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| Home > Publications database > A novel CDTA-based bifunctional chelator for 52g/55Mn(II)-labeled bimodal PET/MR tracers |
| Poster (Plenary/Keynote) | FZJ-2016-07109 |
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2016
Abstract: Research on contrast agents for MRI increasingly concentrates on paramagnetic MnII complexes as alternative to GdIII chelates commonly used in the clinical setting. Besides being an essential metal in vivo and possessing excellent physical properties for T1-weighted MR applications, an additional feature of MnII is the availability of the positron-emitting isotope 52gMn, a promising candidate for PET imaging. We have recently shown that radiolabeling CDTA (trans-1,2-diaminocyclohexane-N,N,N´,N´-tetraacetic acid) with an isotopic 52g/55Mn mixture gives direct access to the corresponding bimodal PET/MR tracer.[1] This technique ensures that both the PET and MR reporter molecules are present in the required concentrations for each imaging modality (PET is >106 times more sensitive than MRI) as well as chemically identical, thus exhibiting the same in vivo behavior.In order to fully benefit from the synergistic combination of PET and MR imaging, a dual modal manganese tracer should either (i) be specific to a tissue/disease, (ii) have a high relaxivity or (iii) be biomarker responsive. As the design of such optimized probes requires the use of a bifunctional MnII chelator (BFMnC), the CuAAC-reactive compound 1 was synthesized in 6 steps with an overall yield of 25% (CuAAC = CuI-catalyzed azide-alkyne cycloaddition). The model chelator 4-HET-CDTA (2), which was obtained by clicking 1 with 2-azidoethanol followed by deprotection, was used to assess the equilibrium and kinetic properties of the corresponding MnII chelate. The stability constant (log KMnL) and the kinetic inertness (characterized by the dissociation half-life, t1/2) obtained for [Mn(4-HET-CDTA)]2- appeared to be equivalent or 35% higher, respectively, than for [Mn(CDTA)]2- (see Table). Additionally, the 27% relaxivity increase observed for [Mn(4-HET-CDTA)]2- compared to [Mn(CDTA)]2- indicates that the novel complex is monoaquated (q = 1). Parameter [Mn(4-HET-CDTA)]2- [Mn(CDTA)]2- [2]Stability constant – log KMnL a 13.80 14.32Dissociation half-life – t1/2 (h) b 16.23 12.00Relaxivity – r1 (mM-1s-1) c 4.56 3.6Conditions: a = 0.15 M NaCl, 25°C; b pH = 7.4, [Cu2+] = 10-5 M, 25°C; c 20 MHz, 25°C.Current efforts focus on the design of PSMA-targeted 52g/55Mn-tracers for hybrid PET/MR imaging of prostate cancer (PSMA = prostate-specific membrane antigen). Notably, an azide-containing, tert-butyl-protected PSMA-binding motif was prepared and efficiently coupled to BFMnC 1 by CuAAC in >70% yield. Radiolabeling of the obtained conjugate with isotopic 52g/55Mn upon deprotection is under progress, aiming at the first evaluation of manganese-based PET/MR probes in animal models.
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