Synthesis of Intrinsically Disordered Fluorinated Peptides for Modular Design of High‐Signal 19F MRI Agents

19F MRI is valuable for in vivo imaging due to the only trace amounts of fluorine in biological systems. Because of the low sensitivity of MRI however, designing new fluorochemicals remains a significant challenge for achieving sufficient 19F signal. Here, we describe a new class of high‐signal, water‐soluble fluorochemicals as 19F MRI imaging agents. A polyamide backbone is used for tuning the proteolytic stability to avoid retention within the body, which is a limitation of current state‐of‐the‐art perfluorochemicals. We show that unstructured peptides containing alternating N‐ϵ‐trifluoroacetyllysine and lysine provide a degenerate 19F NMR signal. 19F MRI phantom images provide sufficient contrast at micromolar concentrations, showing promise for eventual clinical applications. Finally, the degenerate high signal characteristics were retained when conjugated to a large protein, indicating potential for in vivo targeting applications, including molecular imaging and cell tracking. Ungeordnete Symmetrie: Eine neue Klasse von wasserlöslichen, peptidbasierten fluorierten Molekülen als Kontrastmittel für die 19F‐Kernspintomographie wird beschrieben. Die Synthesestrategie nutzt eine alternierende Abfolge von positiven Ladungen und fluorierten Aminosäuren, die zu einem ungeordneten Peptid mit überlappenden 19F‐Resonanzen führen, die ein einzelnes, intensives Signal für die Verwendung als 19F‐MRI‐Reagens ergeben.