Radiolysis (self-radiolysis of radiopharmaceuticals)

Radiolysis is the chemical decomposition of a radiopharmaceutical caused by its own emitted radiation, primarily through the radiolysis of water in the formulation, which generates highly reactive free radicals (such as hydroxyl radicals) that go on to damage the targeting molecule or its chelator. It is distinct from radioactive decay of the radionuclide itself; radiolysis affects the chemical integrity of the drug molecule the radionuclide is attached to, and it is measured as a fall in radiochemical purity over time.

Radiolysis is a particularly significant problem for high-activity, high-specific-activity therapeutic radiometal preparations such as 177Lu-labelled PSMA and somatostatin-receptor ligands, because beta particles emitted by 177Lu interact with the surrounding water to produce radicals that attack the peptide or chelator. Published data show 177Lu-PSMA-617 radiochemical purity falling from about 98% to roughly 80% within 24 hours at room temperature without adequate protection, and falling to single-digit percentages within 24 hours with no radioprotectant at all, whereas with adequate antioxidant protection and cold storage it can be kept above 95% for 48 hours or longer.

Radiolysis is controlled in manufacturing and formulation by adding radioprotectant ('quencher') compounds, most commonly ascorbic acid/sodium ascorbate, often combined with gentisic acid or methionine, which scavenge the reactive radicals before they reach the drug molecule; by keeping the radioactive concentration below a set threshold (diluting the product); and by storing and transporting the finished product refrigerated or frozen. The FDA labels for Lutathera (177Lu-dotatate) and Pluvicto (177Lu-vipivotide tetraxetan) specify their gentisic acid and ascorbate/sodium ascorbate content and corresponding shelf-lives (78 hours and 120 hours respectively) as part of managing radiolysis.