Abstract:BackgroundWe recently developed a chelating platform based on the macrocycle 1,4,7-triazacyclononane with up to three, five-membered azaheterocyclic arms for the development of 68Ga- and 64Cu-based radiopharmaceuticals. Here, a 68Ga-labelled conjugate comprising the bifunctional chelator NODIA-Me in combination with the αvß3-targeting peptide c(RGDfK) has been synthesized and characterized. The primary aim was to evaluate further the potential of our NODIA-Me chelating system for the development of 68Ga-labell… Show more
“…5 Small-animal PET imaging and ex vivo biodistribution studies of corresponding 68 Ga-and 64 Cu-labeled NODIA-Me-NaI-Ahx-PSMA conjugates showed specific accumulation in PSMA-positive LNCaP tumors. 6 Both compounds exhibited rapid renal clearance with low uptake in non-target tissues confirming sufficient stability of 68 Ga-and 64 Cu(NODIA-Me) chelates in vivo. Furthermore, NODIA-Me was recently coupled to the peptide c(RGDfK) for targeting the integrin avß3 receptor.…”
Section: Introductionmentioning
confidence: 84%
“…Besides the labeling efficiency, the stability/inertness of the radiometal complex is of importance for radiopharmaceutical applications. Hence, the stability of 111 6 The octanol/PBS partition coefficient log Doct/PBS of [ 111 In]In-13 was determined to -3.57 ± 0.01 making it slightly more lipophilic than its 64 Cu-and 68 Ga-labeled counterparts with log Doct/PBS values of -3.99 ± 0.05 and -4.27 ± 0.08, respectively.…”
Section: Indium Radiolabeling and Stability Experimentsmentioning
confidence: 99%
“…Corresponding 64 Cu-and 68 Ga-labeled NODIA-Me-NaI-Ahx-PSMA conjugates were recently evaluated by our group. 6 For comparison and to study the influence of the indium complex on biological properties, the binding affinities of 13 and In-13 were determined in competitive binding assays on PSMA-positive LNCaP cells as previously described. 6 A graphical representation of corresponding IC50 curves is given in Figure 3.…”
Multi-step synthetic route provides the ligand NODIA-Me in high yield. Radiolabeling with [111In]InCl3 yields stable complexes in high radiochemical purity and yield.
“…5 Small-animal PET imaging and ex vivo biodistribution studies of corresponding 68 Ga-and 64 Cu-labeled NODIA-Me-NaI-Ahx-PSMA conjugates showed specific accumulation in PSMA-positive LNCaP tumors. 6 Both compounds exhibited rapid renal clearance with low uptake in non-target tissues confirming sufficient stability of 68 Ga-and 64 Cu(NODIA-Me) chelates in vivo. Furthermore, NODIA-Me was recently coupled to the peptide c(RGDfK) for targeting the integrin avß3 receptor.…”
Section: Introductionmentioning
confidence: 84%
“…Besides the labeling efficiency, the stability/inertness of the radiometal complex is of importance for radiopharmaceutical applications. Hence, the stability of 111 6 The octanol/PBS partition coefficient log Doct/PBS of [ 111 In]In-13 was determined to -3.57 ± 0.01 making it slightly more lipophilic than its 64 Cu-and 68 Ga-labeled counterparts with log Doct/PBS values of -3.99 ± 0.05 and -4.27 ± 0.08, respectively.…”
Section: Indium Radiolabeling and Stability Experimentsmentioning
confidence: 99%
“…Corresponding 64 Cu-and 68 Ga-labeled NODIA-Me-NaI-Ahx-PSMA conjugates were recently evaluated by our group. 6 For comparison and to study the influence of the indium complex on biological properties, the binding affinities of 13 and In-13 were determined in competitive binding assays on PSMA-positive LNCaP cells as previously described. 6 A graphical representation of corresponding IC50 curves is given in Figure 3.…”
Multi-step synthetic route provides the ligand NODIA-Me in high yield. Radiolabeling with [111In]InCl3 yields stable complexes in high radiochemical purity and yield.
“…Chemicals and solvents were purchased from Sigma-Aldrich and TCI Europe, and used as received. The bifunctional chelator NODIA-Me 3 was prepared as previously described [ 28 , 29 ]. The peptide c(RGDfK) 7 was purchased from ABX (Radeberg, Germany).…”
Section: Methodsmentioning
confidence: 99%
“…The monomer 8 (Scheme 2 ) was prepared as previously described and characterization data was identical to that previously reported [ 29 ]. Scheme 2 Two synthetic routes for the preparation of the trifunctionalized NOTI-TVA 6 scaffold.…”
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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