In vitro and in vivo evaluation of the bifunctional chelator NODIA-Me in combination with a prostate-specific membrane antigen targeting vector

Läppchen, Tilman; Kiefer, Yvonne; Holland, Jason P.; Bartholomä, Mark

doi:10.1016/j.nucmedbio.2018.03.002

Cited by 13 publications

(20 citation statements)

References 68 publications

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“…In parallel to our [ 177 Lu]Lu-PSMA-617 clinical studies, we were working on developing novel, improved PSMA-targeting tracers that also comprised the Glu-CO-Lys-binding motif, on which many PSMA-targeting tracers are based including PSMA-11 and PSMA-617. In contrast to the precursor syntheses of PSMA-11 and PSMA-617, , synthesis of our tracers was conducted in solution, which required the hydrolysis of the t Bu ester groups of the Glu-CO-Lys-binding motif in the final step . Deprotection of the carboxyl groups was achieved by acid-catalyzed hydrolysis in 5 M hydrochloric acid at ambient temperature.…”

Section: Resultsmentioning

confidence: 99%

“…In contrast to the precursor syntheses of PSMA-11 and PSMA-617, 9,13 synthesis of our tracers was conducted in solution, which required the hydrolysis of the tBu ester groups of the Glu-CO-Lys-binding motif in the final step. 34 Deprotection of the carboxyl groups was achieved by acid-catalyzed hydrolysis in 5 M hydrochloric acid at ambient temperature. During purification of the crudedeprotected bioconjugate via semipreparative HPLC, a fraction was isolated that eluted immediately after the desired product peak.…”

Section: ■ Results and Discussionmentioning

confidence: 99%

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Identification, Characterization, and Suppression of Side Products Formed during the Synthesis of [¹⁷⁷Lu]Lu-PSMA-617

et al. 2021

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In recent years, radiolabeled tracers targeting prostate-specific membrane antigen (PSMA) have had a tremendous impact on prostate cancer management. Here, we report on the formation of radioactive impurities formed during the clinical production of 177Lu-labeled PSMA-617. We provide compelling evidence that these impurities are the result of a spontaneous, thermally mediated condensation reaction of the Glu-CO-Lys moiety resulting in the formation of three different five-membered ring systems. Density functional theory (DFT) calculations show that the condensation and cyclization of the Glu-CO-Lys moiety is thermodynamically spontaneous. In cell experiments, no affinity of these cyclized compounds toward PSMA was observed. HPLC analyses of urine samples from patient studies showed rapid renal excretion of these radioactive cyclized species. Radiolabeling conditions were identified that significantly reduced the formation of cyclized side products yielding 177Lu-labeled PSMA-617 in high radiochemical yield and purity in concordance with current good manufacturing practice (cGMP) requirements.

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Section: Resultsmentioning

confidence: 99%

Section: ■ Results and Discussionmentioning

confidence: 99%

Identification, Characterization, and Suppression of Side Products Formed during the Synthesis of [¹⁷⁷Lu]Lu-PSMA-617

et al. 2021

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“…In a more recent study using 68 Ga-and 64 Cu-labeled PSMA-targeting conjugates comprising NODIA-Me 3, the applicability of this BFC in radiopharmaceutical development was successfully demonstrated [27]. Corresponding 68 Ga-and 64 Cu-labeled NODIA-Me-PSMA conjugates specifically delineated PSMApositive LNCaP tumors with low background accumulation in small-animal PET imaging experiments and ex vivo biodistribution studies [27]. Noteworthy, no significant decomplexation/transchelation of the radiometal chelate was noted in vitro (G 2 % transchelation in copper exchange experiments over 24 h) and in vivo by PET imaging in healthy mice (rapid clearance with 1h post injection), underscoring the use of our chelating platform for radiopharmaceutical applications.…”

Section: Introductionmentioning

confidence: 99%

“…In subsequent studies, NODIA-Me 3 was successfully conjugated to a prostate-specific membrane antigen (PSMA) targeting vector [26]. In a more recent study using 68 Ga-and 64 Cu-labeled PSMA-targeting conjugates comprising NODIA-Me 3, the applicability of this BFC in radiopharmaceutical development was successfully demonstrated [27]. Corresponding 68 Ga-and 64 Cu-labeled NODIA-Me-PSMA conjugates specifically delineated PSMApositive LNCaP tumors with low background accumulation in small-animal PET imaging experiments and ex vivo biodistribution studies [27].…”

Section: Introductionmentioning

confidence: 99%

Proof-of-Concept Study of the NOTI Chelating Platform: Preclinical Evaluation of 64Cu-Labeled Mono- and Trimeric c(RGDfK) Conjugates

et al. 2020

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Purpose: We recently developed a chelating platform based on the macrocycle 1,4,7triazacyclononane with up to three five-membered azaheterocyclic arms for the preparation of 68 Ga-and 64 Cu-based radiopharmaceuticals. Based on this platform, the chelator scaffold NOTI-TVA with three additional carboxylic acid groups for bioconjugation was synthesized and characterized. The primary aims of this proof-of-concept study were (1) to evaluate if trimeric radiotracers on the basis of the NOTI-TVA 6 scaffold can be developed, (2) to determine if the additional substituents for bioconjugation at the non-coordinating NH atoms of the imidazole residues of the building block NOTI influence the metal binding properties, and (3) what influence multiple targeting vectors have on the biological performance of the radiotracer. The cyclic RGDfK peptide that specifically binds to the α v ß 3 integrin receptor was selected as the biological model system. Procedures: Two different synthetic routes for the preparation of NOTI-TVA 6 were explored. Three c(RGDfK) peptide residues were conjugated to the NOTI-TVA 6 building block by standard peptide chemistry providing the trimeric bioconjugate NOTI-TVA-c(RGDfK) 3 9. Labeling of 9 with [ 64 Cu]CuCl 2 was performed manually at pH 8.2 at ambient temperature. Binding affinities of Cu-8, the Cu 2+ complex of the previously described monomer NODIA-Mec(RGDfK) 8, and the trimer Cu-9 to integrin α v ß 3 were determined in competitive cell binding experiments in the U-87MG cell line. The pharmacokinetics of both 64 Cu-labeled conjugates [ 64 Cu]Cu-8 and [ 64 Cu]Cu-9 were determined by small-animal PET imaging and ex vivo biodistribution studies in mice bearing U-87MG xenografts. Results: Depending on the synthetic route, NOTI-TVA 6 was obtained with an overall yield up to 58 %. The bioconjugate 9 was prepared in 41 % yield. Both conjugates [ 64 Cu]Cu-8 and [ 64 Cu]Cu-9 were radiolabeled quantitatively at ambient temperature in high molar activities of A m 20 MBq nmol −1 in less than 5 min. Competitive inhibitory constants IC 50 of c(RDGfK) 7, Cu-8, and Cu-9 were determined to be 159.5 ± 1.3 nM, 256.1 ± 2.1 nM, and 99.5 ± 1.1 nM,

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“…[1][2][3][4] Ligands that are typically used to construct radiopharmaceuticals are bifunctional chelators (BFCs), which are simply chelators with reactive functional groups that can be covalently coupled to targeting vectors (e.g., peptides, nucleotides, antibodies, nanoparticles). [5][6][7][8][9][10] BFCs serve as linkers between the radionuclide and targeting biomolecule and therefore play a crucial role in the success of targeted radionuclide therapy. The BFC is expected to impart high in vivo stability to the radiolabeled biomolecule translating to minimum radiation dose to nontarget organs.…”

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confidence: 99%

Synthetic Approaches to the Bifunctional Chelators for Radionuclides Based On Pyridine-Containing Azacrown Compounds

2019

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Synthetic ways to introduce functional groups (CO2Me, CO2H, OCH2CO2H, OCH2C≡CH, CH2OH, CH2Cl, CH2N3) into the pyridine ring of pyridine-containing azacrown compounds are described. These groups were introduced at position-4 of the pyridine ring, while keeping the macrocyclic carboxylate groups available for metal chelation. The derivatives were obtained by macrocyclization reaction of 4-substituted, trimethyl pyridine-2,4,6-tricarboxylate or by modification of methyl ester group in pyridine fragment of macrocycles. Obtained derivatives can be applied for preparing radiotherapeutic agents by conjugation to different vector biomolecules for targeted drug delivery to cancer cells without damaging healthy tissue.

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In vitro and in vivo evaluation of the bifunctional chelator NODIA-Me in combination with a prostate-specific membrane antigen targeting vector

Cited by 13 publications

References 68 publications

Identification, Characterization, and Suppression of Side Products Formed during the Synthesis of [¹⁷⁷Lu]Lu-PSMA-617

Identification, Characterization, and Suppression of Side Products Formed during the Synthesis of [¹⁷⁷Lu]Lu-PSMA-617

Proof-of-Concept Study of the NOTI Chelating Platform: Preclinical Evaluation of 64Cu-Labeled Mono- and Trimeric c(RGDfK) Conjugates

Synthetic Approaches to the Bifunctional Chelators for Radionuclides Based On Pyridine-Containing Azacrown Compounds

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In vitro and in vivo evaluation of the bifunctional chelator NODIA-Me in combination with a prostate-specific membrane antigen targeting vector

Cited by 13 publications

References 68 publications

Identification, Characterization, and Suppression of Side Products Formed during the Synthesis of [177Lu]Lu-PSMA-617

Identification, Characterization, and Suppression of Side Products Formed during the Synthesis of [177Lu]Lu-PSMA-617

Proof-of-Concept Study of the NOTI Chelating Platform: Preclinical Evaluation of 64Cu-Labeled Mono- and Trimeric c(RGDfK) Conjugates

Synthetic Approaches to the Bifunctional Chelators for Radio­nuclides Based On Pyridine-Containing Azacrown Compounds

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Identification, Characterization, and Suppression of Side Products Formed during the Synthesis of [¹⁷⁷Lu]Lu-PSMA-617

Identification, Characterization, and Suppression of Side Products Formed during the Synthesis of [¹⁷⁷Lu]Lu-PSMA-617

Synthetic Approaches to the Bifunctional Chelators for Radionuclides Based On Pyridine-Containing Azacrown Compounds