AbstractDFO* is an octadentate chelator able to form highly stable chelates with Zirconium‐89 (89Zr) for nuclear medicinal applications in Positron Emission Tomography (PET).[1,2] The synthesis of DFO* and its scale‐up remains challenging by reported synthetic protocols. For this reason, we set out to develop a de novo synthesis of a hydroxamate‐containing building block suitable for the coupling to the commercially available DFO (desferrioxamine B, mesylate salt) yielding, after deprotection, the desired chelator DFO* in a more efficient procedure. Highlights of the new synthesis of DFO* reported herein are less synthetic steps and the isolation of the desired product DFO* by using solid phase extraction (SPE), thus avoiding tedious HPLC purification. DFO* is obtained in excellent purity (92‐98 %) and an overall yield of approximately 29 %. In addition, the isolated trifluoroacetic acid (TFA)‐salt of DFO* displays an improved solubility in organic solvents (DMSO, DMF, methanol), which will facilitate its use for the preparation of structurally diverse derivatives suitable for bioconjugation chemistry and the development of 89Zr‐labeled radiotracers.