High-Yielding Aqueous ¹⁸F-Labeling of Peptides via Al¹⁸F Chelation

The coordination chemistry of a new pentadentate bifunctional chelator (BFC), NODA-MPAA 1, containing the 1,4,7-triazacyclononane-1,4-diacetate (NODA) motif with a methylphenylacetic acid (MPAA) backbone, and its ability to form stable Al18F chelates were investigated. The organofluoroaluminates were easily accessible from the reaction of 1 and AlF3. X-ray diffraction studies revealed aluminum at the center of a slightly distorted octahedron, with fluorine occupying one of the axial positions. The tert-butyl protected prochelator 7, which can be synthesized in one step, is useful for coupling to biomolecules on solid phase or in solution. High yield (55–89%) aqueous 18F-labeling was achieved in 10–15 min with a tumor-targeting peptide 4 covalently linked to 1. Defluorination was not observed for at least 4 h in human serum at 37 °C. These results demonstrate the facile application of Al18F chelation using BFC 1 as a versatile labeling method for radiofluorinating other heat-stable peptides for positron emission imaging

High-Yielding Aqueous ¹⁸F-Labeling of Peptides via Al¹⁸F Chelation

The coordination chemistry of a new pentadentate bifunctional chelator (BFC), NODA-MPAA 1, containing the 1,4,7-triazacyclononane-1,4-diacetate (NODA) motif with a methylphenylacetic acid (MPAA) backbone, and its ability to form stable Al18F chelates were investigated. The organofluoroaluminates were easily accessible from the reaction of 1 and AlF3. X-ray diffraction studies revealed aluminum at the center of a slightly distorted octahedron, with fluorine occupying one of the axial positions. The tert-butyl protected prochelator 7, which can be synthesized in one step, is useful for coupling to biomolecules on solid phase or in solution. High yield (55–89%) aqueous 18F-labeling was achieved in 10–15 min with a tumor-targeting peptide 4 covalently linked to 1. Defluorination was not observed for at least 4 h in human serum at 37 °C. These results demonstrate the facile application of Al18F chelation using BFC 1 as a versatile labeling method for radiofluorinating other heat-stable peptides for positron emission imaging

Year of presentation and case-fatality rate.

Year of presentation and case-fatality rate.</p

New Lyophilized Kit for Rapid Radiofluorination of Peptides

Radiolabeling compounds with positron-emitting radionuclides often involves a time-consuming, customized process. Herein, we report a simple lyophilized kit formulation for labeling peptides with ¹⁸F, based on the aluminum-fluoride procedure. The prototype kit contains IMP485, a NODA (1,4,7-triazacyclononane-1,4-diacetate)-MPAA (methyl phenylacetic acid)-di-HSG (histamine-succinyl-glycine) hapten-peptide, [NODA-MPAA-d-Lys­(HSG)-d-Tyr-d-Lys­(HSG)-NH₂], used for pretargeting, but we also examined a similar kit formulation for a somatostatin-binding peptide [IMP466, NOTA-d-Phe-<u>Cys-Phe-d-Trp-Lys-Thr-Cys</u>-Throl] bearing a NOTA ligand to determine if the benefits of using a kit can be extended to other AlF-binding peptides. The NODA-MPAA ligand forms a single stable complex with (AlF)²⁺ in high yields. In order to establish suitable conditions for a facile kit, the formulation was optimized for pH, peptide to Al³⁺ ratio, bulking agent, radioprotectant, and the buffer. For optimal labeling, the kit was reconstituted with an aqueous solution of ¹⁸F^– and ethanol (1:1), heated at 100–110 °C for 15 min, and then simply and rapidly purified using one of two equally effective solid-phase extraction (SPE) methods. Al¹⁸F-IMP485 was isolated as a single isomer complex, in high yield (45–97%) and high specific activity (up to 223 GBq/μmol), within 20 min. The labeled product was stable in human serum at 37 °C for 4 h and <i>in vivo</i>, urine samples showed the intact product was eliminated. Tumor targeting of the Al¹⁸F-IMP485 in nude mice bearing human colon cancer xenografts pretargeted with an anti-CEACAM5 bispecific antibody showed very low uptake (0.06% ± 0.02 ID/g) in bone, further illustrating its stability. At 1 h, pretargeted animals had high Al¹⁸F-IMP485 tumor uptake (28.1% ± 4.5 ID/g), with ratios of 9 ± 4, 123 ± 38, 110 ± 43, and 120 ± 108 for kidney, liver, blood and bone, respectively. Tumor uptake remained high at 3 h postinjection, with increased tumor/nontumor ratios. The NOTA-somatostatin-binding peptide also was fluorinated with good yield and high specific activity in the same kit formulation. However, yields were somewhat lower than those achieved with IMP485 containing the NODA-MPAA ligand, likely reflecting this ligand’s superior binding properties over the simple NOTA. These studies indicate that ¹⁸F-labeled peptides can be reproducibly prepared as stable Al–F complexes with good radiochemical yield and high specific activity using a simple, one-step, lyophilized kit followed by a rapid purification by SPE that provides the ¹⁸F-peptide ready for patient injection within 30 min

Relationship between the monthly rainfall and the timing of clinical presentation.

Relationship between the monthly rainfall and the timing of clinical presentation.</p

Cases of disease recurrence with potential explanations.

<p>Cases of disease recurrence with potential explanations.</p

Clinical manifestations and organ involvement.

Clinical manifestations and organ involvement.</p

Disease risk factors and their relationship with mortality.

<p>Disease risk factors and their relationship with mortality.</p

Disease severity, outcome and supportive care over the course of the study.

<p>Disease severity, outcome and supportive care over the course of the study.</p

Data collection and its completeness.

<p>Data collection and its completeness.</p