Synthesis of tritium-labeled Lu-PSMA-617 - Alternative tool for biological evaluation of radiometal-based pharmaceuticals
22 thg 4, 2025 | 16:49

Synthesis of tritium-labeled Lu-PSMA-617 - Alternative tool for biological evaluation of radiometal-based pharmaceuticals



Prostate cancer (PCa) is the second most common occurring cancer (14.1%) and the fifth leading cause of cancer death (6.8%) in men worldwide (Sung et al., 2021). A well-established PCa target, known as prostate-specific membrane antigen (PSMA), is readily overexpressed on the surface of PCa cells in a vast majority of PCa patients (Mannweiler et al., 2009). Based on the high PSMA abundance, several PSMA-targeting radioligands for imaging, endoradiotherapy, and intra-operative surgery of PCa were developed and are currently being evaluated in many centers around the world (Benesova et al., 2015; Cardinale et al., 2020; Chen et al., 2011; Deberle et al., 2020; Eder et al., 2012, 2021; Schottelius et al., 2019; Weineisen et al., 2015; Zechmann et al., 2014). Among these, the theranostic PSMA-617 emerged as a highly effective ligand for both diagnosis (Afshar-Oromieh et al., 2015; Eppard et al., 2017; Muller et al., 2019) and Targeted Radionuclide Therapy (TRNT) (Kratochwil et al., 2016; Rathke et al., 2021; Sartor et al., 2021; Yadav et al., 2021). In 2022, [177Lu]Lu-PSMA-617 received the U.S. Food and Drug Administration (FDA) and European Commission (EC) approvals as the first TRNT for metastasized castration- and chemo-resistant PCa (Mullard, 2022). However, the high therapeutic potential and successful clinical applications of 177Lu worldwide (Czernin and Calais, 2021) are associated with strong concerns about its limited future availability due to high demand and restricted capacity of production facilities (Vogel et al., 2021).

Despite the widespread clinical utilization of mid-energetic radiometals like lutetium-177 (177Lu; t1/2 = 6.65 d; EβMAX = 497 keV, EβAVE = 134 keV; Eγ1 = 208 keV (10.4%), Eγ2 = 113 keV (6.2%)), the extremely low-energetic super heavy hydrogen tritium (3H or T; t1/2 = 12.3 y; EβMAX = 18.6 keV, EβAVE = 5.7 keV) is still one of the most widely used radionuclides in pre-clinical biological settings. This is not only due to the practical advantages of tritium-labeled compounds in the pharmaceutical development process (Atzrodt et al., 2018b; Kopf et al., 2022), but also due to the complex infrastructural demands (controlled vs. supervised area) and the radiation safety standards associated with therapeutic radiometals (Talip et al., 2020). The necessary incorporation of metal-chelating ligands for stable coordination of various radiometals (Rey, 2010) hampers the general application of tritium as a reporter radionuclide in radiometal-based pharmaceutical development.

Tritium has many properties of an ideal radioactive label and it is, thus, widely used in biological and pharmaceutical research (Atzrodt et al., 2018a, 2018b; Elmore and Bragg, 2015; Lockley et al., 2012). The major application fields of tritium include in vitro assays for receptor characterization and identification of novel receptor ligands, as well as determination of the target selectivity in malignant tissues (Hinz et al., 2018; Krauser, 2013). It can be detected with a high sensitivity in biological matrices and at high spatial resolution (up to single-digit μm). Tritium can also be directly incorporated into drug candidates resulting in high molar activity. Most importantly, tritium labeling does not alter the chemical structure, physicochemical properties, or biological activity of the parent molecule (Kopf et al., 2022) and the long half-life enables an extended shelf-life for tritium-labeled pharmaceuticals if radiolytic decomposition can be minimized (Waterfield et al., 1968; Wolf, 2021). On the other hand, its waste management is clearly not as favorable as for radiometals when considering the extremely long half-life of tritium.

Based on the above described properties of PSMA-targeting radioligands and both radionuclides, the ([ring-3H]Nal)PSMA-617 and ([α,ß-3H]Nal)Lu-PSMA-617 were prepared as the isotopologues of PSMA-617 and [177Lu]Lu-PSMA-617, respectively (Fig. 1). Naturally-occurring lutetium (natLu) consists of two isotopes – stable 175Lu (97.4%) and quasi-stable 176Lu (2.6%; 3.78 × 1010 y) – and represents a most suitable surrogate for radioactive 177Lu. The radiolytic stability and the biological properties of these novel tritium-labeled PSMA-617 derivatives were compared to [177Lu]Lu-PSMA-617 under in vitro conditions.

The overall synthesis followed two different strategies and tritium was incorporated either in the aromatic or in the aliphatic moiety of the 2-naphthyl-l-alanine (2-Nal) residue. First, a direct tritium-halogen exchange in position 1 of the 2-naphthyl moiety of the hexa (tBu)-protected PSMA-617 precursor was performed. The resulting aryl-labeled ([ring-3H]Nal)PSMA-617 exhibited sufficient radiolytic stability with ∼5% HTO formation after six months. The second strategy focused on the introduction of tritium into the aliphatic α- and β-positions of the l-alanyl moiety. The key step of the synthesis was the enantioselective reduction of (Z)-methyl 2-acetamido-3-(naphthalene-2-yl)acrylat










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Prostate cancer (PCa) is the second most common occurring cancer (14.1%) and the fifth leading cause of cancer death (6.8%) in men worldwide (Sung et al., 2021). A well-established PCa target, known as prostate-specific membrane antigen (PSMA), is readily overexpressed on the surface of PCa cells in a vast majority of PCa patients (Mannweiler et al., 2009). Based on the high PSMA abundance, several PSMA-targeting radioligands for imaging, endoradiotherapy, and intra-operative surgery of PCa were developed and are currently being evaluated in many centers around the world (Benesova et al., 2015; Cardinale et al., 2020; Chen et al., 2011; Deberle et al., 2020; Eder et al., 2012, 2021; Schottelius et al., 2019; Weineisen et al., 2015; Zechmann et al., 2014). Among these, the theranostic PSMA-617 emerged as a highly effective ligand for both diagnosis (Afshar-Oromieh et al., 2015; Eppard et al., 2017; Muller et al., 2019) and Targeted Radionuclide Therapy (TRNT) (Kratochwil et al., 2016; Rathke et al., 2021; Sartor et al., 2021; Yadav et al., 2021). In 2022, [177Lu]Lu-PSMA-617 received the U.S. Food and Drug Administration (FDA) and European Commission (EC) approvals as the first TRNT for metastasized castration- and chemo-resistant PCa (Mullard, 2022). However, the high therapeutic potential and successful clinical applications of 177Lu worldwide (Czernin and Calais, 2021) are associated with strong concerns about its limited future availability due to high demand and restricted capacity of production facilities (Vogel et al., 2021).

Despite the widespread clinical utilization of mid-energetic radiometals like lutetium-177 (177Lu; t1/2 = 6.65 d; EβMAX = 497 keV, EβAVE = 134 keV; Eγ1 = 208 keV (10.4%), Eγ2 = 113 keV (6.2%)), the extremely low-energetic super heavy hydrogen tritium (3H or T; t1/2 = 12.3 y; EβMAX = 18.6 keV, EβAVE = 5.7 keV) is still one of the most widely used radionuclides in pre-clinical biological settings. This is not only due to the practical advantages of tritium-labeled compounds in the pharmaceutical development process (Atzrodt et al., 2018b; Kopf et al., 2022), but also due to the complex infrastructural demands (controlled vs. supervised area) and the radiation safety standards associated with therapeutic radiometals (Talip et al., 2020). The necessary incorporation of metal-chelating ligands for stable coordination of various radiometals (Rey, 2010) hampers the general application of tritium as a reporter radionuclide in radiometal-based pharmaceutical development.

Tritium has many properties of an ideal radioactive label and it is, thus, widely used in biological and pharmaceutical research (Atzrodt et al., 2018a, 2018b; Elmore and Bragg, 2015; Lockley et al., 2012). The major application fields of tritium include in vitro assays for receptor characterization and identification of novel receptor ligands, as well as determination of the target selectivity in malignant tissues (Hinz et al., 2018; Krauser, 2013). It can be detected with a high sensitivity in biological matrices and at high spatial resolution (up to single-digit μm). Tritium can also be directly incorporated into drug candidates resulting in high molar activity. Most importantly, tritium labeling does not alter the chemical structure, physicochemical properties, or biological activity of the parent molecule (Kopf et al., 2022) and the long half-life enables an extended shelf-life for tritium-labeled pharmaceuticals if radiolytic decomposition can be minimized (Waterfield et al., 1968; Wolf, 2021). On the other hand, its waste management is clearly not as favorable as for radiometals when considering the extremely long half-life of tritium.

Based on the above described properties of PSMA-targeting radioligands and both radionuclides, the ([ring-3H]Nal)PSMA-617 and ([α,ß-3H]Nal)Lu-PSMA-617 were prepared as the isotopologues of PSMA-617 and [177Lu]Lu-PSMA-617, respectively (Fig. 1). Naturally-occurring lutetium (natLu) consists of two isotopes – stable 175Lu (97.4%) and quasi-stable 176Lu (2.6%; 3.78 × 1010 y) – and represents a most suitable surrogate for radioactive 177Lu. The radiolytic stability and the biological properties of these novel tritium-labeled PSMA-617 derivatives were compared to [177Lu]Lu-PSMA-617 under in vitro conditions.

The overall synthesis followed two different strategies and tritium was incorporated either in the aromatic or in the aliphatic moiety of the 2-naphthyl-l-alanine (2-Nal) residue. First, a direct tritium-halogen exchange in position 1 of the 2-naphthyl moiety of the hexa (tBu)-protected PSMA-617 precursor was performed. The resulting aryl-labeled ([ring-3H]Nal)PSMA-617 exhibited sufficient radiolytic stability with ∼5% HTO formation after six months. The second strategy focused on the introduction of tritium into the aliphatic α- and β-positions of the l-alanyl moiety. The key step of the synthesis was the enantioselective reduction of (Z)-methyl 2-acetamido-3-(naphthalene-2-yl)acrylat










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