6-mercaptomethylpyridine-3-carboxylic acid (MEMNIC): a new reagent for peptide labeling with Tc-99m

Jw. Babich et al., 6-mercaptomethylpyridine-3-carboxylic acid (MEMNIC): a new reagent for peptide labeling with Tc-99m, INORG CHIM, 323(1-2), 2001, pp. 23-36
Citations number
Categorie Soggetti
Inorganic & Nuclear Chemistry
Journal title
ISSN journal
0020-1693 → ACNP
Year of publication
23 - 36
SICI code
As part of our ongoing research into the development of peptide based radio pharmaceuticals, we have explored 2-mercaptopyridines and 2-mercapto-pyrimi dines (2MPs) as coligands to control the radiochemical speciation of Tc-99m -labeled hydrazinonicotinamide (HYNIC) derivatized chemotactic peptides. In an attempt to develop an aminothiol ligand with greater stability, we synt hesized 6-mereaptomethylpyridine-3-carboxylic acid (MEMNIC). assuming a fiv e-member chelate ring complex would be more stable than the four-membered r ing possible with 2MPs. Initial experiments suggested that Tc-99m-MEMNIC wa s stable in vivo and led to our investigation of it as a bifunctional chela tor for Tc-99m labeling of peptides. The utility of MEMNIC was tested in a rabbit model of infection. The N-epsilon MEMNIC derivative of For-MLFK was prepared using the N-hydroxysuccinimidyl ester of MEMNIC. For-MLFK-MEMNIC w as labeled via Tc-99m-mannitol and its imaging and biodistribution properti es compared to Tc-For-MLFK-HYNIC and Tc-For-MLFCys (labeled via the free th iol of cysteine). Sites of infection were produced in New Zealand white rab bits (n = 6/peptide) by injection of a suspension of Escherichia coli in a posterior thigh. Twenty-four hours after infection, the rabbits were inject ed intravenously with 0.5 mCi of HPLC purified Tc-99m-peptide and imaged at 2.5 and 18 h p.i. The animals were sacrificed at 18 h and tissue activity determined. At 2.5 and 18 It, the organ distribution of Tc-For-MLFK-HYNIC a nd Tc-For-MLFK-MEMNIC were qualitatively similar with the exception of high er renal accumulation of the latter, whereas Tc-For-MLFKCys showed rapid an d prolonged accumulation in bowel. ROI analysis gave target/background rati os of 3.91 +/- 0.32 and 11.89 +/- 2.21 for Tc-For-MLFK-HYNIC, 5.09 +/- 0.66 and 9.88 +/- 1.12 for Tc-For-MLFK-MEMNIC and 2.59 +/- 0.16 and 1.70 +/- 0. 37 for Tc-For-MLFCys, at 2.5 and 18 h. Tissue radioactivity measurements (1 8 h) demonstrated that compared to Tc-For-MLFK-HYNIC, the accumulation of T c-For-MLFK-MEMNIC was less in all organs except in kidney which was greater . Direct labeling of the thiol group of cysteine led to lower accumulation in all organs compared to Tc-For-MLFK-MEMNIC, except in GI tract which was fivefold higher. While, Tc-For-MLFK-MEMNIC had half the accumulation of Tc- For-MLFK-HYNIC in infected muscle and pus, the lower accumulation in most o rgans and normal muscle resulted in good infection localization. These resu lts indicate that MEMNIC can be successfully used to label peptides with Tc -99m while exhibiting good in vivo stability. The chemistry of MEMNIC with the {M(V)O}(3+) core characteristic of technetiun and its Group V congener rhenium was modeled by investigating the reactions of 2-mercaptomethylpyrid ine with appropriate Re(V)-oxo precursors in the presence of a variety of c oligands, With diolate type tridentate donors of the class {X(CH2CH2O)(2)}( 2-) (X = -NR, O, S), the '3+2' compounds [ReO{eta (3)-(OCH2CH2)(2)S}{eta (2 )-SCH2C5H4N}] (2) and [ReO{eta (3)-(OCH2CH2)(2)NCH3}{eta (2) -SCH2C5H4N}] ( 3) were isolated. In contrast, with the more sterically demanding dirmercap to class of tridentate ligands {S(CH2CH2S)(2)}(2-), the '3+1' species [ReO{ eta (3)-(SCH2CH2)(2)S}{eta (1)-(SCH2C5H4N)}] was isolated. (C) 2001 Elsevie r Science B.V. All rights reserved.