Yang Hua, Gao Feng, McNeil Brooke, Zhang Chengcheng, Yuan Zheliang, Zeisler Stefan, Kumlin Joel, Zeisler Jutta, Bénard François, Ramogida Caterina, Schaffer Paul
Life Sciences Division, TRIUMF, 4004 Wesbrook Mall, Vancouver, BC, V6T 2A3, Canada.
Department of Chemistry, Simon Fraser University, 8888 University Dr, Burnaby, BC, V5A 1S6, Canada.
EJNMMI Radiopharm Chem. 2021 Jan 13;6(1):3. doi: 10.1186/s41181-020-00119-4.
Cu is one of the few radioisotopes that can be used for both imaging and therapy, enabling theranostics with identical chemical composition. Development of stable chelators is essential to harness the potential of this isotope, challenged by the presence of endogenous copper chelators. Pyridyl type chelators show good coordination ability with copper, prompting the present study of a series of chelates DOTA-xPy (x = 1-4) that sequentially substitute carboxyl moieties with pyridyl moieties on a DOTA backbone.
We found that the presence of pyridyl groups significantly increases Cu labeling conversion yield, with DOTA-2Py, -3Py and -4Py quantitatively complexing Cu at room temperature within 5 min (1 × 10 M). [Cu]Cu-DOTA-xPy (x = 2-4) exhibited good stability in human serum up to 24 h. When challenged with 1000 eq. of NOTA, no transmetallation was observed for all three Cu complexes. DOTA-xPy (x = 1-3) were conjugated to a cyclized α-melanocyte-stimulating hormone (αMSH) peptide by using one of the pendant carboxyl groups as a bifunctional handle. [Cu]Cu-DOTA-xPy-αMSH retained good serum stability (> 96% in 24 h) and showed high binding affinity (Ki = 2.1-3.7 nM) towards the melanocortin 1 receptor.
DOTA-xPy (x = 1-3) are promising chelators for Cu. Further in vivo evaluation is necessary to assess the full potential of these chelators as a tool to enable further theranostic radiopharmaceutical development.
铜是少数可用于成像和治疗的放射性同位素之一，能够实现具有相同化学成分的诊疗一体化。稳定螯合剂的开发对于发挥该同位素的潜力至关重要，然而内源性铜螯合剂的存在对其构成了挑战。吡啶基型螯合剂与铜显示出良好的配位能力，促使本研究合成了一系列螯合物DOTA-xPy（x = 1-4），这些螯合物在DOTA主链上用吡啶基部分依次取代羧基部分。
我们发现吡啶基的存在显著提高了铜标记转化率，DOTA-2Py、-3Py和-4Py在室温下5分钟内就能定量络合铜（1×10⁻⁶M）。[⁶⁴Cu]Cu-DOTA-xPy（x = 2-4）在人血清中长达24小时都表现出良好的稳定性。当用1000当量的NOTA进行挑战时，所有三种铜络合物均未观察到转金属化现象。通过使用一个侧链羧基作为双功能手柄，将DOTA-xPy（x = 1-3）与环化的α-黑素细胞刺激素（αMSH）肽偶联。[⁶⁴Cu]Cu-DOTA-xPy-αMSH保持了良好的血清稳定性（24小时内>96%），并对黑皮质素1受体显示出高结合亲和力（Ki = 2.1-3.7 nM）。
DOTA-xPy（x = 1-3）是有前景的铜螯合剂。有必要进行进一步的体内评估，以评估这些螯合剂作为推动进一步诊疗放射性药物开发工具的全部潜力。
