Characterization of Non-Specific Uptake and Retention Mechanisms of [177Lu]Lu-PSMA-617 in the Salivary Glands

The radionuclide therapy [177Lu]Lu-PSMA-617 was recently FDA-approved for treatment of metastatic castration-resistant prostate cancer. Salivary gland toxicity is currently considered as the main dose-limiting side effect. However, its uptake and retention mechanisms in the salivary glands remain elusive. Therefore, our aim was to elucidate the uptake patterns of [177Lu]Lu-PSMA-617 in salivary gland tissue and cells by conducting cellular binding and autoradiography experiments. Briefly, A-253 and PC3-PIP cells, and mouse kidney and pig salivary gland tissue, were incubated with 5 nM [177Lu]Lu-PSMA-617 to characterize its binding. Additionally, [177Lu]Lu-PSMA-617 was co-incubated with monosodium glutamate, ionotropic or metabotropic glutamate receptor antagonists. Low, non-specific binding was observed in salivary gland cells and tissues. Monosodium glutamate was able to decrease [177Lu]Lu-PSMA-617 in PC3-PIP cells, mouse kidney and pig salivary gland tissue. Kynurenic acid (ionotropic antagonist) decreased the binding of [177Lu]Lu-PSMA-617 to 29.2 ± 20.6% and 63.4 ± 15.4%, respectively, with similar effects observed on tissues. (RS)-MCPG (metabotropic antagonist) was able to decrease the [177Lu]Lu-PSMA-617 binding on A-253 cells to 68.2 ± 16.8% and pig salivary gland tissue to 53.1 ± 36.8%. To conclude, we showed that the non-specific binding on [177Lu]Lu-PSMA-617 could be reduced by monosodium glutamate, kynurenic acid and (RS)-MCPG.

[1]  M. Manz,et al.  Cross-reactivity to glutamate carboxypeptidase III causes undesired salivary gland and kidney uptake of PSMA-targeted small-molecule radionuclide therapeutics , 2022, European Journal of Nuclear Medicine and Molecular Imaging.

[2]  James M. Kelly,et al.  Advances in PSMA theranostics , 2022, Translational oncology.

[3]  Youqing Wang,et al.  Prostate Cancer Incidence and Mortality: Global Status and Temporal Trends in 89 Countries From 2000 to 2019 , 2022, Frontiers in Public Health.

[4]  John F. Trant,et al.  Identification of alternative protein targets of glutamate-ureido-lysine associated with PSMA tracer uptake in prostate cancer cells , 2022, Proceedings of the National Academy of Sciences.

[5]  K. Rahbar,et al.  Lutetium-177-PSMA-617 for Metastatic Castration-Resistant Prostate Cancer. , 2021, The New England journal of medicine.

[6]  K. Herrmann,et al.  The salivary glands as a dose limiting organ of PSMA- targeted radionuclide therapy: A review of the lessons learnt so far. , 2021, Nuclear medicine and biology.

[7]  H. Wester,et al.  Design of PSMA ligands with modifications at the inhibitor part: an approach to reduce the salivary gland uptake of radiolabeled PSMA inhibitors? , 2021, EJNMMI Radiopharmacy and Chemistry.

[8]  D. Elashoff,et al.  The Impact of Monosodium Glutamate on 68Ga-PSMA-11 Biodistribution in Men with Prostate Cancer: A Prospective Randomized, Controlled Imaging Study , 2021, The Journal of Nuclear Medicine.

[9]  F. Bénard,et al.  The Effects of Monosodium Glutamate on PSMA Radiotracer Uptake in Men with Recurrent Prostate Cancer: A Prospective, Randomized, Double-Blind, Placebo-Controlled Intraindividual Imaging Study , 2020, The Journal of Nuclear Medicine.

[10]  M. Kruszewski,et al.  Targeted Radionuclide Therapy of Prostate Cancer—From Basic Research to Clinical Perspectives , 2020, Molecules.

[11]  P. Choyke,et al.  Comparison of Prostate-Specific Membrane Antigen Expression Levels in Human Salivary Glands to Non-Human Primates and Rodents. , 2020, Cancer biotherapy & radiopharmaceuticals.

[12]  Daniela A. Ferraro,et al.  First Clinicopathologic Evidence of a Non–PSMA-Related Uptake Mechanism for 68Ga-PSMA-11 in Salivary Glands , 2019, The Journal of Nuclear Medicine.

[13]  P. Meyer,et al.  [177Lu]Lu-PSMA-617 Salivary Gland Uptake Characterized by Quantitative In Vitro Autoradiography , 2019, Pharmaceuticals.

[14]  F. Bénard,et al.  Monosodium Glutamate Reduces 68Ga-PSMA-11 Uptake in Salivary Glands and Kidneys in a Preclinical Prostate Cancer Model , 2018, The Journal of Nuclear Medicine.

[15]  L. Smit,et al.  Physiologic distribution of PSMA-ligand in salivary glands and seromucous glands of the head and neck on PET/CT. , 2018, Oral surgery, oral medicine, oral pathology and oral radiology.

[16]  R. Schibli,et al.  Albumin-Binding PSMA Ligands: Optimization of the Tissue Distribution Profile. , 2018, Molecular pharmaceutics.

[17]  J. Konvalinka,et al.  Mouse glutamate carboxypeptidase II (GCPII) has a similar enzyme activity and inhibition profile but a different tissue distribution to human GCPII , 2017, FEBS open bio.

[18]  F. Mottaghy,et al.  225Ac-PSMA-617 for PSMA-Targeted α-Radiation Therapy of Metastatic Castration-Resistant Prostate Cancer , 2016, The Journal of Nuclear Medicine.

[19]  Tim Holland-Letz,et al.  The Theranostic PSMA Ligand PSMA-617 in the Diagnosis of Prostate Cancer by PET/CT: Biodistribution in Humans, Radiation Dosimetry, and First Evaluation of Tumor Lesions , 2015, The Journal of Nuclear Medicine.

[20]  J. Konvalinka,et al.  Structural and biochemical characterization of the folyl‐poly‐γ‐l‐glutamate hydrolyzing activity of human glutamate carboxypeptidase II , 2014, The FEBS journal.

[21]  William C. Eckelman,et al.  First-in-Man Evaluation of 2 High-Affinity PSMA-Avid Small Molecules for Imaging Prostate Cancer , 2013, The Journal of Nuclear Medicine.

[22]  M. Buchtová,et al.  The pig as an experimental model for clinical craniofacial research , 2012, Laboratory animals.

[23]  W. Gahl,et al.  Sialin (SLC17A5) functions as a nitrate transporter in the plasma membrane , 2012, Proceedings of the National Academy of Sciences.

[24]  A. Haese*,et al.  High level PSMA expression is associated with early psa recurrence in surgically treated prostate cancer , 2011, The Prostate.

[25]  S. Larson,et al.  89Zr-DFO-J591 for ImmunoPET of Prostate-Specific Membrane Antigen Expression In Vivo , 2010, The Journal of Nuclear Medicine.

[26]  Guan Yang,et al.  Histological and Ultrastructural Characterization of Developing Miniature Pig Salivary Glands , 2010, Anatomical record.

[27]  S. Landas,et al.  Expression of Prostate-Specific Membrane Antigen in Normal and Malignant Human Tissues , 2006, World Journal of Surgery.

[28]  J. Coyle,et al.  Folylpoly-gamma-glutamate carboxypeptidase from pig jejunum. Molecular characterization and relation to glutamate carboxypeptidase II. , 1998, The Journal of biological chemistry.

[29]  M. Pomper,et al.  Bioisosterism of urea-based GCPII inhibitors: Synthesis and structure-activity relationship studies. , 2010, Bioorganic & medicinal chemistry letters.

[30]  R. Wellner,et al.  Beta-adrenergic responsiveness in a human submandibular tumor cell line (A253). , 1989, In Vitro Cellular & Developmental Biology.