TY - JOUR
T1 - Brush border enzyme-cleavable linkers
T2 - Evaluation for reducing renal uptake of radiolabeled prostate-specific membrane antigen inhibitors
AU - Vaidyanathan, Ganesan
AU - Kang, Choong Mo
AU - McDougald, Darryl
AU - Minn, Il
AU - Brummet, Mary
AU - Pomper, Martin G.
AU - Zalutsky, Michael R.
N1 - Publisher Copyright:
© 2018 Elsevier Inc.
PY - 2018/7/1
Y1 - 2018/7/1
N2 - Introduction: Radiolabeled, low-molecular-weight prostate-specific membrane antigen (PSMA) inhibitors based on the Glu-ureido pharmacophore show promise for the detection and treatment of castration-resistant prostate cancer; however, high renal retention of activity, related in part to overexpression of PSMA in kidneys can be problematic. The goal of the current study was to investigate the use of brush border enzyme-cleavable linkers as a strategy for reducing kidney activity levels from radiolabeled PSMA inhibitors. Methods: PSMA-769 (6), a derivative of the prototypical PSMA inhibitor (((S)‑1‑carboxy‑5‑(4‑iodobenzamido)pentyl)carbamoyl)glutamate (12) modified to contain a Gly-Tyr linker, and its protected tin precursor (11) were synthesized starting from the basic pharmacophore molecule Lys-urea-Glu. An analogue of 6 containing D‑tyrosine in lieu of L‑tyrosine (PSMA-769-D-tyrosine) and the corresponding tin precursor (D-11) also were synthesized. Both radioiodinated and 211At-labeled 6 were synthesized by radiohalogenation of 11 and deprotection in situ. Similarly, radioiodinated D-6 was synthesized from D-11. Paired label biodistribution of [125I]12 and [131I]6 was performed in normal mice and in SCID mice bearing both PC3 PIP (PSMA+) and PC3 flu (PSMA−) subcutaneous prostate carcinoma xenografts. The biodistribution of [131I]6 and [211At]6 was also evaluated in this tumor model. Biodistribution of the two radioiodinated diastereomers of 6 was evaluated in normal mice and urine samples were analyzed for the presence of 4‑iodohippuric acid. Results: Compounds [131I]6 and [211At]6 were synthesized from 11 in overall radiochemical yields of 32.5 ± 0.1% (n = 4) and 22% (n = 1), respectively; radiochemical purity was >95%. In normal mice, renal uptake of [131I]6 was 1.4-, 2.8- and 161-fold lower than that seen for co-injected [125I]12 at 1 h, 4 h and 21 h, respectively. In tumor-bearing mice, kidney uptake of [131I]6 was similar to that for [125I]12 (P > 0.05) at 1 h and 4 h but was 6- to 7-fold lower at 21 h; however, [131I]6 uptake in PC3 PIP tumors was also lower than that seen for [125I]12 at 21 h (12.6 ± 3.4%ID/g vs. 36.8 ± 12.4%ID/g). Uptake of [211At]PSMA-769 in PC3 PIP tumors was slightly higher than that seen for [131I]PSMA-769 at 4 h (9.6 ± 1.6%ID/g versus 7.8 ± 1.6%ID/g; P = 0.002); its uptake in a number of normal tissues also was higher. In normal mice, kidney uptake of [125I]PSMA-769 at 4 h was about 73% of that seen for [131I]PSMA-769-D-tyrosine. Activity in the urine of mice receiving [125I]PSMA-769 contained mainly 4‑[125I]iodohippuric acid while unmetabolized intact molecule was present in the case of [125I]PSMA-769-D-tyrosine. Conclusion: Use of this brush border enzyme-cleavable linker reduced kidney uptake and resulted in improved tumor:kidney uptake ratios. Although further structural improvements are needed, this linker approach might be useful as a component in strategies for reducing renal uptake of radiolabeled PSMA inhibitors.
AB - Introduction: Radiolabeled, low-molecular-weight prostate-specific membrane antigen (PSMA) inhibitors based on the Glu-ureido pharmacophore show promise for the detection and treatment of castration-resistant prostate cancer; however, high renal retention of activity, related in part to overexpression of PSMA in kidneys can be problematic. The goal of the current study was to investigate the use of brush border enzyme-cleavable linkers as a strategy for reducing kidney activity levels from radiolabeled PSMA inhibitors. Methods: PSMA-769 (6), a derivative of the prototypical PSMA inhibitor (((S)‑1‑carboxy‑5‑(4‑iodobenzamido)pentyl)carbamoyl)glutamate (12) modified to contain a Gly-Tyr linker, and its protected tin precursor (11) were synthesized starting from the basic pharmacophore molecule Lys-urea-Glu. An analogue of 6 containing D‑tyrosine in lieu of L‑tyrosine (PSMA-769-D-tyrosine) and the corresponding tin precursor (D-11) also were synthesized. Both radioiodinated and 211At-labeled 6 were synthesized by radiohalogenation of 11 and deprotection in situ. Similarly, radioiodinated D-6 was synthesized from D-11. Paired label biodistribution of [125I]12 and [131I]6 was performed in normal mice and in SCID mice bearing both PC3 PIP (PSMA+) and PC3 flu (PSMA−) subcutaneous prostate carcinoma xenografts. The biodistribution of [131I]6 and [211At]6 was also evaluated in this tumor model. Biodistribution of the two radioiodinated diastereomers of 6 was evaluated in normal mice and urine samples were analyzed for the presence of 4‑iodohippuric acid. Results: Compounds [131I]6 and [211At]6 were synthesized from 11 in overall radiochemical yields of 32.5 ± 0.1% (n = 4) and 22% (n = 1), respectively; radiochemical purity was >95%. In normal mice, renal uptake of [131I]6 was 1.4-, 2.8- and 161-fold lower than that seen for co-injected [125I]12 at 1 h, 4 h and 21 h, respectively. In tumor-bearing mice, kidney uptake of [131I]6 was similar to that for [125I]12 (P > 0.05) at 1 h and 4 h but was 6- to 7-fold lower at 21 h; however, [131I]6 uptake in PC3 PIP tumors was also lower than that seen for [125I]12 at 21 h (12.6 ± 3.4%ID/g vs. 36.8 ± 12.4%ID/g). Uptake of [211At]PSMA-769 in PC3 PIP tumors was slightly higher than that seen for [131I]PSMA-769 at 4 h (9.6 ± 1.6%ID/g versus 7.8 ± 1.6%ID/g; P = 0.002); its uptake in a number of normal tissues also was higher. In normal mice, kidney uptake of [125I]PSMA-769 at 4 h was about 73% of that seen for [131I]PSMA-769-D-tyrosine. Activity in the urine of mice receiving [125I]PSMA-769 contained mainly 4‑[125I]iodohippuric acid while unmetabolized intact molecule was present in the case of [125I]PSMA-769-D-tyrosine. Conclusion: Use of this brush border enzyme-cleavable linker reduced kidney uptake and resulted in improved tumor:kidney uptake ratios. Although further structural improvements are needed, this linker approach might be useful as a component in strategies for reducing renal uptake of radiolabeled PSMA inhibitors.
KW - Astatine-211
KW - Brush border enzyme-cleavable linker
KW - Kidney uptake
KW - PSMA
KW - Radioiodine
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U2 - 10.1016/j.nucmedbio.2018.05.002
DO - 10.1016/j.nucmedbio.2018.05.002
M3 - Article
C2 - 29803076
AN - SCOPUS:85047243523
SN - 0969-8051
VL - 62-63
SP - 18
EP - 30
JO - Nuclear Medicine and Biology
JF - Nuclear Medicine and Biology
ER -