Objective:

To synthesize current evidence on prostate-specific membrane antigen (PSMA)–targeted positron emission tomography (PET) for detecting and characterizing brain metastases originating from non-prostatic solid tumors, and to delineate its diagnostic and translational potential in neuro-oncology.

Background:

Although PSMA-PET has transformed prostate cancer imaging and theranostics, its application in non-prostatic malignancies—particularly intracranial metastases—remains underexplored. PSMA expression in these tumors predominantly localizes to tumor neovasculature, rather than to tumor cells themselves, raising questions about sensitivity, specificity, and blood–brain barrier (BBB) permeability. Initial clinical observations suggest that PSMA-PET could identify brain metastases from renal, lung, and breast primaries with high contrast due to low physiologic cerebral background.

Design/Methods:

A structured literature search was performed in PubMed, Embase, and Web of Science (up to october 2025) using (“PSMA” AND “PET” AND “brain metast*” AND “non-prostatic”). Studies were eligible if they evaluated PSMA-ligand uptake or PSMA immunoexpression in brain metastases from non-prostatic primaries. Extracted data included lesion detection rate, SUVmax range, histologic correlation, and BBB integrity. 

Results:

Across small case reports/series and limited cohorts, PSMA-PET visualized BMs from renal cell carcinoma, lung adenocarcinoma, hepatocellular carcinoma, breast cancer, and melanoma, typically with high contrast versus normal brain. Uptake correlated more consistently with microvascular PSMA than with tumor-cell PSMA, consistent with immunohistochemistry (IHC) in gliomas and BMs. Reported limitations include inter-lesional heterogeneity (neovascular density, BBB integrity, partial-volume effects), occasional low-uptake lesions, and interpretive pitfalls (benign/inflammatory PSMA avidity). Evidence for response assessment and radioligand therapy is preliminary.

Conclusions:

PSMA-targeted PET is a promising adjunct to MRI for non-prostatic BMs due to vascular PSMA binding and low brain background, but current evidence is fragmented and mostly retrospective. Standardized prospective studies with MRI integration and IHC correlation are required to define diagnostic accuracy, prognostic value, and any role in theranostics before routine adoption in neurology/neuro-oncology.