<br>提高 PET 成像用 18 元大环螯合剂的 [52Mn]Mn(II) 配合物的体内稳定性,Journal of Medicinal Chemistry

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提高 PET 成像用 18 元大环螯合剂的 [52Mn]Mn(II) 配合物的体内稳定性
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2024-06-27 , DOI: 10.1021/acs.jmedchem.4c00812
Charlene Harriswangler ₁ , James M Omweri _{2,

3} , Shefali Saini _{2,

3} , Laura Valencia ₄ , David Esteban-Gómez ₁ , Madalina Ranga ₅ , Nicol Guidolin ₅ , Zsolt Baranyai ₅ , Suzanne E Lapi _{2,

3} , Carlos Platas-Iglesias ₁

Affiliation

我们报道了^大^环螯合剂 PYAN [3,6,10,13-tetraaza-1,8(2,6)-dipyridinacyclotetradecaphane] 和 CHXPYAN [(4 ¹ R , 4 ² R ,10 ¹ R ,10 ² R )-3,5,9,11-四氮杂-1,7(2,6)-联吡啶-4,10(1,2)-二环己环十二烷]。 Mn-PYAN 和 Mn-CHXPYAN 的 X 射线晶体结构证明，通过大环氮原子的配位，八面体几何形状发生了扭曲。循环伏安法研究证明了由于 Mn(II)/Mn(III) 对而产生的可逆过程，表明该复合物具有抗氧化性。 CHXPYAN 形成比 PYAN 更热力学稳定和动力学惰性的 Mn(II) 络合物。使用放射性同位素锰 52（ ⁵² Mn， t _1/2 = 5.6 天）进行的放射化学研究证明，CHXPYAN 的放射化学产率高于 PYAN。两种[ ⁵² Mn]Mn(II) 配合物在小鼠和人血清中保持稳定，因此进行了体内稳定性研究。正电子发射断层扫描/计算机断层扫描和生物分布测定表明，[ ⁵² Mn]Mn-PYAN 具有与[ ⁵² Mn]MnCl ₂相似的分布模式，显示出肾脏中持续的放射性积累。相反，[ ⁵² Mn]Mn-CHXPYAN 在体内保持稳定，迅速从肝脏和肾脏中清除。

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Improving the In Vivo Stability of [52Mn]Mn(II) Complexes with 18-Membered Macrocyclic Chelators for PET Imaging

We report the [^natMn/⁵²Mn]Mn(II) complexes of the macrocyclic chelators PYAN [3,6,10,13-tetraaza-1,8(2,6)-dipyridinacyclotetradecaphane] and CHXPYAN [(4¹R,4²R,10¹R,10²R)-3,5,9,11-tetraaza-1,7(2,6)-dipyridina-4,10(1,2)-dicyclohexanacyclododecaphane]. The X-ray crystal structures of Mn-PYAN and Mn-CHXPYAN evidence distorted octahedral geometries through coordination of the nitrogen atoms of the macrocycles. Cyclic voltammetry studies evidence reversible processes due to the Mn(II)/Mn(III) pair, indicating that the complexes are resistant to oxidation. CHXPYAN forms a more thermodynamically stable and kinetically inert Mn(II) complex than PYAN. Radiochemical studies with the radioactive isotope manganese-52 (⁵²Mn, t_1/2 = 5.6 days) evidenced better radiochemical yields for CHXPYAN than for PYAN. Both [⁵²Mn]Mn(II) complexes remained stable in mouse and human serum, so in vivo stability studies were carried out. Positron emission tomography/computed tomography scans and biodistribution assays indicated that [⁵²Mn]Mn-PYAN has a distribution pattern similar to that of [⁵²Mn]MnCl₂, showing persistent radioactivity accumulation in the kidneys. Conversely, [⁵²Mn]Mn-CHXPYAN remained stable in vivo, clearing quickly from the liver and kidneys.

更新日期：2024-06-27

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