Development and dosimetry of Pb-203/Pb-212 labeled PSMA ligands – Bringing “the Lead” into PSMA-Targeting Alpha Therapy?
27 March 2019 (online)
The development of a prostate-specific membrane antigen (PSMA)-ligand for labeling with different radioisotopes of lead and the approximation of the dosimetry of a simulated Pb-212 based alpha-therapy by using its Pb-203 imaging analogue.
Four novel Glu-urea-based ligands containing the chelators p-SCN-Bn-TCMC or DO3AM were synthesized. Affinity and PSMA-specific internalization were studied in C4 – 2 cells, biodistribution in C4 – 2 tumor bearing mice. The most promising compound, Pb-203-CA012, was transferred to clinical application. Two patients underwent planar scintigraphy scans at 0.4h, 4h, 18h, 28h and 42h post-injection, accompanied with urine and blood-sampling. The time-activity-curves of source organs were extrapolated from Pb-203 to Pb-212 and the calculated residence times of Pb-212 were forwarded to its unstable daughter nuclides. QDOSE and OLINDA were used for dosimetry calculations.
In-vitro, CA012 possess low nanomolar binding-affinities towards PSMA and specific ligand-induced internalization of 15.6 ± 2.1%ID/106 cells. It was stable in serum for 72h. In-vivo, CA012 revealed high specific tumor-uptake compared to other organs, especially a rapid kidney-clearance from 5.1 ± 2.5%ID/g at 1h p.i. to 0.9 ± 0.1%ID/g at 24h. In patients, an effective dose of 6 – 7 mSv was estimated for 250 – 300 MBq of diagnostic Pb-203-CA012. Assuming instant decay of daughter nuclides, a therapeutic activity of 100 MBq of Pb-212-CA012 is projected to equivalent doses of 0.6 SvRBE5 for red-marrow, 4.3 SvRBE5 for salivary glands, 4.9 SvRBE5 for kidneys, 0.7 SvRBE5 for liver and 0.2 SvRBE5 for other organs; representative tumor lesions averaged 13.2 SvRBE5. Compared to clinical experience with Bi-213-PSMA-617 and Ac-225-PSMA-617 the projected MTD is about 150 MBq/cycle.
Pb-212-CA012 is a promising candidate for PSMA-targeting alpha-therapy (PSMA-TαT) of prostate cancer. The dosimetry estimate of radiopharmaceuticals decaying with the release of instable daughter nuclides has some inherent limitations, thus clinical translation should be done cautiously.