Title: Development and dosimetry of 203Pb/212Pb-labelled PSMA ligands: bringing “the lead” into PSMA-targeted alpha therapy?
Authors: DOS SANTOS JOSE CARLOSSCHAEFER MARTINBAUDER-WÜST ULRIKELEHNERT WENCKELEOTTA KARINMORGENSTERN ALFREDKOPKA KLAUSHABERKORN UWEMIER WALTERKRATOCHWIL CLEMENS
Citation: EUROPEAN JOURNAL OF NUCLEAR MEDICINE AND MOLECULAR IMAGING vol. 46 no. 5 p. 1081-1091
Publisher: SPRINGER
Publication Year: 2019
JRC N°: JRC112445
ISSN: 1619-7070 (online)
URI: http://publications.jrc.ec.europa.eu/repository/handle/JRC112445
DOI: 10.1007/s00259-018-4220-z
Type: Articles in periodicals and books
Abstract: Purpose: The development of a prostate-specific membrane antigen (PSMA)-ligand for labeling with different isotopes of lead and the approximation of the dosimetry of a simulated 212Pb-based alpha-therapy by using its 203Pb imaging analogue. Methods: Four novel Glu-urea-based ligands containing the chelators p-SCN-Bn-TCMC or DO3AM were synthesized. Affinity and internalization were studied in C4-2 cells, biodistribution in C4-2 tumor bearing mice. The most promising compound 203Pb-CA012 was translated to clinical application. Two patients underwent planar scintigraphy scans at 0.4 h, 4 h, 18 h, 28 h and 42 h post-injection, accompanied with urine and blood-sampling. The time-activity-curves of source organs were extrapolated from 203Pb to 212Pb and the calculated residence times of 212Pb were forwarded to its unstable daughter nuclides. QDOSE and OLINDA were used for dosimetry calculations. Results: All the ligands possess low nanomolar affinities towards PSMA. The compounds CA09 and CA012 additionally showed specific ligand-induced internalization up to 27.37 ± 2.37 and 15.63 ± 2.06 percent of the injected activity, respectively. The radiolabeled 203Pb-PSMA ligands were stable in serum for 72 h. Small animal imaging and organ distribution analysis of CA012 revealed high specific uptake in the tumor tissue when compared to other organs. This compound also showed a rapid clearance from the kidneys 5.1 ± 2.5 at 1 h to 0.9 ± 0.1 %ID/g at 24 h. In patients an effective dose of approximately 6-7 mSv was estimated for 250-300 MBq of diagnostic 203Pb-CA012. Assuming instant decay of daughter nuclides, a therapeutic activity of 100 MBq of 212Pb-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. Conclusion: The ligands CA009 and CA012 are promising agents to target PSMA with various isotopes of lead. According to its projected patient dosimetry 212Pb-CA012 is a potential candidate for PSMA-targeting alpha-therapy. The dosimetry estimate of radiopharmaceuticals decaying with the release of instable daughter nuclides has some inherent limitations, thus clinical translation should be done cautiously. Once 212Pb becomes more broadly available, further evaluation is warranted.  
JRC Directorate:Nuclear Safety and Security

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