7, and the median heart to liver count ratio was 1.0. We conclude that uptake of (99m)TcO(BAT-NI) in ischaemic myocardium does not depend on the nitroimidazole moiety but is intrinsic to the BAT complex. Clinical use of the (99m)TcO(BAT)-labelled tracers seems unlikely owing to their low uptake and their low ischaemic tissue contrast on planar images in vivo.
    European journal of nuclear medicine and molecular imaging 05/2003; 30(4):494-501. · 5.11 Impact Factor
  • Journal of Labelled Compounds and Radiopharmaceuticals 01/2003; 46:175-186. · 1.24 Impact Factor
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    ABSTRACT: On the basis of the avid uptake of radioiodinated benzamides by melanoma cells, (99m)Tc complexes containing the structural elements of N-(dialkylaminoalkyl)benzamide pharmacophores have been synthesized and evaluated in vitro and in vivo for melanoma uptake. One of the complexes Tc-12 containing the ligand 4-(S-benzoyl-2-thioacetyl-glycyl-glycylamido)-N-(2-diethylaminoethyl)benzamide (11) displayed the highest melanoma uptake. The 1-h melanoma uptake values and the corresponding blood counts indicate an interdependence of tumor uptake and bioavailability of the (99m)Tc complexes.
    Journal of Medicinal Chemistry 01/2003; 45(26):5802-5. · 5.61 Impact Factor
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    ABSTRACT: Conventional MRI often fails to distinguish between progressive tumour and radiation injury, because both appear as mass lesions with unspecific Gd-DTPA enhancement. Furthermore, the sensitivity of FDG PET for the evaluation of malignant lesions in the brain is limited owing to high cortical uptake. The aim of this study was to assess the potential of alternative SPET tracers in the same group of patients. 35.2+/-20.1 months after stereotactic radiotherapy (59.3+/-4.2 Gy) of low-grade astrocytomas (median WHO II), 16 patients, presenting 25 Gd-DTPA-enhancing lesions on MRI, were examined by SPET. Lesions were classified as progressive tumour (PT, n=17) or non-PT (nPT, n=8) based on prospective follow-up (clinical examination, MRI, proton-MR spectroscopy) for 25.6+/-6.7 months after SPET. SPET scans were performed 15 and 60 min after injection of 694+/-67 MBq hexakis(2-methoxyisobutylisonitrile)(99m)Tc(I) (MIBI). 3-[(123)I]iodo-alpha-methyl- L-tyrosine (IMT) SPET was acquired 15 min after injection of 291+/-58 MBq IMT. Lesion-to-normal tissue ratios (l/n) for IMT (l/n(IMT)) and MIBI (l/n(MIBI)) were calculated using a reference region mirrored to the contralateral hemisphere. Using IMT, significantly higher ratios ( P<0.001) were found in PT (1.7+/-0.4) than in nPT (1.1+/-0.1). For MIBI, there was no statistically significant difference ( P=0.206) between PT (3.7+/-2.8) and nPT (1.8+/-1.8). Sensitivities for MIBI and IMT were 53% and 94%, and specificities 75% and 100%, respectively. Positive predictive values for MIBI and IMT respectively reached 80% and 100%, and negative predictive values were 46% and 90%. In conclusion, in contrast to MIBI, IMT showed almost no overlap between the PT and the nPT group. The sensitivity, specificity and predictive values of IMT SPET were obviously higher than those of MIBI SPET. IMT is considered to be a useful tracer for differentiating PT from nPT in the follow-up of irradiated low-grade astrocytomas.
    European journal of nuclear medicine and molecular imaging 11/2002; 29(11):1455-61. · 5.11 Impact Factor
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    ABSTRACT: While fluorine-18 2-fluoro-2-deoxy-D-glucose (FDG) positron emission tomography (PET) is helpful in the pretherapeutic evaluation of head and neck cancer, it is only available in selected centres. Therefore, single-photon emission tomography (SPET) tracers would be desirable if they were to demonstrate tumour uptake reliably. This multitracer study was performed to evaluate the pretherapeutic uptake of the SPET tracers iodine-123 alpha-methyl-L-tyrosine (IMT) and technetium-99m hexakis-2-methoxyisobutylisonitrile (99mTc-MIBI) in primary carcinomas of the hypopharynx and larynx and to compare the results with those of FDG PET. We examined 22 fasted patients (20 male, 2 female, mean age 60.5+/-10.2 years) with histologically confirmed carcinoma of the hypopharynx (n=9) or larynx (n=13), within 1 week before therapy. In 20 patients a cervical PET scan was acquired after intravenous injection of 232+/-43 MBq 18F-FDG. Data analysis was semiquantitative, being based on standardised uptake values (SUVs) obtained at 60-90 min after injection. After injection of 570+/-44 MBq 99mTc-MIBI, cervical SPET scans (high-resolution collimator, 64x64 matrix, 64 steps, 40 s each) were obtained in 19 patients, 15 and 60 min after tracer injection. Finally, 15 min after injection of 327+/-93 MBq 123I-IMT (medium-energy collimator, 64x64 matrix, 64 steps, 40 s each) SPET scans were acquired in 15 patients. All images were analysed visually and by calculating the tumour to nuchal muscle ratio. Eighteen of 20 (90%) carcinomas showed an increased glucose metabolism, with a mean SUV of 8.7 and a mean carcinoma to muscle ratio of 7.3. The IMT uptake was increased in 13 of 15 (87%) patients, who had a mean carcinoma to muscle ratio of 2.9. Only 13 of 19 (68%) carcinomas revealed pathological MIBI uptake, with a mean tumour to muscle ratio of 2.2 and no significant difference between early and late MIBI SPET images (P=0.23). In conclusion, in the diagnosis of primary carcinomas of the hypopharynx and larynx, IMT SPET achieved a detection rate comparable to that of FDG PET. IMT SPET was clearly superior to MIBI SPET in this population. A further evaluation of the specificity of IMT in a larger number of patients appears justified.
    European journal of nuclear medicine and molecular imaging 04/2002; 29(3):324-30. · 5.11 Impact Factor
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    ABSTRACT: Oligonucleotides offer an enormous potential for therapeutical and diagnostic applications. Unfortunately the cellular uptake is a fundamental problem for the application of antisense oligonucleotides. Oligonucleotides are large charged molecules which are unable to penetrate the cellular membrane by diffusion. The resulting low cellular uptake can be circumvented by employing derivatized oligonucleotides. For this purpose we have recently developed oligonucleotide derivatives which are conjugated to octreotate, a cyclic octapeptide (1). Upon binding to somatostatin receptors (known to be overexpressed in various tumors), these conjugates can be internalized by receptor mediated endocytosis. Therefore the new conjugates consist of the oligonucleotide, which is linked via the 5′‐end to the N‐terminus of octreotate. The oligonucleotide sequence is complementary to the sequence of the protooncogene bcl‐2, which is known to be overexpressed in lymphoma. To monitor the fate of modified oligonucleotides in vivo as well as to enable the use of modified oligonucleotides for the scintigraphic imaging, labeling procedures had to be developed. This procedure also had to be suitable for the labeling of phosphorothioate‐modified oligonucleotides. Due to pharmacological advantages as compared to unmodified phosphodiester oligonucleotides, these synthetic oligonucleotides are utilized for in vivo applications. Using [γ‐32P]‐ATP and T4 polynucleotide kinase, oligonucleotides can be conveniently labeled at the 5′‐end. In order to enable the labeling of 5′‐conjugated oligonucleotides at the 3′‐end, the labeling with calf thymus terminal deoxynucleotidyl transferase (terminal transferase) and dideoxyadenosine‐5′‐[α‐32P]triphosphate ([α‐32P]‐ddATP) was investigated.
    Journal of Labelled Compounds and Radiopharmaceuticals 05/2001; 44. · 1.24 Impact Factor
  • 01/2001; 42:115P-115P.
  • Journal of Labelled Compounds and Radiopharmaceuticals 01/2001; 44. · 1.24 Impact Factor
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    ABSTRACT: Several radioiodinated N-(dialkylaminoalkyl)benzamides have been used for planar scintigraphy and single-photon emission computed tomography (SPECT) of melanoma metastases. In a quest for improved melanoma uptake and tissue selectivity, structure-activity studies for N-(2-diethylaminoethyl)benzamides with variation of phenyl substituents were performed using C57Bl/6 mice bearing B16 melanoma. Compounds 2 (4-amino-5-bromo-N-(2-diethylaminoethyl)-3-[(131)I]iodo-2-methoxybenz amide) and 6 (4-acetamido-N-(2-diethylaminoethyl)-5-[(131)I]iodo-2-methoxybenzamid e) showed at 6 h post iv injection, for example, melanoma uptake of 16.6 and 23.2% ID/g, respectively (mean values, n = 3). Uptake was 3-5 times higher (P < 0.01) than observed with benzamides known from the literature and was probably facilitated by the relatively slow urinary excretion of 2 or 6. In contrast, analogues lacking either the MeO, Ac, AcNH, or Br substituents exhibited reduced tumor uptake and high urinary excretion of radioactivity in various benzamide metabolites. Uptake of radioiodinated benzamides in B16 melanoma is not mediated by a specific mechanism such as sigma-receptor binding. 2 and 6 exhibited similar melanoma uptake values but quite different sigma(1)-receptor affinities of K(i) = 0.278 +/- 0.018 and 5.19 +/- 0.40 microM, respectively. Uptake studies with IMBA (N-(2-diethylaminoethyl)-3-[(131)I]iodo-4-methoxybenzamide) or BZA (N-(2-diethylaminoethyl)-4-[(131)I]iodobenzamide) showed that with increasing dose of unlabeled compound the measured uptake of label was unchanged (IMBA) or even enhanced (BZA) while receptor binding of label decreased. Differential and equilibrium density-gradient centrifugation revealed that most of the radioactivity from labeled IMBA was associated with fractions containing melanin granules. Thus, structure-activity studies indicate that blood clearance rates and metabolic stability are the main determinants for benzamide uptake in melanoma. The high uptake and slow clearance of 6 offer considerable potential for melanoma imaging in patients, and this compound may also prove to be useful for radionuclide therapy.
    Journal of Medicinal Chemistry 11/2000; 43(21):3913-22. · 5.61 Impact Factor
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    ABSTRACT: Enormous progress has been made in the development of antisense oligodeoxynucleotides (ODNs) as therapeutic agents inhibiting gene expression. Unfortunately, the therapeutical application of ODNs is still held back because of the low cellular uptake and the lack of specific transport into particular cells. In this paper, we report a drug-targeting system using somatostatin receptors (SSTRs) which are overexpressed in various tumors. Phosphorothioate ODNs were covalently linked to Tyr(3)-octreotate, an analogue of somatostatin. The peptide was assembled by solid-phase synthesis, oxidized to form the cyclic disulfide, and subsequently derivatized with a N-terminal maleimido functionality. 5'-Thiol derivatized phosphorothioate-ODNs directed against the protooncogene bcl-2 were conjugated to this maleimido-modified peptide. Binding studies revealed that the conjugates retain specific binding with nanomolar affinities to SSTRs (IC(50)-values between 1.83 and 2.52 nM). Furthermore, melting studies with complementary DNA revealed that the terminal conjugation of the ODNs did not significantly affect their hybridization affinity.
    Bioconjugate Chemistry 10/2000; 11(6):855-60. · 4.58 Impact Factor
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    ABSTRACT: ‘3+1' Mixed-ligand [99mTc]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, Et2N(CH2)2] and N-(2-dialkylamino)ethanethiol [alkyl = X = Et, Bu, morpholinyl] using Sn2+ as the reducing agent resulted in the formation of ‘3+1' mixed-ligand technetium-99m complexes [TcO(SN(R)S)(SNX2)] 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.
    Journal of Medicinal Chemistry 06/2000; 43(14). · 5.61 Impact Factor
  • A Mohammed, C Nicholl, U Titsch, M Eisenhut
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    ABSTRACT: The syntheses and radiolabelling of 27 new N-(alkylaminoalkyl)-4-methoxy-, -4-hydroxy-, and -4-aminobenzamides are described and evaluated in C57B1/6 mice with subcutaneously transplanted B16 melanoma in order to screen the optimal chemical structure for melanoma scintigraphy. Using T1(TFA)3 for 131I- labelling, a series of radioiodinated 4-methoxy benzamide derivatives proved to exhibit superior melanoma uptake with outstanding melanoma/non-target-tissue ratios. From the benzamide derivatives tested, N-(2-(1'-piperidinyl)ethyl-3-[131I]iodo-4-methoxybenzamide and N-(2-diethylaminoethyl)-3-[131I]iodo-4-methoxybenzamide demonstrated best results. The introduction of 4-hydroxy and 4-amino groups led to less favourable benzamides. While the former compounds showed little melanoma uptake, the latter revealed unfavourable melanoma/non-target-tissue ratios. Additionally, it could be shown that an amino group was inevitably necessary for melanoma uptake, and that dialkylation of the amide nitrogen and replacing CONH by CH2NH revealed less advantageous results.
    Nuclear Medicine and Biology 08/1997; 24(5):373-80. · 2.52 Impact Factor
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    ABSTRACT: The development of an effective radiopharmaceutical with affinity for malignant melanoma has been a research goal for some time. The early detection of melanoma metastases would greatly improve the therapy outcome for this disease. This article describes the synthesis of radioiodinated IMBA, N-(2-diethylaminoethyl)-3-[123I/131I]iodo-4-methoxybenzamide 8, its organ distribution, its comparison with BZA and other benzamides, and demonstrates the scintigraphic efficacy of the title compound with three melanoma patients. The syntheses and radioiodination of eight benzamide derivatives are described. After intravenous injection into C57B16-mice subcutaneously transplanted with B16 melanoma, the organ distribution of the respective benzamides were investigated at 1 and 6 hr. n-octanol/phosphate buffer partition coefficients. The wholebody retention, erythrocyte and serum protein bound fractions of radioiodinated benzamides were measured. While structural changes in the amide substituents of N-(2-dialkylaminoalkyl)-4-iodobenzamides 2-7 resulted in no improvement in organ distribution compared with BZA, the 3-iodo-4-methoxyphenyl form of IMBA showed high melanoma uptake with significantly higher melanoma/nontarget tissue ratios. Compared with BZA the average ratio improved after 1 hr by a factor of eight and was still four times better after 6 hr. BZA and IMBA exhibit almost identical n-octanol/ phosphate buffer partition coefficients, however, IMBA has a faster urinary excretion facilitated by a lower affinity to erythrocytes and serum proteins; this could explain the improved tissue partinioning observed. Scintigraphy of patients with melanoma metastases confirmed the promising characteristics derived from the animal studies. Due to rapid background clearance and high melanoma affinity, IMBA showed high tumor contrast already at 4 hr after injection which makes it a promising new radiopharmaceutical for the scintigraphic detection of melanoma metastases.
    Journal of Nuclear Medicine 02/1997; 38(1):127-33. · 5.77 Impact Factor