Solid-Phase-Supported Approach for the Preparation of Bioresponsive and Multifunctional MRI Probes

Abstract

The development of bifunctional imaging probes can often be challenging with difficult and time-consuming solution phase chemistry protocols and purification techniques. A solid phase synthetic protocol was therefore utilized to produce a functionalized derivative of a potent bismacrocyclic calcium-responsive contrast agent for magnetic resonance imaging. Through a convenient building block approach, the applicability of this methodology in the preparation and simple future development of multifunctional imaging probes was demonstrated.

Solid-phase synthesis and evaluation of tumour-targeting phenylboronate-based MRI contrast agents

“…A few cases have been already described where conventional solid-phase peptide synthesis was exploited to build molecular parts of contrast agents. [17][18][19][20] Several solid supports are reported in the literature to specifically bind boronic acids, including citronellic acid attached to Rink's amide resin, polystyrene derivatised with 2-methyl-2-(hydroxymethyl)-1,3-propanediol, 21 catechol pendant polystyrene polymer, 22 and more recently, 1-glycerol Merrifield resin. 23 Among these, polystyrene functionalized with diethanolamine groups (DEAM-PS resin) seems to be endowed with more effective binding properties, and requires mild conditions to release the boronic acids after their derivatization.…”

RGD-Peptide Functionalization Affects the In Vivo Diffusion of a Responsive Trimeric MRI Contrast Agent through Interactions with Integrins

“…The synthesis of Gd 3 L 3 -RGD was achieved using the SPPS method, which is most commonly used for the production of peptides. This methodology represents an incredibly convenient approach to the preparation of targeted probes for molecular imaging, since it enables the synthesis of the peptidic backbone in a linear and practical fashion. − Moreover, the obtained peptide chain can be subsequently functionalized, exploiting the side-chain functional groups of the amino acids to couple chelators for paramagnetic ions to serve as MRI-active units or ligands for targeting purposes. Thus, we exploited this convenient strategy to successfully prepare an RGD-bearing polypeptide, combined with macrocyclic units to serve as precursors for the MRI agent.…”

Solid phase synthesis in the development of magnetic resonance imaging probes

“…138 In our group, we employed SPS as an alternate synthetic methodology to synthesise bismacrocyclic calcium-responsive MRI probes, which previously showed a strong response in to Ca 2+ in cellular model systems. [139][140][141] For this, we also utilised a building block approach, which included two different DO3A-type macrocycles and an EGTA-derived chelator, all synthesised in solution prior to assembly on resin. Initiating from a Rink amide resin, a short peptide linker (Lys(Mtt)-Gly-Gly) was assembled following standard SPS techniques, followed by conversion of the NH 2 terminal to a carboxylic acid through treatment with succinic anhydride.…”

“…Concurrently, we also revealed useful SPS chemistry for the removal of phthalimide as an amino protecting group with ethylene diamine at room Fig. 14 Schematic representation of the synthetic methodology utilised to develop a Ca 2+ -responsive MRI CA and its final chemical structure. 141 temperature, as well as the use of alkylation to introduce the final DO3A-type building block. The whole construct was then deprotected and removed from then resin in one step before complexation with Gd 3+ to give the final SCA (Fig.…”