A new synthesis of cystamine modified Eu3+ DOTAM-Gly-Phe-OH: a conjugation ready temperature sensitive MRI contrast agent

Abstract

Several approaches towards asymmetrically derivatized peptide-decorated cyclens that yield lanthanide metal chelators, in which three of the nitrogen atoms of cyclen share a common substituent and the fourth nitrogen atom is differentially substituted, have been evaluated. The most effective route consisted of selective monoalkylation followed by peralkylation with a second different electrophile. The unique substituent also possessed a masked sulfanyl group that was suitable for subsequent chemoselective conjugation chemistry.

Alternatives to Gadolinium-Based Metal Chelates for Magnetic Resonance Imaging

“…In another report, Suchy et al synthesized a new ligand to alter the in vivo biodistribution of their targeted oligopeptide derivatives 237. They conjugated ligand 57 to a cell-penetrating peptide, a cystamine derivative, with the expectation that the disulfide bond when cleaved in a reductive intracellular environment may result in trapping the agent within the cell.…”

“…This route was also adapted for the synthesis of peptide-based DOTA tetraamides. Utilizing this strategy, a large library of ligands and their subsequent lanthanide complexes were produced in excellent yields 235–237…”

Mono‐ and Tetraalkyne Modified Ligands and Their Eu3+ Complexes – Utilizing “Click” Chemistry to Expand the Scope of Conjugation Chemistry

“…N ‐Chloroacetyl–Gly– L ‐Tyr( O ‐propargyl)–OMe ( 18a , Scheme ) was purified by column chromatography and obtained in 55 % yield, based on 17 . Halogen exchange using crude 18a , under conditions previously established in our laboratory24a,25,26 (NaI in acetone), proceeded smoothly and afforded N ‐iodoacetyl–Gly– L ‐Tyr( O ‐propargyl)–OMe ( 18b , Scheme ) in 48 % overall yield (based on 17 ).…”

“…The reaction was performed by the dropwise addition of a concentrated solution of electrophile in chloroform to a solution of 4a in chloroform at 0 °C. The addition of external base was not required to promote the monoalkylation 26. However, this methodology failed when the monoalkylation of 4a with 18a was attempted.…”

“…Moreover, we have also found that these unique properties are retained when the phenylalanine moieties are replaced with tyrosine to form Eu 3+ –DOTAM–Gly– L ‐Tyr–OH ( 14b , Figure 2), yet lost when replaced by tryptophan 25. In order to develop conjugation chemistry for Eu 3+ –DOTAM–Gly– L ‐Phe–OH, we have prepared some asymmetrically substituted precursors,26 which have been utilized for the synthesis of cell‐penetrating peptide conjugates of 14a : homodimetallic disulfide‐bridged Eu 3+ complexes derived from 14a 27 as well as homo‐ and heterodimetallic (Eu 3+ and Tm 3+ ) complexes featuring the Eu 3+ –DOTAM–Gly– L ‐Phe–OH structural subunit 28. The presence of free hydroxy groups in the structure of 14b along with the fact that this replacement does not affect the magnetic properties associated with 14a prompted us to investigate the possibilities of the conjugation chemistry of the complex with 14b .…”