N,N-bis(2-mercaptoethyl)methylamine: A new coligand for Tc-99m labeling of hydrazinonicotinamide peptides

Sangeeta R. Banerjee, Kevin P. Maresca, Karin A. Stephenson, John F. Valliant, John W. Babich, Wendy A. Graham, Marlene Barzana, Qing Dong, Alan J. Fischman, Jon Zubieta

Research output: Contribution to journalArticlepeer-review

18 Scopus citations


Hydrazinonicotinamide (HYNIC) forms stable coordination complexes with Tc-99m when reacted with TC(V)oxo species such as Tc-mannitol or other Tc-polyhydric complexes. However, radio-HPLC of [Tc-For-MLFK-HYNIC] labeled via Tc-polyhydric ligands demonstrated multiple radiochemical species each with unique biodistribution patterns. This is likely due to the fact that Tc can bind to the hydrazino moiety, as well as polyhydric ligands, in a variety of coordination geometries. Tridentate ligands, such as bis(mercaptoethyl) methylamine (NS2), may constrain the possible coordination geometries and improve overall stability. To investigate this, we synthesized NS 2, converted the [Tc-mannitol-For-MLFK-HYNIC] to the corresponding NS2-containing complex [Tc-NS2-For-MLFK-HYNIC], and compared its infection imaging and biodistribution properties with [Tc-mannitol-For-MLFK-HYNIC]. Conversion to the NS2 complex was confirmed by HPLC which showed a single unique hydrophobic species with retention time greater than the [Tc-mannitol-For-MLFK-HYNIC] complex. Imaging experiments with both preparations were performed in rabbits with E. coli infections in the left thigh. Tissue radioactivity measurements demonstrated that compared to Tc-mannitol-peptide, accumulation of Tc-NS2-peptide was lower in blood, heart, and normal muscle and higher in spleen, infected muscle, and pus (p < 0.01). These results indicate that the Tc-NS 2-peptide complex is chemically more homogeneous and exhibits improved infection localization and biodistribution properties. In an effort to model the interactions of the metal-HYNIC core with NS2 and related ligand types, the reactions of [ReCl3(NNC5H 4NH)(NHNC5H4N)] and [99TcCl 3(NNC5H4NH)(NHNC5H4N)], effective structural analogues for the {M(NNC5H4NH x)2} core, with NS2, C5H 3N-2,6-(CH2SH)2, O(CH2CH 2SH)2, and S(CH2CH2SH)2 were investigated and the compounds [M{CH3N(CH2CH 2S)2}(NNC5H4N)(NHNC 5H4N] (M = 99Tc (5a), Re (5b)), [Re{C 5H3N-2,6-(CH2S)2}(NNC 5H4N)(NHNC5H4N)]·CH 2Cl2·0.5MeOH (7), [Re{SCH2CH 2)2O} (NNC5H4N)(NHNC 5H4N)] (8), and [Re{(SCH2CH2) 2S}(NNC5H4NH)(NHNC5H 4N)]Cl (9) were isolated. Similarly, the reaction of [ReCl 3(NNC5H4NH)(NHNC5H4N)] with the bidentate ligands pyridine-2-methanethiol and 3-(trimethlysilyl) pyridine-2-thiol led to the isolation of [ReCl(C5H 4N-2-CH2S) (NNC5H4N)(NHNC 5H4N)] (10) and [Re(2-SC5H3N-3- SiMe3)2 (NNC5H4N)(NHNC 5H4N)] (11), respectively, while reaction with N-methylimidazole-2-thiol yielded the binuclear complex [Re(OH)Cl(SC 3H2N2CH3)2(NNC 5H4N)2 (NHNC5H4N) 2] (12). The analogous metal-(HYNIC-OH) precursor, [ReCl 3{NNC5H5NH(CO2R)} {NHNC 5H3N(CO2R)}] (R = H, 13a; R = CH3, 13b) has been prepared and coupled to lysine to provide [RCl 3{NNC5H3NH(CONHCH2CH 2CH2CH2CH(NH2)CO2H)} {NHNC5H3NH(CONHCH2CH2CH 2CH2CH(NH2)CO2H)}]·2HCl (14·2HCl), while the reaction of the methyl ester 13b with 2-mercaptopyridine yields [Re(2-SC5H4N) 2{NNC5H3N(CO2Me)}{NHNC 5H3N(CO2Me)}] (15). While the chemical studies confirm the robustness of the M-HYNIC core (M = Tc, Re) and its persistence in ligand substitution reactions at adjacent coordination sites of the metal, the isolation of oligomeric structures and the insolubility of the peptide conjugates of 13, 14, and 15 underscore the difficulty of characterizing these materials on the macroscopic scale, an observation relevant to the persistent concerns with reagent purity and identity on the tracer level.

Original languageEnglish (US)
Pages (from-to)885-902
Number of pages18
JournalBioconjugate Chemistry
Issue number4
StatePublished - 2005

ASJC Scopus subject areas

  • Biotechnology
  • Bioengineering
  • Biomedical Engineering
  • Pharmacology
  • Pharmaceutical Science
  • Organic Chemistry


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