Clinical Translation of a Dual Integrin-and GRPR-targeting PET Radiotracer 68Ga-DOTA-RGD-RM26 in Glioma

Purpose: Radiopharmaceuticals targeting integrin α V β 3 and gastrin-releasing peptide receptor (GRPR) are widely applied for imaging of patients with gliomas. This study aims to evaluate an integrin α V β 3 and GRPR dual-targeting PET radiotracer, 68 Ga-labeled DOTA-RGD-RM26 ( 68 Ga-DOTA-RGD-RM26) in patients with glioma and other brain tumors. Patients and Methods: The radiotracer 68 Ga-DOTA-RGD-RM26 was synthesized based on the previously reported peptide RGD-RM26-03 (LNC1015). Preclinical evaluation was assessed in the U87 xenograft model using Micro-PET/CT. Clinical applicability was evaluated in 34 patients with brain tumors (36 lesions), with head-to-head comparisons to single-targeting tracers 68 Ga-RM26 and 68 Ga-RGD in 7 and 11 glioma patients, respectively. Results: 68 Ga-DOTA-RGD-RM26 demonstrated high affinity and specificity for integrin α V β 3 -positive and GRPR-positive U87 tumors. Tumor uptake of 68 Ga-DOTA-RGD-RM26 was higher than that of 68 Ga-RM26 and 68 Ga-RGD, with longer tumor retention. The radiotracer was well tolerated by all patients, with no reported side effects. The detection rate for gliomas was 84.6% (22/26) on 68 Ga-DOTA-RGD-RM26 PET/CT, with 95% (19/20) sensitivity for high-grade gliomas (HGGs). HGGs exhibited higher SUV max , SUV mean , and tumor-to-background (T/B) ratio compared with low-grade gliomas (LGGs) ( P <0.001). T/B ratios based on the SUV mean were higher for 68 Ga-DOTA-RGD-RM26 than for 68 Ga-RM26 (28.4±11.2 vs. 16.8±5.8, P =0.009) and 68 Ga-RGD (20.2±8.3 vs. 11.2±4.5, P =0.004). Spearman analysis revealed significant correlations between 68 Ga-DOTA-RGD-RM26 uptake parameters (SUV max , SUV mean and T/B ratio) and WHO grading and Ki-67% in 26 glioma lesions ( P =0.01). The radiotracer also performed well in other types of brain tumors. Conclusions: 68 Ga-DOTA-RGD-RM26 exhibits superior tumor uptake and retention compared with single-targeting tracers, making it a promising tracer for the diagnosis and staging of gliomas and other brain tumors with integrin α V β 3 and GRPR expression.