Development and Preclinical Evaluation of [211At]PSAt-3-Ga: An Inhibitor for Targeted α-Therapy of Prostate Cancer.
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Development and Preclinical Evaluation of [211At]PSAt-3-Ga : An Inhibitor for Targeted α-Therapy of Prostate Cancer. / El Fakiri, Mohamed; Ayada, Nawal; Müller, Marius; Hvass, Lars; Gamzov, Teodor H; Clausen, Anne Skovsbo; Geis, Nicolas M; Steinacker, Nils; Hansson, Ellinor; Lindegren, Sture; Aneheim, Emma; Jensen, Holger; Eder, Ann-Christin; Jensen, Andreas I; Poulie, Christian B M; Kjaer, Andreas; Eder, Matthias; Herth, Matthias M.
In: Journal of nuclear medicine : official publication, Society of Nuclear Medicine, Vol. 65, No. 4, 2024, p. 593-599.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Development and Preclinical Evaluation of [211At]PSAt-3-Ga
T2 - An Inhibitor for Targeted α-Therapy of Prostate Cancer.
AU - El Fakiri, Mohamed
AU - Ayada, Nawal
AU - Müller, Marius
AU - Hvass, Lars
AU - Gamzov, Teodor H
AU - Clausen, Anne Skovsbo
AU - Geis, Nicolas M
AU - Steinacker, Nils
AU - Hansson, Ellinor
AU - Lindegren, Sture
AU - Aneheim, Emma
AU - Jensen, Holger
AU - Eder, Ann-Christin
AU - Jensen, Andreas I
AU - Poulie, Christian B M
AU - Kjaer, Andreas
AU - Eder, Matthias
AU - Herth, Matthias M
N1 - © 2024 by the Society of Nuclear Medicine and Molecular Imaging.
PY - 2024
Y1 - 2024
N2 - The application of prostate-specific membrane antigen (PSMA)-targeted α-therapy is a promising alternative to β --particle-based treatments. 211At is among the potential α-emitters that are favorable for this concept. Herein, 211At-based PSMA radiopharmaceuticals were designed, developed, and evaluated. Methods: To identify a 211At-labeled lead, a surrogate strategy was applied. Because astatine does not exist as a stable nuclide, it is commonly replaced with iodine to mimic the pharmacokinetic behavior of the corresponding 211At-labeled compounds. To facilitate the process of structural design, iodine-based candidates were radiolabeled with the PET radionuclide 68Ga to study their preliminary in vitro and in vivo properties before the desired 211At-labeled lead compound was formed. The most promising candidate from this evaluation was chosen to be 211At-labeled and tested in biodistribution studies. Results: All 68Ga-labeled surrogates displayed affinities in the nanomolar range and specific internalization in PSMA-positive LNCaP cells. PET imaging of these compounds identified [ 68Ga]PSGa- 3 as the lead compound. Subsequently, [ 211At]PSAt- 3-Ga was synthesized in a radiochemical yield of 35% and showed tumor uptake of 19 ± 8 percentage injected dose per gram of tissue (%ID/g) at 1 h after injection and 7.6 ± 2.9 %ID/g after 24 h. Uptake in off-target tissues such as the thyroid (2.0 ± 1.1 %ID/g), spleen (3.0 ± 0.6 %ID/g), or stomach (2.0 ± 0.4 %ID/g) was low, indicating low in vivo deastatination of [ 211At]PSAt- 3-Ga. Conclusion: The reported findings support the use of iodine-based and 68Ga-labeled variants as a convenient strategy for developing astatinated compounds and confirm [ 211At]PSAt- 3 as a promising radiopharmaceutical for targeted α-therapy.
AB - The application of prostate-specific membrane antigen (PSMA)-targeted α-therapy is a promising alternative to β --particle-based treatments. 211At is among the potential α-emitters that are favorable for this concept. Herein, 211At-based PSMA radiopharmaceuticals were designed, developed, and evaluated. Methods: To identify a 211At-labeled lead, a surrogate strategy was applied. Because astatine does not exist as a stable nuclide, it is commonly replaced with iodine to mimic the pharmacokinetic behavior of the corresponding 211At-labeled compounds. To facilitate the process of structural design, iodine-based candidates were radiolabeled with the PET radionuclide 68Ga to study their preliminary in vitro and in vivo properties before the desired 211At-labeled lead compound was formed. The most promising candidate from this evaluation was chosen to be 211At-labeled and tested in biodistribution studies. Results: All 68Ga-labeled surrogates displayed affinities in the nanomolar range and specific internalization in PSMA-positive LNCaP cells. PET imaging of these compounds identified [ 68Ga]PSGa- 3 as the lead compound. Subsequently, [ 211At]PSAt- 3-Ga was synthesized in a radiochemical yield of 35% and showed tumor uptake of 19 ± 8 percentage injected dose per gram of tissue (%ID/g) at 1 h after injection and 7.6 ± 2.9 %ID/g after 24 h. Uptake in off-target tissues such as the thyroid (2.0 ± 1.1 %ID/g), spleen (3.0 ± 0.6 %ID/g), or stomach (2.0 ± 0.4 %ID/g) was low, indicating low in vivo deastatination of [ 211At]PSAt- 3-Ga. Conclusion: The reported findings support the use of iodine-based and 68Ga-labeled variants as a convenient strategy for developing astatinated compounds and confirm [ 211At]PSAt- 3 as a promising radiopharmaceutical for targeted α-therapy.
U2 - 10.2967/jnumed.123.267043
DO - 10.2967/jnumed.123.267043
M3 - Journal article
C2 - 38423784
VL - 65
SP - 593
EP - 599
JO - The Journal of Nuclear Medicine
JF - The Journal of Nuclear Medicine
SN - 0161-5505
IS - 4
ER -
ID: 387556814