CXCR4-targeted PET imaging of glioblastoma using [68Ga]Ga-TD-01: from pharmacokinetics and dosimetry to theranostic potential

Abstract Background Glioblastoma multiforme (GBM) is an aggressive brain tumor with poor prognosis and limited treatment options. Chemokine receptor type 4 (CXCR4) plays a key role in GBM invasion and therapy resistance, making it an attractive target for molecular imaging and theranostics. We developed [ 68 Ga]Ga-TD-01, a next-generation positron emission tomography (PET) radiotracer for CXCR4 imaging, and evaluated its pharmacokinetics, dosimetry, and translational potential. Results In mice bearing orthotopic GL261 GBM, dynamic PET/MRI, receptor blocking studies, and kinetic modeling demonstrated a specific binding component and high tumor-to-background contrast. [ 68 Ga]Ga-TD-01 showed high tumor uptake (5.4 ± 4.3%ID/g at 9 min), low uptake in normal brain (2.2 ± 1.7%ID/g), and a tumor-to-background ratio of 2.9 ± 0.2 at 60 min, which was significantly reduced by CXCR4 blockade. PET pharmacokinetic modeling confirmed increased tumor retention (Vt of 0.5 ± 0.07 ml/cm 3 for tumor; Vt of 0.2 ± 0.05 ml/cm 3 for brain). The radiotracer exhibited high in vivo stability, rapid renal clearance, and favorable biodistribution. CXCR4 expression was confirmed in both murine and human GBM tissues by RNAscope. Human dosimetry extrapolation estimated an effective dose of 4.6 mSv for a standard PET scan, comparable to approved tracers. Conclusions When compared with reported data for [ 68 Ga]Ga-Pentixafor, [ 68 Ga]Ga-TD-01 showed tumor uptake within the reported range and low background accumulation; however, no direct head-to-head comparison was performed. These results support [ 68 Ga]Ga-TD-01 as a promising CXCR4-targeted imaging agent and a candidate for further theranostic development.