# A novel design platform for diaCEST agents

> **NIH NIH R21** · UT SOUTHWESTERN MEDICAL CENTER · 2022 · $246,000

## Abstract

Abstract
Magnetic resonance imaging (MRI) is one of the most important clinical imaging modalities because it can
provide high resolution images of soft tissues in a non-invasive manner. Gadolinium contrast media enhance
image contrast by shortening the T1 and T2 relaxation times of tissue water protons. Alternatively, image contrast
can be generated using chemical exchange saturation transfer (CEST) mechanism. CEST requires the existence
of at least two slowly exchanging pools of protons with different NMR chemical shifts, and generates contrast by
transferring saturated 1H spins from the small pool (agent) to the bulk (tissue) water pool. The key parameters
in CEST are the exchange rate constant (kex) and the chemical shift (frequency) separation of the exchanging
pools (Δω). CEST requires slow exchange condition, (kex ≤ Δω). CEST agents can be exogenous or endogenous
diamagnetic molecules (diaCEST) or paramagnetic metal complexes (paraCEST) with labile protons. ParaCEST
agents exhibit large frequency difference that easily satisfies the requirement for CEST but they have potential
toxicity due to in vivo metal release. DiaCEST agents are metal free by their chemical nature but the chemical
shift separation of diaCEST agents is usually less than 5 ppm from the bulk water. This small frequency
separation poses severe limitations on current diaCEST agents such as poor selectivity due to the spectral
overlap with other exchanging proton resonances, strong interference from tissue background magnetization
transfer and direct water saturation. Here we propose to develop a new diaCEST platform technology that would
overcome the shortcomings of current diaCEST agents by relying on slowly exchanging, highly downfield shifted
(15 ppm from water) protons present in structurally constrained monoprotonated peri-naphthalene derivatives.
Synthesis and in vitro characterization of the proposed agents will be accomplished in Specific Aim 1. The goal
of Specific Aim 2 is to demonstrate the in vivo applicability of these probes in imaging experiments in mice. The
proposed agents would offer several advantages over existing CEST agents including improved CEST efficiency,
high selectivity without interference from proteins and fats, easier data analysis due to weaker tissue
magnetization transfer effect and asymmetry, significantly reduced or eliminated direct water saturation, pH-
independent CEST effect and improved safety profile due to metal free composition. This platform would allow
the design and synthesis of non-specific agents without the confounding effect of pH as well as the construction
of targeted and responsive MR agents through the modification of the naphthalene backbone.

## Key facts

- **NIH application ID:** 10407995
- **Project number:** 5R21EB031367-02
- **Recipient organization:** UT SOUTHWESTERN MEDICAL CENTER
- **Principal Investigator:** Zoltan Kovacs
- **Activity code:** R21 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2022
- **Award amount:** $246,000
- **Award type:** 5
- **Project period:** 2021-06-01 → 2024-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10407995

## Citation

> US National Institutes of Health, RePORTER application 10407995, A novel design platform for diaCEST agents (5R21EB031367-02). Retrieved via AI Analytics 2026-05-27 from https://api.ai-analytics.org/grant/nih/10407995. Licensed CC0.

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