Conjugation of a novel histidine derivative to biomolecules and labelling with [99mTc(OH2)3(CO)3]+Electronic supplementary information (ESI) available: complete 1H and 13C NMR spectra of 14, 15, 16 and 19. See http://www.rsc.org/suppdata/ob/b4/b405575f/

Abstract

The new histidine derivative 3-[1-[3-(9H-fluoren-9-ylmethoxycarbonylamino)-propyl]-1H-imidazol-4-yl]-2-(3-trimethylsilanyl-ethylcarboxyamino)-propionic acid methyl ester (7) has been prepared via alkylation of the histidine urea derivative (7S)-5,6,7,8-tetrahydro-7-(methoxycarbonyl)-5-oxoimidazo-[1,5-c]-pyrimidine (2) with Fmoc-protected 3-iodopropyl-amine, followed by ring opening with 2-trimethylsilylethanol. After Fmoc cleavage by HNEt2, the histidine amine derivative was coupled to biotin, to the pentapeptide leucine-enkephalin and to Vitamin B12-b-acid by amide formation, employing TBTU as the coupling reagent. In order to make the histidine accessible for labelling, the teoc protecting group was removed by either NBu4F (for the biotin conjugate) or by TFA (for the enkephalin and B12 conjugates). Reaction of a 10(-4) M solution of the bioconjugates with [99mTc(H2O)3(CO)3]+ at 50 degrees C for 30 min led to the formation of one single new peak in the HPLC radiochromatogram in each case, confirming quantitative labelling of the respective biomolecules. To assess the nature of the labelled compounds, the rhenium analogues with Re(CO)3 were also synthesised and similar retention times confirmed the identity with the 99mTc labelled conjugates.

Molecular Assembly of Multifunctional 99mTc Radiopharmaceuticals Using “Clickable” Amino Acid Derivatives

“…Starting from side-chain-functionalized N(a)-propargyl lysine derivatives, conjugates containing a 99m Tc-based imaging probe for SPECT and two different moieties (e.g., tumor-targeting vectors, pharmacological modifiers, affinity tags, or second imaging probes) can be assembled using the Cu I -catalyzed alkyneazide cycloaddition in efficient one-pot protocols. This strategy was successfully applied to the preparation of a 99m Tc-labeled conjugate comprising a tumor-targeting peptide sequence (bombesin (7)(8)(9)(10)(11)(12)(13)(14)) and a low-molecular-weight albumin binder, a pharmacological modifier that prolongs the blood circulation time of the conjugate. Evaluation of the conjugate in vitro and in vivo provided promising results for its use as an imaging agent for the visualization of tumors positive for the gastrin-releasing peptide receptor.…”

Mono‐, bi‐, or tridentate ligands? The labeling of peptides with 99mTc‐carbonyls

“…Analogously, ring opening is performed with an alcohol group as well and the amine group on the linker is selectively deprotected. 25 This derivative of histidine can be coupled to the C-terminus of a peptide by routine techniques. We have introduced such histidine derivatives in the peptide enkephalin and in vitamin B12.…”

Vitamin B12–Metal Conjugates for Targeted Chemotherapy and Diagnosis: Current Status and Future Prospects

“…[63] This approach exploits the modification of an amino acid to incorporate a tridentate terminus and a terminus for attachment to biomolecules at different positions within the backbone. Thus, the pendant b-, c-, and d-propionic groups of the vitamin B 12 corrin framework can be coupled with tridentate ligands such as N ε -derivatized histidine residues, [64,65] S-derivatized cysteine residues, [66] or picolylamine-monoacetic acid (PAMA), [67] thus varying the length of the alkyl spacer. The subsequent labeling with the {fac- but not to human transcobalamin II.…”