Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
. 2022 Jun 28;27(13):4143.
doi: 10.3390/molecules27134143.

Production and Quality Control of [177Lu]Lu-PSMA-I&T: Development of an Investigational Medicinal Product Dossier for Clinical Trials

Valentina Di Iorio  1 , Stefano Boschi  2 , Cristina Cuni  1 , Manuela Monti  1 , Stefano Severi  1 , Giovanni Paganelli  1 , Carla Masini  1
Affiliations

Production and Quality Control of [177Lu]Lu-PSMA-I&T: Development of an Investigational Medicinal Product Dossier for Clinical Trials

Valentina Di Iorio et al. Molecules. .

Abstract

Since prostate cancer is the most commonly diagnosed malignancy in men, the theranostic approach has become very attractive since the discovery of urea-based PSMA inhibitors. Different molecules have been synthesized starting from the Glu-urea-Lys scaffold as the pharmacophore and then optimizing the linker and the chelate to improve functional characteristics. This article aimed to highlight the quality aspects, which could have an impact on clinical practice, describing the development of an Investigational Medicinal Product Dossier (IMPD) for clinical trials with [177Lu]Lu-PSMA-I&T in prostate cancer and other solid tumors expressing PSMA. The results highlighted some important quality issues of the final preparation: radiolabeling of PSMA-I&T with lutetium-177 needs a considerably longer time compared with the radiolabeling of the well-known [177Lu]Lu-PSMA-617. When the final product was formulated in saline, the stability of [177Lu]Lu-PSMA-I&T was reduced by radiolysis, showing a decrease in radiochemical purity (<95% in 24 h). Different formulations of the final product with increasing concentrations of ascorbic acid have been tested to counteract radiolysis and extend stability. A solution of 20 mg/mL of ascorbic acid in saline prevents radiolysis and ensures stability over 30 h.

Keywords: IMPD; [177Lu]Lu-PSMA-I&T; prostate cancer; quality assurance.

PubMed Disclaimer

Conflict of interest statement

The authors declare no conflict of interest.

Figures

Figure 1
Figure 1
The chemical structure of PSMA- I&T.
Figure 2
Figure 2
Relevant chromatograms of the final products of [177Lu]Lu-PSMA-I&T with radiometric and UV detector: Peak 1 = [177Lu]Lu-PSMA-I&T, Peak 2 = Gentisic acid, Peak 3 = [177Lu]Lu-PSMA-I&T, Peak 4 = PSMA-I&T.
Figure 3
Figure 3
Chromatograms of standard solutions of natLu-PSMA-I&T (20 μL of a 0.1 mg/mL solution) and PSMA-I&T (20 μL of a 0.04 mg/mL solution). Rt of natLu-PSMA-I&T is slightly lower than that Rt of [177Lu]Lu-PSMA-I&T with radiometric detection because it is positioned after the UV detector.
Figure 4
Figure 4
[177Lu]Lu-PSMA-I&T (radiometric detector) during stability studies, at T = 0, T = 24 h, T = 30. In the table inside the figure are reported relative areas of [177Lu]Lu-PSMA-I&T as a percentage of the total areas.
Figure 5
Figure 5
Flow chart of the radiolabeling of PSMA-I&T. PC = In-Process Control.
See this image and copyright information in PMC

References

    1. Siegel R., Ma J., Zou Z., Jemal A. Cancer statistics, 2014. Cancer J. Clin. 2014;64:9–29. doi: 10.3322/caac.21208. - DOI - PubMed
    1. Ferlay J., Steliarova-Foucher E., Lortet-Tieulent J., Rosso S., Coebergh J.W.W., Comber H., Forman D., Bray F. Cancer incidence and mortality patterns in Europe: Estimates for 40 countries in 2012. Eur. J. Cancer. 2013;49:1374–1403. doi: 10.1016/j.ejca.2012.12.027. - DOI - PubMed
    1. Schroöder F.H., Hugosson J., Roobol M.J., Tammela T.L.J., Zappa M., Nelen V., Kwiatkowski M., Lujan M., Määttänen L., Lilja H., et al. Screening and prostate cancer mortality: Results of the European Randomised Study of Screening for Prostate Cancer (ERSPC) at 13 years of follow-up. Lancet. 2014;384:2027–2035. doi: 10.1016/S0140-6736(14)60525-0. - DOI - PMC - PubMed
    1. Silver D.A., Pellicer I., Fair W.R., Heston W.D., Cordon-Cardo C. Prostate-specific membrane antigen expression in normal and malignant human tissues. Clin. Cancer Res. 1997;3:81–85. - PubMed
    1. Sweat S.D., Pacelli A., Murphy G.P., Bostwick D.G. Prostate-specific membrane antigen expression is greatest in prostate adenocarcinoma and lymph node metastases. Urology. 1998;52:637–640. doi: 10.1016/S0090-4295(98)00278-7. - DOI - PubMed