Optimized Solid Phase-Assisted Synthesis of Dendrons Applicable as Scaffolds for Radiolabeled Bioactive Multivalent Compounds Intended for Molecular Imaging

Abstract

Dendritic structures, being highly homogeneous and symmetric, represent ideal scaffolds for the multimerization of bioactive molecules and thus enable the synthesis of compounds of high valency which are e.g., applicable in radiolabeled form as multivalent radiotracers for in vivo imaging. As the commonly applied solution phase synthesis of dendritic scaffolds is cumbersome and time-consuming, a synthesis strategy was developed that allows for the efficient assembly of acid amide bond-based highly modular dendrons on solid support via standard Fmoc solid phase peptide synthesis protocols. The obtained dendritic structures comprised up to 16 maleimide functionalities and were derivatized on solid support with the chelating agent DOTA. The functionalized dendrons furthermore could be efficiently reacted with structurally variable model thiol-bearing bioactive molecules via click chemistry and finally radiolabeled with 68 Ga. Thus, this solid phase-assisted dendron synthesis approach enables the fast and straightforward assembly of bioactive multivalent constructs for example applicable as radiotracers for in vivo imaging with Positron Emission Tomography (PET).

Improving the stability of peptidic radiotracers by the introduction of artificial scaffolds: which structure element is most useful?

“…In order to obtain the corresponding chelator‐modified BBN (7–14) dimers, the thiol‐bearing monomers 2 – 7 were reacted with a dendritic maleimide‐dimer scaffold structure ( 13 ) comprising a protected thiol functionality for further derivatization with the chelator. The resulting peptide dimers were in the following first reacted with TCEP ( tris (2‐carboxyethyl)phosphine hydrochloride) giving the thiol‐bearing intermediate products 14 – 19 in yields of 22–64% and subsequently with NODAGA‐maleimide, yielding the BBN (7–14) ‐dimer labeling precursors 20 – 25 (Scheme B) in yields of 11–73%.…”

“…Fmoc‐aminohexanoic acid, TCEP and maleimide‐NODAGA (NODAGA = (1,4,7‐triazacyclononane‐4,7‐diyl)diacetic acid‐1‐glutaric acid) were purchased from SigmaAldrich and CheMatech, respectively. S ‐trityl‐mercaptoacetic acid, the S‐t Bu‐thio‐protected maleimide dimer 13 and DOTA‐PESIN were synthesized according to published procedures. Peptides were synthesized following a standard Fmoc‐based solid phase peptide synthesis protocol .…”

Protection of gut microbiome from antibiotics: development of a vancomycin-specific adsorbent with high adsorption capacity

“…The yield became lower with increasing generations, probably because of the steric repulsion in the crowded termini of the dendrons of higher generations. Indeed, the 4th generation is reported to be the maximum for quantitative preparation [23]. The amount of loaded ligand per weight of MP was not very different between MP-G3 and MP-G4 (Table 1) because the weights of the dendritic ligand units (68% for MP-G3 and 83% for MP-G4) comprised most of the total weights of these MPs.…”

Radiolabeled Dendrimers for Nuclear Medicine Applications

“…Relative to the monomer, the affinities of hexadecimers to immobilized α v β 3 integrin and U87MG cells were up to 131 and 124 times, respectively. In the following work, this synthesis approach using dendrimer as scaffold structures for radiolabeled bioactive multivalent molecules was further applied for other peptides [ 117 , 118 ]. For instance, PESIN peptide is regarded as a promising ligand to gastrin releasing peptide receptor (GRPR) which is overexpressed on various tumors.…”