Dynamic 68Ga‑PSMA‑11 PET reveals blood-brain barrier permeability as the primary driver of tracer uptake in glioma: a pharmacokinetic modeling study

Prostate‑specific membrane antigen (PSMA) PET is increasingly used in glioma for tumor delineation and patient selection for PSMA‑targeted radioligand therapy. However, whether high tracer uptake reflects true target‑specific binding or non‑specific leakage across a disrupted blood-brain barrier (BBB) remains unresolved. This ambiguity limits the rational application of PSMA‑based theranostics in neuro‑oncology. We aimed to quantitatively separate these contributions using dynamic 68 Ga‑PSMA‑11 PET with pharmacokinetic modeling. This prospective study enrolled 49 consecutive patients with suspected glioma (mean age 50 ± 13 years; 21 male). All underwent static 68 Ga‑PSMA‑11 PET/MRI; 16 patients additionally underwent 40‑minute dynamic 68 Ga‑PSMA‑11 PET/CT. Pharmacokinetic parameters ( K 1 : blood‑to‑tissue transfer rate; k 3 : specific binding rate; K i : net influx rate) were derived using two‑tissue compartment models (irreversible for tumors/parotid, reversible for normal brain). SUVmax was correlated with kinetic parameters and with histopathologic PSMA expression (H‑score, immunoblotting) in spatially matched samples. In BBB‑intact normal brain, K 1 and K i were near zero. In gliomas, both parameters were significantly elevated and correlated strongly with SUVmax ( K 1 : r = 0.67, P = 0.006; K i : r = 0.70, P = 0.003). In contrast, k 3 did not reach statistical significance across tissues ( P = 0.074) and showed no significant correlation with SUVmax ( r = 0.24, P = 0.37). SUVmax correlated with PSMA expression only within contrast‑enhancing (BBB‑disrupted) intratumoral regions ( r = 0.71, P = 0.01), not in non‑enhancing peritumoral tissue or whole‑lesion analysis. These findings indicate that BBB permeability, rather than specific binding rate, is the dominant correlate of PSMA PET signal intensity in glioma. Dynamic 68 Ga‑PSMA‑11 PET enables quantitative separation of BBB permeability ( K 1 ) from specific target binding ( k 3 ) in gliomas. K 1 serves as a non‑invasive, quantitative imaging biomarker of regional BBB integrity. Static SUVmax conflates delivery and binding and does not reliably reflect target availability. This “BBB‑gated” paradigm provides a mechanistic framework for interpreting PSMA PET signals in brain tumors and has direct implications for patient selection in PSMA‑targeted radioligand therapy. Chinese Clinical Trial Registry, ChiCTR2300076481. Registered 10 October 2023, https://www.chictr.org.cn .