*2.1. Synthesis of the Ligand (IP-001)*

The synthesis of the nastorazepide core (**5**) was performed as previously reported [19] with only few modifications, with an overall yield of 23%. The assemblage of the linker started with a condensation reaction between N-Boc-hexanediamine (**1**) and 1,10 -carbonyldiimidazole (CDI)-activated N-Fmoc-N"-succinyl-4,7,10-trioxa-1,13-tridecanediamine (**2**) to yield compound **3**. The selective elimination of the Boc-protecting group was then achieved through a reaction with 30% trifluoroacetic acid (TFA) in dichloromethane (DCM) to obtain the corresponding amino-derivate **4** in a quantitative yield. After the activation of the carboxylic group with CDI, nastorazepide (**5**) was condensed with the linker **4** to yield compound **6**. The fluorenylmethoxycarbonyl (Fmoc)-protecting group was eliminated by a reaction with 50% morpholine in dimethylformamide (DMF) to obtain compound **7**, which was subsequently reacted with the DOTA(tBu)<sup>3</sup> ester to give the functionalized nastorazepide-based ligand **8**. The carboxylic functions of the DOTA chelators were finally deprotected with 30% TFA in DCM to yield IP-001 (Scheme 1). The formation of the intermediate compounds was monitored by <sup>1</sup>H-NMR (Figures S1–S5 in Supplementary Materials), and the final product of the reaction was also characterized by HRMS (Figures S6 and S7). The overall yield of the process was around 5%. Predictions of lipophilicity and other pharmacokinetic properties for IP-001 and Z-360 are reported in Table 1.

**Scheme 1.** Reaction conditions: a: **2**, 1,10 -carbonyldiimidazole (CDI), MeCN; triethylamine (TEA), **1**, MeCN. 1 h (reflux); 2 h (RT). b: trifluoroacetic acid (TFA) (30%), dichloromethane (DCM) (0 ◦C). 1 h (RT). c: **5**, CDI, MeCN; TEA, **4**, MeCN. 1 h (reflux); 1 h (RT) d: Morpholine 50%, **6**, dimethylformamide (DMF) (0 ◦C). 1.5 h (RT). e: benzotriazol-1-yloxytris(dimethylamino)phosphonium hexafluorophosphate (BOP), TEA, 1,4,7,10-tetraazacyclododecane-1,4,7,10 tetraacetic acid (DOTA)(tBu)<sup>3</sup> ester, DMF, **7**. 24 h (RT) f: **8**, TFA (30%), DCM, (0 ◦C). 16 h (RT).


**Table 1.** Predicted properties for Z-360 and IP-001. W-LogP: Wildman's logP; TPSA: topological polar surface area; GI: gastrointestinal; BBB: blood brain barrier; ESOL: Estimated aqueous SOLubility; P-gp: P-glycoprotein; CYP: P-cytochrome.
