Pharmacokinetic\nPositron Emission Tomography Imaging\nof an Optimized CD38-Targeted <sup>68</sup>Ga-Labeled Peptide in Multiple\nMyeloma: A Pilot Study

Multiple myeloma (MM) is an incurable disease characterized\nby\nits clinical and prognostic heterogeneity. Despite conventional chemotherapy\nand autologous hematopoietic stem cell transplantation, the management\nof relapsed and refractory MM disease poses significant challenges,\nboth medically and socioeconomically. CD38, highly expressed on the\nsurface of MM cells, serves as a distinct tumor biological target\nin MM. Peptides offer advantages over antibodies, enabling precise\ntumor imaging and facilitating early tumor diagnosis and dynamic immunotherapy\nmonitoring. In this study, we developed PF381, a CD38-targeted peptide,\nand investigated its role in diagnosis, biodistribution, and dosimetry\nthrough <sup>68</sup>Ga-labeling for preclinical evaluation in tumor-bearing\nmodels. We screened a microchip-based combinatorial chemistry peptide\nlibrary to obtain the amino acid sequence of PF381. Affinity for human\nCD38 was evaluated by SPRi. PF381 was conjugated with DOTA for radiolabeling\nwith <sup>68</sup>Ga, and the complex was characterized by HPLC. PET\nimaging was performed in murine tumor models after the administration\nof [<sup>68</sup>Ga]Ga-DOTA-PF381. Biodistribution analysis compared\nCD38-positive H929 and CD38-negative U266 tumors, and human radiation\ndosimetry was estimated. Tumor sections were stained for CD38 expression.\nSPRi showed that PF381 had a high affinity for CD38 with a KD of 2.49\n× 10<sup>–8</sup> M. HPLC measured a radiolabeling efficiency\nof 78.45 ± 7.91% for [<sup>68</sup>Ga]Ga-DOTA-PF381, with >98%\nradiochemical purity. PET imaging revealed rapid and persistent accumulation\nof radioactivity in CD38-positive H929 tumors, contrasting with negligible\nuptake in CD38-negative U266 tumors. Biodistribution confirmed higher\nuptake in H929 tumors (0.75 ± 0.03%ID/g) vs U266 (0.26 ±\n0.08%ID/g, <i>P</i> < 0.001). The kidney received the\nhighest radiation dose (3.57 × 10<sup>–02</sup> mSv/MBq),\nwith an effective dose of 1.41 × 10<sup>–02</sup> mSv/MBq.\nImmunofluorescence imaging supported PET and biodistribution findings.\nWe developed a novel peptide targeting CD38 and proved that <sup>68</sup>Ga-labeled PF381 had rapid targeting and good tumor penetration capabilities.\nTherefore, <sup>68</sup>Ga-labeled PF381 could achieve high sensitivity\nin vivo imaging for CD38-positive hematological malignancies.