Comparison of divalent transition metal ion paraCEST MRI contrast agents

Abstract

Transition-metal-ion-based paramagnetic chemical exchange saturation transfer (paraCEST) agents are a promising new class of compounds for magnetic resonance imaging (MRI) contrast. Members in this class of compounds include paramagnetic complexes of Fe(II), Co(II), and Ni(II). The development of the coordination chemistry for these paraCEST agents is presented with an emphasis on the choice of the azamacrocycle backbone and pendent groups with the goals of controlling the oxidation state, spin state, and stability of the complexes. Chemical exchange saturation transfer spectra and images are compared for different macrocyclic complexes containing amide or heterocyclic pendent groups. The potential of paraCEST agents that function as pH- and redox-activated MRI probes is discussed.

Figure 1

Crystal structures of A) [Mn(TCMC)]²⁺and B) [Yb(TCMC)(H₂O)]³⁺. Reprinted with permission from references [38] and [37], respectively.

Figure 2

A) ¹H NMR spectra for [Fe(TCMC)]²⁺ in CD₃CN and B) [Yb(TCMC)(H₂O)]³⁺ in H₂O. The * indicates the location of amide NH protons. The broad proton resonances are assigned as macrocycle CH protons. Adapted with permission from references [40] and [37].

Figure 3

Crystal structure of [Ni(TCMT)]²⁺. Reprinted with permission from reference [45].

Figure 4

A) ¹H NMR spectra of [Fe(AMPT)]²⁺ in D₂O, pD 7.0, (B) [Ni(NOPE)]²⁺ in D₂O. Adapted with permission from references [22, 25].

Figure 5

Crystal structures of A) deprotonated [Ni(H_–2BZT)], (B) [Ni(TPT)]²⁺ (C) [Zn(TPT)]²⁺ showing complex cation geometry. Adapted with permission from references [–57].

Figure 6

Illustration of a ¹H NMR spectrum of a CEST agent (top), corresponding CEST spectrum (middle), and representation of water signal intensity (bottom). Reprinted with permission from reference [61].

Figure 7

CEST spectra of A) [Fe(STHP)]²⁺ (○) and [Fe(TCMC)]²⁺ (▲); B) [Ni(CCRM)]²⁺ (◇) and [Ni(NOPE)]²⁺ (○); C) [Co(NOPE)]²⁺ (○) and [Co(TCMC)]²⁺ (▲); D) [Ni(TCMT)]²⁺ (▲), [Fe(TCMT)]²⁺ (⋄), and [Co(TCMT)]²⁺ (○). All samples contained 10 mM complex, 20 mM HEPES buffer pH ~7.4, and 100 mM NaCl B₁ = 24 μT (1000 Hz) presaturation for 2 s at 37 ºC,. CEST spectra modified from references [22, 23, 25, 26].

Figure 8

CEST spectra (11.7 T NMR) of 4 mM [Fe(AMPT)]²⁺ (black line), 100 mM NaCl, pH 7.0 (B₁= 11 μT, 4 s, 25 ºC); 3mM [Fe(BZT)]²⁺ (red line), 100 mM NaCl, pH 6.3 (B₁= 23 μT, 3 s, 25 ºC); and 8 mM [Co(TPT)]²⁺ (blue line), 100 mM NaCl, 20 mM HEPES, pH 7.0 (B₁= 24 μT, 3 s, 37 ºC). Insert shows expanded CEST spectrum of [Fe(AMPT)]²⁺ [21, 22, 24].

Figure 9

Phantom images of [Ni(NOPE)]²⁺ on a 4.7 T MR scanner. Center contains only 20 mM HEPES,100 mM NaCl. Concentration of [Ni(NOPE)]²⁺ varies: D1 2mM, D2 4mM, and D3 8 mM with 20 mM HEPES pH~ 7.4, 100 mM NaCl at 37º C. Reprinted with permission from reference [25].

Figure 10

Transition metal ions to date that show promise as paraCEST agents.

Scheme 1

Divalent transition metal ion-based paraCEST agents.

Scheme 2

Macrocyclic complexes with pyridine pendents

Scheme 3

Representative Ln^III paraCEST agents