Mechanism 06 of 16

Enzyme-target binding and internalisation

The tracer is an inhibitor, not a substrate. It docks in the catalytic pocket of an enzyme whose business end faces out of the cell, and binding itself triggers the cell to swallow it.

Prostate-specific membrane antigen is glutamate carboxypeptidase II, a transmembrane enzyme with its active site extracellular and expression roughly 100- to 1000-fold higher on prostate cancer than on benign prostate tissue. The urea-based ligands wedge into the zinc-containing pocket and are internalised — which produces both the high tumour-to-background ratio and, with Lu-177, a therapeutic dose delivered inside the cell.

PSMA is not prostate-specific, and knowing where it is normally expressed is most of what protects you from a false positive. Salivary and lacrimal glands, kidneys, liver, spleen, small bowel — and the coeliac and other sympathetic ganglia, which sit exactly where a retroperitoneal node would and catch out every trainee once.

PSMA ligandinternalised complexPSMA / GCPII

Docking in the active site. The extracellular catalytic domain of PSMA/GCPII sticks out of the membrane; the ligand is a small-molecule inhibitor that wedges into it. Binding drives clathrin-mediated internalisation, so the label finishes inside an endosome. Swap Ga-68 for Lu-177 in the same chelator and the identical journey delivers β⁻ dose from inside the cell.

The agents

Ga-68 PSMA-11 / gozetotideIlluccix · Locametz

PET

Ga-68 · t½ 68 min · generator or cyclotron produced

Handle: PSMA (glutamate carboxypeptidase II) extracellular domain
Trapping: Urea-based inhibitor binds the catalytic pocket; the complex is internalised into endosomes.
Use: Initial staging of high-risk prostate cancer, biochemical recurrence, and selection for Lu-177 PSMA-617.
Pitfall: Renally excreted — bladder activity can obscure a local recurrence, so consider delayed or post-void images. Short half-life limits distribution radius.

F-18 piflufolastatPylarify (DCFPyL)

PET

F-18 · t½ 110 min · unit-dose distributable

Handle: PSMA catalytic pocket
Trapping: Same binding motif on an F-18 scaffold; shorter positron range gives better spatial resolution than Ga-68.
Use: Staging and biochemical recurrence; detection rate rises steeply with PSA (roughly 40% below PSA 0.5, over 90% above PSA 5).
Pitfall: Shares all PSMA pitfalls below; urinary activity is present but the longer half-life permits delayed imaging.

F-18 flotufolastatPosluma (rhPSMA-7.3)

PET

F-18 · t½ 110 min · approved 2023

Handle: PSMA catalytic pocket
Trapping: A radiohybrid ligand engineered for reduced urinary excretion.
Use: Staging and recurrence, with a cleaner pelvis when local recurrence is the question.
Pitfall: Newest of the group; availability and reader familiarity are still catching up.

PSMA pitfalls — all agentsread this before reporting

PET

applies to every PSMA ligand

Handle: —
Trapping: PSMA is not prostate-specific.
Use: Physiologic uptake: lacrimal and salivary glands, kidneys, liver, spleen, small bowel, and the coeliac and sympathetic ganglia — symmetric, linear, para-aortic, and the single most common false positive for nodal disease.
Pitfall: Benign avidity in Paget disease, fibrous dysplasia, healing fractures and rib lesions. Other tumours express it: renal cell (neovasculature), hepatocellular, glioblastoma, thyroid, sarcoma. And dedifferentiated or neuroendocrine prostate cancer is PSMA-negative — when imaging and PSA disagree, add FDG.

Lu-177 PSMA-617Pluvicto (vipivotide tetraxetan)

Therapy

Lu-177 · t½ 6.6 d · β⁻ with imageable γ

Handle: PSMA catalytic pocket
Trapping: The same inhibitor carrying a β⁻ emitter. Internalisation is what converts a surface-bound label into a cytotoxic intracellular dose.
Use: PSMA-positive metastatic castration-resistant prostate cancer; the label has since been expanded to the taxane-naive setting.
Pitfall: Xerostomia and lacrimal toxicity follow directly from physiologic salivary uptake. Myelosuppression and fatigue. Requires a screening PSMA PET — and, in practice, an FDG PET when discordance is suspected, since FDG-positive PSMA-negative disease will not respond.

Ga-68 / F-18 FAPIinvestigational in the US

PET

Ga-68 or F-18 · quinoline-based inhibitor

Handle: Fibroblast activation protein on cancer-associated fibroblasts
Trapping: Binds the stroma rather than the tumour cell, with almost no background in brain, liver or mucosa.
Use: Strong where FDG is weak: pancreatic, cholangiocarcinoma, gastric signet-ring, peritoneal and low-grade disease; fast imaging without fasting.
Pitfall: Fibroblast activation is not cancer-specific — arthritis, healing tissue, fibrosis, myocardial scar and IgG4 disease all take it up.

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