S-Trityl protection of bis-amino bis-thiol (BAT) chelator enables flexible derivatisation and facile labelling with technetium-99m (original) (raw)
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Nuclear Medicine and Biology, 1996
We have synthesized and characterized seven ligands derived from 2-aminocyclopentene-ldithiocarboxylic acid with different donor sets ( SN2-, SNO'-, SNN2-, SNN03-and SNNN3-) and different substituents on the sulfur moieties -SR (with R = H, CH, or C,H,O(CH,)CH).
Tetrahedron Letters, 1989
A novel bifunctional chelate, 1, was designed and synthesized for labeling of proteins and small molecules with technetium-99m. The new chelate contains a free carboxyl group which is available for covalent attachment to free amino groups on biologically-important molecules. The resulting chelator may bind reduced technetium-99m such that the label is stable in vitro and in vivo. The labeling of biologically important molecules by means of bifunctional chelating agents has become routine since its introduction by Sundberg et al.1 The success of this technique relies upon a bifunctional chelating agent which possess both a powerful metal chelating group and a second functional group that covalently binds to protein or other molecules of interest without adversely altering their properties. Radioactive metal ions attached by chelation to proteins such as monoclonal antibodies have been used clinically for diagnosis of cancer.2r3 Recent applications of bifunctional chelating agents in the medical sciences have been described.4p5 As is described therein several diaminodithiol ligands have been used as chelators to carry technetium-99m across the normal blood-brain barrier to image normal brain.6'8 In the present report we describe the synthesis of a new diaminodithiol ligand, A, design to couple with free amino groups of proteins and small molecules and to permit subsequent specific binding with technetium-99m as shown in Scheme 1.
Bioconjugate Chemistry, 2004
The PN 2 S N- (N-(3-diphenylphosphinopropionyl)glycyl)cysteine ligand was conjugated to methoxypoly(ethylene glycol)-amino (mPEG-NH 2 ) 5 and 20 kDa to yield PN 2 S(Trt)-PEG 5000 1 and PN 2 S(Trt)-PEG 20000 2, and then detritylated to PN 2 S-PEG 5000 4 and PN 2 S-PEG 20000 5. When an acidic solution of 99m TcO 4is added to 4 or 5 in solid form, a quantitative yield in a single labeled species, 99m Tclabeled PN 2 S-PEG 5000 9 and 99m Tc-labeled PN 2 S-PEG 20000 10, respectively, is obtained. The reaction occurs in less than 15 min at room temperature for 4 and 35°C for 5. This labeling procedure avoids the use of an external reducing agent, and it is based on the amphiphilic properties of PN 2 S-PEGs. Once in water, 4 and 5 self-assemble in micelles, which catalyze the metal reduction by means of an electron pair transfer from the phosphorus to technetium. The [ 99m TcO] 3+ species is then coordinated, and at micelle level, both the (P)ON 2 S and the PN 2 S coordinations are possible, as demonstrated by reacting 99m Tc-gluconate and ReOCl 3 (PPh 3 ) 2 with 4 and 5 and with the oxidized analogous (P)ON 2 S-PEG 5000 6. Compounds 9 and 10 exhibited a high stability both in vitro and in vivo. Biodistribution studies in mice also indicated that PN 2 S linking and 99m Tc labeling do not modify PEG behavior in water and in vivo since the polymer dictates the fate of the conjugate. MW 20 kDa; Na 99m TcO4 -, sodium pertechnetate; PBS, phosphate buffer solution; NHS, N-hydroxysuccinimide; ReOCl3(PPh3)2, trans-oxotrichloro bistriphenylphosphine rhenium(V); saline, physiological solution (0.9% NaCl); SnCl2, tin(II) chloride; TEA, triethylamine; TFA, trifluoroacetic acid. 99m Tc labeling of PEGylated PN 2 S ligands
Organic & biomolecular chemistry, 2015
In a bid to find an efficient means to radiolabel biomolecules under mild conditions for PET imaging, a bifunctional (18)F prosthetic molecule has been developed. The compound, dubbed [(18)F]FPyPEGCBT, consists of a 2-substituted pyridine moiety for [(18)F]F(-) incorporation and a 2-cyanobenzothiazole moiety for coupling to terminal cysteine residues. The two functionalities are separated by a mini-PEG chain. [(18)F]FPyPEGCBT could be prepared from its corresponding 2-trimethylammonium triflate precursor (100 °C, 15 min, MeCN) in preparative yields of 11% ± 2 (decay corrected, n = 3) after HPLC purification. However, because the primary radiochemical impurity of the fluorination reaction will not interact with 1,2-aminothiol functionalities, the (18)F prosthetic could be prepared for bioconjugation reactions by way of partial purification on a molecularly imprinted polymer solid-phase extraction cartridge. [(18)F]FPyPEGCBT was used to (18)F-label a cyclo-(RGDfK) analogue which was m...
Journal of Labelled Compounds and Radiopharmaceuticals, 2006
An attempt has been made to develop a suitable protecting group for the thiolate function for 99m Tc binding ligands having such function and which could be deprotected automatically during 99m Tc-chelation without the use of any additional reagents. As a model ligand a simple molecule like l-cysteine was selected. Seven S-protected derivatives of this amino acid were synthesized, radiolabelled with technetium-99 m under a variety of experimental conditions and the yield of the desired chelate was compared to that of 99m Tc-l-cysteine, the authentic standard chelate, by HPLC. The corresponding 99 Tc chelate of cysteine from l-cystine and S-thiomethyl l-cysteine was also prepared. It was found that the 99 Tc chelates exhibited similar retention profiles to those of the corresponding 99m Tc chelates in reverse phase HPLC. The results of the biodistribution studies after 99m Tc chelation were likewise compared to those of 99m Tc-l-cysteine. The effect of probenecid on renal excretion was studied only on the 99m Tc chelate of S-thiomethyl-l-cysteine to determine whether tubular excretion was involved. The results suggest that the S-thiomethyl group could be used as an ideal protective group to mask the high reactivity of thiolate functions attached to different 99m Tc binding ligands. Copyright
Zn Complex of Diaminedithiol Tetradentate Ligand as a Stable Precursor for 99mTc-Labeled Compounds
Molecules
The diaminedithiol (N2S2) tetradentate ligand constitutes a useful chelating molecule for preparing 99mTc-labeled compounds of high in vivo stability in high radiochemical yields. However, since the thiol groups in the N2S2 ligand are easy to be oxidized to disulfide bonds, they need to be protected with an appropriate protecting group, which hinders the broad applications of the N2S2 ligand for radiopharmaceuticals. In this study, a Zn chelate of N2S2 was evaluated as a precursor for purification-free 99mTc-labeled N2S2 under the mild and simple procedure. Zn-N2S2 was prepared by reacting Zn acetate with N2S2, and the Zn-N2S2 remained stable under aerobic conditions at room temperature. 99mTc-N2S2 was obtained over 90% radiochemical yields at room temperature by a one-pot reaction, consisting of Zn-N2S2 (10−5 M), 99mTcO4−, ethylenediaminetetraacetic acid (EDTA), and a reducing agent (Sn2+) at pH = 5.5 to 7.5. 99mTc-N2S2 was also obtained over 90% radiochemical yields when the react...
2004
A new biomolecule labeling method that utilizes the [ 99m Tc(N)(PNP)] 2+ metal fragment is presented. Thus, a series of nitrido mixed-ligand M(V) complexes (M ) 99m Tc, 99g Tc, Re), [M(N)(Ln)(PNP)], where Ln is the dianionic form of a dithiolate or substituted-dithiolate ligand and PNP is an aminodiphosphine, is described. 99m Tc complexes can be prepared using either a two-step or a three-step procedure starting from generator-eluted pertechnetate through a prereduced mixture of [ 99m Tc(N)]-containing species, followed by sequential or contemporary addition of the relevant dithiolate and aminodiphosphine. The reactions of 2,3-dimercaptopropionic acid (H 2 L1) with [Tc(N)(PNP)] 2+ were investigated in detail. It was found that this bidentate ligand coordinated the metal fragment through the [S -,S -] donor atom pair, to yield neutral mixed-ligand complexes [ 99m Tc(N)(L1)(PNP)] in high specific activity. The additional carboxylic functional group was not involved in metal coordination, thus remaining available for conjugation to target-specific molecules. Dithiolates incorporating pendant functional group(s) gave rise to a 1:1
Journal of Organometallic Chemistry, 2004
2 + 1'' Dithiocarbamate (DTC)-isocyanide (ISO) system was studied to label amino acids and model peptides with 99m TcðCOÞ þ 3 fragment. Two ways were used: (i) conjugation via free carboxy group of bifunctional DTC [S 2 CNMe À 2 (L3), S 2 CNHCH 2 COO 2À (L1) and S 2 C(C 4 H 7 N)COO 2À (L2)] using pre-labeling procedure and (ii) conjugation via isocyanide ligand [tert-BuNC (L4), EtOC(O)CH 2 NHC(O)CH 2 NC (L5), and gly-gly-gly-CH 2 NHC(O)CH 2 NC (L6)]. Complexes M(CO) 3 L2L4 À (1a, 1b), M(CO) 3 -L3L4 À (2a, 2b) and bioconjugates M(CO) 3 L1L5 (5a, 5b), and M(CO) 3 L1L6 (6b) (a, M = Re; b, 99m Tc) were synthesized. Bioconjugates 4a and 4b were prepared by reaction of histidine methyl ester with 2a and 2b, respectively. All rhenium complexes were characterized by 1 H and 13 C NMR, IR, and MS spectroscopy and complexes with 99m Tc, by HPLC using rhenium analogs as references.