Biolocalization and cell labeling properties of neutral-lipophilic 99mTc-amine-phenol chelates

Corlija, M.; Volkert, Wynn A.; John, Christy S.; Pillai, M.R.A.; Lo, Jason; Troutner, D.E.; Holmes, Richard A.

doi:10.1016/0883-2897(91)90074-u

Cited by 5 publications

(4 citation statements)

References 8 publications

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“…All four ligands form 99mTc complexes with an initial high (>85%) radiochemical purity (RCP), when formed by standard stannous reduction (using stannous tartrate) of pertechnetate in the presence of 1. of ligand at pH 9.O. 27 The complexes with a propylene bridge between the amines (PNSA and DMSA) are reasonably stable up to 2 h after reconstitution, whereas the complexes from ligands with ethylene and butylene bridges degrade quickly.28 Reversed-phase HPLC traces of products of 99mTc complexation of PNSA indicate that several complexes may be formed; the proportion of each complex appears pH dependent, with one complex predominating at pH 10.5.27 The structure of the "Tc complex of PNSA was reported as a 0-TcOTc=0 dimer.31…”

Section: Resultsmentioning

confidence: 99%

“…We prepared the 99mTc complex of the BAPN using conditions similar to those of Corlija et al 27 (stannous reduction of pertechnetate under slightly alkaline conditions). The product eluted as a broad tailing band from a PRP-1 reversed-phase HPLC system (80/20 MeOH/ 0.1 M NH4OAc pH 4.6, 2 mL/min, void volume = 1.06 min) with a retention time of 2.5 min.…”

Section: Resultsmentioning

confidence: 99%

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The Synthesis and in vitro Evaluation of a 99mTechnetium-Nitroimidazole Complex Based on a Bis(amine-phenol) Ligand: Comparison to BMS-181321

Ramalingam

Raju²,

Nanjappan³

et al. 1994

J. Med. Chem.

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We have developed a 99mTechnetium complex for imaging of hypoxic tissue (BMS-181321). Recently, another nitroimidazole derivative, based upon a bis(amine-phenol) ligand, was described in the patent literature. To compare this compound to BMS-181321, we have synthesized the ligand, prepared its 99mTc complex, and evaluated its performance in two in vitro assays of bioefficacy: membrane permeability and uptake in normoxic and anoxic cardiocytes. In attempting to reproduce the synthesis of the ligand described in the patent application, we found that one intermediate could not be made by the method described, and alternative routes were investigated. Complexation of the bis(amine-phenol) nitroimidazole with 99mTc gave an apparent single complex; this appeared as a broad peak on HPLC analysis. Purification by a solid-phase method gave a complex with 95% radiochemical purity. This complex was not permeable to cultured bovine brain endothelial cells nor did it show preferential uptake in anoxic myocytes.

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Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

The Synthesis and in vitro Evaluation of a 99mTechnetium-Nitroimidazole Complex Based on a Bis(amine-phenol) Ligand: Comparison to BMS-181321

Ramalingam

Raju²,

Nanjappan³

et al. 1994

J. Med. Chem.

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“…A nitrophenol ligand, N, N-bis(2-hydroxy-5-nitrobenzyl)-1,3-diamino-2-hydroxypropane (HNBAHP), was reported previously as possible agent for noninvasive imaging of hypoxic cells. This ligand combines the radiosensitizer properties of aromatic nitro compounds [9,10] and the stability of technetium aminophenol complexes [11,12]. Preliminary biodistribution (imaging) data for HNBAHP after intravenous administration demonstrated that most of radioactivity remained in the abdominal area with negligible radioactivity in the tumor within the first 20 h. Such characteristics restrict the applicability of these complexes in nuclear medicine.…”

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Synthesis and Stability of New Nitrophenol Complexes of 99m Tc as Possible Hypoxia Imaging Radiopharmaceuticals

Jalilian¹,

Binehshmarvasti²,

Kumar

et al. 2005

Radiochemistry

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Seven new nitrophenol derivatives were synthesized; their 99m Tc complexes (N 2 OS chelates), which are possible hypoxia tumor imaging agents, were prepared by the reaction with [ 99m Tc]NaTcO 4 in the presence of SnCl 2 at pH 10. The in vitro biostabilty of the complexes was evaluated. The purity and stability (in human and rat serum) of the complexes were evaluated by chromatographic methods (TLC, HPLC). The most stable (for more than 6 h) is the complex of 99m Tc with 3-[3`-N-(2``-hydroxy-5``-nitrobenzylamino)-2`-hydroxypropyl]-1-methylthiourea. Many radiolabeled nitroimidazole derivatives have been developed for noninvasive imaging of hypoxic tissues. The most important compounds contain 123 I [1, 2], 18 F [3, 4], and 82 Br [5]. Linder et al. have also reported preparation of 99m Tc complexes of nitroimidazole-BATO derivatives [6, 7]. Di Rocco et al.showed that these complexes bind to ischemic tissue of cerebral infarction in rats and in hypoxic myocardium in rabbits [8]. A nitrophenol ligand, N, N-bis(2-hydroxy-5-nitrobenzyl)-1,3-diamino-2-hydroxypropane (HNBAHP), was reported previously as possible agent for noninvasive imaging of hypoxic cells. This ligand combines the radiosensitizer properties of aromatic nitro compounds [9, 10] and the stability of technetium aminophenol complexes [11,12]. Preliminary biodistribution (imaging) data for HNBAHP after intravenous administration demonstrated that most of radioactivity remained in the abdominal area with negligible radioactivity in the tumor within the first 20 h. Such characteristics restrict the applicability of these complexes in nuclear medicine.In order to improve the biodistribution and pharmacokinetics of Tc complexes of HNBAHP, we synthesized a series of asymmetric nitrophenol-containing ligands II!VII (see scheme below), prepared their 99m Tc complexes, and evaluated their stability. EXPERIMENTALThe chemicals were purchased from Aldrich. 4-Dimethylaminophenyl isothiocyanate (97%) was pur-ÄÄÄÄÄÄÄÄÄÄÄÄ 1 This article was submitted by the authors in English. chased from Lancaster, Caledon Laboratories (Canada). All chemicals were recrystallized before use. The 1 H and 13 C NMR spectra were recorded on a Bruker AM-300 spectrometer using TMS as internal reference. The IR spectra (KBr pellets) were recorded over the range 4000 3 400 cm !1 with a Nicolet DX FTIR spectrophotometer. The FAB mass spectra were recorded with an AEI-MS-12 mass spectrometer. Thin-layer chromatography (TLC) of nonradioactive products was performed on TLC aluminum sheets, 20 0 20 cm, silica gel 60 F254, (E-Merck, EM Science, Gibbstown, USA). The analytical HPLC to determine the specific activity was performed with a Shimadzu LC-10AT device equipped with two detector systems: a flow scintillation analyzer (Packard-150 TR) and a UV-visible detector (Shimadzu). A Si 2 9 ; ; ; O 2 N OH Br + 9 ; =9 9 NH 2 OH NH 2 2 9 ; ; ; 9 ; =9 9 O 2 N OH NH 2 NH 76

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“…In order to develop agents for non-invasive imaging of hypoxic cells, a nitrophenol ligand, N,N-bis(2-hydroxy-5-nitrobenzyl)-1,3-diamino-2-hydroxypropane (HNBAHP), had previously been synthesized as an approach to tissue hypoxia imaging. This ligand system incorporated the radiosensitizer properties of aromatic nitro-compounds [9, 10] and the stability of technetium-aminophenol complexes [11,12] into one moiety. Preliminary biodistribution (imaging) data for HNBAHP after intravenous administration demonstrated that most of radioactivity remained in the abdominal area, with negligible radioactivity in the tumor within the first 20 h. Thus, the applicability of these complexes in nuclear medicine was restricted because of a high radioactivity level in the abdominal area and the slow accumulation of radioactivity in the tumor.…”

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Synthesis, radiolabeling and stability of new nitrophenol complexes of Technetium-99m as possible hypoxia imaging radiopharmaceuticals

Jalilian¹,

Binehshmarvasti²,

Kumar

et al. 2006

Pharm Chem J

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The synthesis of seven 99m Tc-labeled nitrophenol radiosensitizers (N 2 OS chelates) was undertaken for evaluating their in vitro biostabilty as possible hypoxia tumor imaging agents. The title compounds (2 -7) were successively synthesized, characterized, and finally radiolabeled ( 99m Tc-NaTcO 4 , stannous chloride, pH 10) to obtain the new complexes (8a -8f) for evaluation. The purity and stability of complexes (in human and rat serum) were evaluated by chromatographic methods (radio-TLC, ITLC, HPLC). The most stable complex (over 6 h) was 99m Tc-labeled 3-[3¢-N-(2²-hydroxy-5²-nitrobenzylamino)-2¢-propanol]-1-(4¢-methyl)thiourea (8e). Biodistribution studies of 8e in mammary tumor-bearing rats are in progress.Many radiolabeled nitroimidazole derivatives have been developed for non-invasive imaging of hypoxic tissues. The most important compounds contain iodine-123 [1, 2], fluorine-18 [3, 4] and bromine-82 [5]. Linder et al. [6,7] have also reported preparation of technetium-99m ( 99m Tc) complexes of nitroimidazole-BATO derivatives. Di Rocco et al. [8] showed that these complexes bind to ischemic tissue of cerebral infarction in rats and in hypoxic myocardium in rabbits. In order to develop agents for non-invasive imaging of hypoxic cells, a nitrophenol ligand, N,N-bis(2-hydroxy-5-nitrobenzyl)-1,3-diamino-2-hydroxypropane (HNBAHP), had previously been synthesized as an approach to tissue hypoxia imaging. This ligand system incorporated the radiosensitizer properties of aromatic nitro-compounds [9, 10] and the stability of technetium-aminophenol complexes [11,12] into one moiety. Preliminary biodistribution (imaging) data for HNBAHP after intravenous administration demonstrated that most of radioactivity remained in the abdominal area, with negligible radioactivity in the tumor within the first 20 h. Thus, the applicability of these complexes in nuclear medicine was restricted because of a high radioactivity level in the abdominal area and the slow accumulation of radioactivity in the tumor.In order to improve the biodistribution and pharmacokinetics of Tc-labeled complexes of HNBAHP, we have synthesized a series of asymmetric nitrophenol-containing ligands (2 -7) labeled with technetium-99m. These preparations were studied for biostability in human and rat serum. RESULTS AND DISCUSSION Chemistry. Preparation of 3-[3¢-N-(2²-hydroxy-5²-nitrobenzylamino)-2¢-propanol]-1-substituted-thioureas.Sulfur-donor compounds produce suitable and stable complexes in comparison to nitrogen and oxygen. Amine 1 tends to be a hydrophilic compound and the resulting conjugates (2 -7) would have higher lipophilic properties. In this respect, various aryl and alkylthiourea derivatives were produced and labeled with 99m Tc in order to evaluate their hypoxic cell binding. In the first step, compound 1 was prepared from 1,3-diamino-2-hydroxypropane and 2-hydroxy-5-nitrobenzylbromide. Various N 2 SO ligands (2 -7) were synthesized with high yield by condensation of aryl/alkyl isothiocyanates and 1 in order to form possible chelates for h...

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Biolocalization and cell labeling properties of neutral-lipophilic 99mTc-amine-phenol chelates

Cited by 5 publications

References 8 publications

The Synthesis and in vitro Evaluation of a 99mTechnetium-Nitroimidazole Complex Based on a Bis(amine-phenol) Ligand: Comparison to BMS-181321

The Synthesis and in vitro Evaluation of a 99mTechnetium-Nitroimidazole Complex Based on a Bis(amine-phenol) Ligand: Comparison to BMS-181321

Synthesis and Stability of New Nitrophenol Complexes of 99m Tc as Possible Hypoxia Imaging Radiopharmaceuticals

Synthesis, radiolabeling and stability of new nitrophenol complexes of Technetium-99m as possible hypoxia imaging radiopharmaceuticals

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