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

Liam Connah,Rajendra Joshi,João D G Correia,Sandip Vibhute,Giuseppe Gambino,Goran Angelovski

doi:10.1021/acs.orglett.9b01341

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.

Highlights

Solid-phase synthetic (SPS) methods have been frequently used as an alternative to conventional solutionphase techniques, eventually finding its application in the development of magnetic resonance imaging (MRI) probes.[6−11] Introduced by Bruce Merrifield in the 1960s, solid-phase synthetic (SPS) has been typically used in the area of peptide synthesis, as it allows for the building of a molecule in a stepwise fashion on an insoluble solid support.[12−14]
Of particular importance was the preparation of a bismacrocyclic smart” contrast agents (SCAs), which generates a strong response in the presence of Ca2+, and in cellular model systems.[16,17]
The previously developed solution-phase procedure allowed for its convenient preparation; the symmetric nature did not allow for the incorporation of additional functionalities without damaging the response toward Ca2+

Summary

Organic Letters

The use of an insoluble solid support gave significant advantages over standard solution-phase chemistry techniques,[15] : (i) the ability to drive reactions to completion through the use of excess reagents; (ii) the minimization of physical losses; (iii) quick washing steps after each reaction instead of tedious solution-phase workups and purification; (iv) to allow for the synthesis of more complex molecules and (v) the possibility to fully automate the synthetic procedure. Its N-alkylation with N-(3-bromopropyl)phthalamide gave 2, which was reduced to give the BB1 This approach resulted in a DO2A-based macrocyclic component with one functional group (an aromatic amine) available for coupling to the peptide scaffold and another (phthalamide-protected amine) which can be selectively deprotected and used for further synthetic transformations. The orthogonal Mtt protecting group of lysine was removed with a solution of TFA/ triisopropylsilane/dichloromethane (3:3:94) to afford the primary amine. This was coupled to biotin with HATU yielding 11. We have developed a solid-phase synthetic protocol for the preparation of functionalized and bioresponsive bismacrocyclic SCAs. We diversified our building block synthesis to incorporate SPS-friendly functional groups such as phthalimide, which we successfully deprotected using mild conditions. Synthetic procedures for preparation of BB1, BB2, and Gd2L; purification procedure for Gd2L; HABA assay; additional relaxometric titration experiments; parameters for MRI phantom measurements; NMR and HR mass spectra; LC-MS and HPLC data (PDF)

■ ACKNOWLEDGMENTS

Findings

■ REFERENCES