Octadentate chelators for zirconium- and other metal-based radiopharmaceuticals
release_hst42vk6n5bclphwgnxqx5dmq4
by
Christian Buchwalder
References
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radioimmuno-conjugates in 58% and 54% radiochemical yield, respectively, and radiochemical purities of >99% (radio-SE-HPLC).
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The three radioimmunoconjugates with THPN, DFO, or DFO* chelates were diluted (1:4 v/v) with mouse plasma. The mixtures were incubated for seven days at 37 °C and aliquots were analyzed by ITLC (mobile phase: EDTA, 50 mM, pH 5.0) at the start and after 1, 3, 5, and 7 days of incubation. The experiment was conducted in duplicate. As a control, 89 Zr-oxalate was incubated in mouse plasma.
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Trans-Cyclooctene (TCO) Modification of Trastuzumab Trastuzumab was modified with TCO groups similarly to published procedures. 172, 202- 204 A solution of freshly purified trastuzumab (210 μL, 2.80 mg, 19.2 nmol) was diluted with PBS (413 μL) that was adjusted to pH 8.8 with 0.1 M NaHCO3. To this was added a solution of TCO- NHS (succinimidyl (E)-cyclooct-4-en-1-yl carbonate) in anhydrous DMSO (7.2 μL, 25 g/L, 673 nmol) to give a 35:1 molar ratio of TCO:mAb, while keeping the total DMSO concentration below 2%. The mixture was briefly vortexed and then incubated in the dark for 1 h at 21 °C with agitation (500 rpm). The TCO-mAb conjugate was purified by size-exclusion chromatography (PD-10), which was eluted in fractions with PBS (pH 7.4) and antibody concentrations were determined spectrophotometrically. The most concentrated fraction was analyzed for its number of reactive TCO groups/mAb, which was determined as 1.8. It was further analyzed by SE-HPLC (method E): tR = 13.0 min; (unmodified mAb: tR = 12.8 min).
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DLS: Z-avg. (d) 16.9 ± 0.4 nm; PDI: 0.23 ± 0.02. Unmodified HPG-NH2 (control): SE-HPLC (method D ): tR = 15.2 min; DLS: Z-avg. (d) 16
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Zr-Radiolabeling of HPG-Chelator Conjugates In three separate reaction vials, HPG-chelator solution (THPN, DFO, or DFO*) was added to a neutralized 89 Zr-oxalate solution (~170 μL, ~32 MBq, ~870 μCi, pH ~7), it was briefly vortexed and the mixtures were incubated at 21 °C with gentle agitation (350 rpm). Aliquots were analyzed by ITLC and more HPG-chelator solution was added in portions until quantitative radiolabeling was achieved. Added HPG-chelate volumes were 67.4, 75.6, and 66.6 μL for the THPN, DFO, and DFO* conjugates, respectively and total reaction volumes were ~250 μL. After 3 h reaction time, the reactions were purified by size exclusion chromatography (PD MiniTrap G-25), and eluted with water in seven fractions. Isolated radiochemical yields for all three reactions were 97% and radiochemical purities were >99% (HPLC). The most active product fractions were pooled and analyzed by radio-SE-HPLC, ITLC, and DLS.
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Zr-THPN-HPG Conjugate: radio-SE-HPLC (method D): tR = 15.3 min; DLS: Z-avg. (d)
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± 1.0 nm; PDI: 0.25 ± 0.02. 89 Zr-DFO-HPG Conjugate: radio-SE-HPLC (method D): tR = 15.3 min; DLS: Z-avg. (d) 14.8 ± 0.2 nm; PDI: 0.22 ± 0.01. 89 Zr-DFO*-HPG Conjugate: radio-SE- HPLC (method D): tR = 15.3 min; DLS: Z-avg. (d) 18.3 ± 0.7 nm; PDI: 0.29 ± 0.03.
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Zr-chelate-HPG conjugates with THPN, DFO, or DFO* prepared as described above were diluted 1:4 (v/v) with human blood plasma from a healthy donor. The mixtures were incubated for 5 days at 37 °C with gentle agitation (350 rpm). Aliquots were analyzed by ITLC aliquot was removed, diluted with methanol, and analyzed by mass spectrometry. ESI-MS (m/z)
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Sm III complexation. A solution of SmCl3 in D2O (220 μL, 5 mM, ~1.1 μmol) was added to a solution of THPN in a D2O/H2O (4:1) mixture (250 μL, 4.4 mM, ~1was removed, diluted with methanol, and analyzed by mass spectrometry. ESI-MS (m/z) 1056.4 [ML+2H] + (calcd. 1056.3); 1129.9 [M3L2+H] 2+ (calcd. 1129.3).
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Gd III complexation. A solution of GdCl3 in water (276 μL, 4 mM, ~1.1 μmol) was added to a solution of THPN in D2O (100 μL, 11 mM, ~1.1 μmol). The mixture was incubated overnight at ambient temperature with agitation (700 rpm). An aliquot was removed, diluted with methanol, and analyzed by mass spectrometry. ESI-MS (m/z) 1062.5 [ML+2H] + (calcd. 1062.3);
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Tb III complexation. A solution of TbCl3 in D2O (220 μL, 5 mM, ~1.1 μmol) was dropwise added to a solution of THPN in D2O (250 μL, 4.4 mM, ~1.1 μmol). The mixture was incubated for 25 min at ambient temperature with agitation (700 rpm). A portion of the reaction mixture (200 μL) was removed, basified by addition of NaOH to pH ~8 (~20 μL, 0.1 M), and the mixture was incubated for another 25 min at ambient temperature with agitation. An aliquot was removed, diluted with methanol, and analyzed by mass spectrometry. ESI-MS (m/z) 1063.5
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Lu III complexation. THPN (5.3 mg, 5.4 μmol) was dissolved with heating in a mixture of methanol, water, and 0.1 M Na2CO3 (20:5:1) and was allowed to cool to ambient temperature. To this ligand solution was dropwise added a solution of LuCl3 in methanol (410 μL, 13.1 mM, microcentrifuge tube, centrifuged, the supernatant was removed, and the white precipitate was analyzed by mass spectrometry. ESI-MS (m/z) 1079.4 [ML+2H] + (calcd. 1079.3); 1101.4 [ML+H+Na] + (calcd. 1101.3);
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Bi III complexation. A freshly prepared solution of anhydrous BiCl3 in methanol (275 μL, 4 mM, ~1.1 μmol) was dropwise added to a solution of THPN in methanol (300 μL, 3.7 mM, ~1.1 μmol). The mixture was incubated for 1.5 h at ambient temperature with agitation (700 rpm). An aliquot was removed, diluted with methanol, and analyzed by mass spectrometry. ESI-MS (m/z) 659.8 [M2L] 2+ (calcd. 660.2).
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