Objective: Overexpressed cell surface receptors such as CXCR4—a G-protein-coupled receptor—play critical roles in tumor metastasis and represent significant molecular targets for cancer imaging and therapy. Cyclic pentapeptides, including FC131 and its analogues, exhibit high affinity and specificity for CXCR4; however, the inherent lipophilicity 124I-FC131 results in significant retention in the liver and spleen, thereby limiting its utility as a PET imaging agent. To address this challenge, tyrosine sulfonation has been employed to reduce lipophilicity while preserving receptor binding affinity, thereby improving biodistribution. Additionally, modifications to the naphthylalanine residue have been explored to further mitigate lipophilicity. This study focuses on the evaluation of sulfonated FC131 analogues and their conjugation with radionuclides such as 18F, 86Ga, 177Lu, and 213Bi for enhanced cancer imaging and therapeutic applications. Methods and Results: CXCR4-targeting ligands were synthesized using a combination of solid-phase peptide synthesis and solution-phase chemistry, with the primary aim of designing and optimizing lead peptide structures (Figure 1). Competitive binding assays have been performed on CXCR4+ Jurkat cells (hCXCR4), with investigations into internalization, externalization, lipophilicity, and metabolic stability to come. nat/177Lu-Pentixather was selected as the reference compound for competitive binding assays, with preliminary assays showing several of the naphthylalanine replacements result in retention of single digit nM binding affinity for CXCR4 while reducing lipophilicity. Conclusion: The combined strategies of tyrosine sulfonation and targeted residue modification are expected to optimize pharmacokinetic profiles, improve biodistribution, and enhance the therapeutic and imaging potential of CXCR4-targeting peptides.