Synthesis, radiolabeling, and pre-clinical evaluation of [44Sc]Sc-AAZTA conjugate PSMA inhibitor, a new tracer for high-efficiency imaging of prostate cancer

Ghiani, Simona; Hawala, Ivan; Szikra, Dezső; Trencsényi, György; Baranyai, Zsolt; Nagy, Gábor; Vágner, Adrienn; Stefanìa, Rachele; Pandey, Sushma; Maiocchi, Alessandro

doi:10.1007/s00259-020-05130-0

Cited by 15 publications

(19 citation statements)

References 24 publications

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“…However, the tumor uptake of the SA.KuE conjugates was lower than that of the gallium-68 and lutetium-177 labeled PSMA-617 radioligands [10,11]. Ghiani et al recently described a novel scandium-44 labeled PSMA radioligand with even higher tumor accumulation than the PSMA-617 counterpart [41]. Nevertheless, a direct comparison between the presented results and those reported by other groups is not possible because of the differences in xenograft models and experimental setups.…”

Section: Discussionmentioning

confidence: 66%

“…However, the reported binding affinities and internalization ratios of AATA 5 -PSMA-617 and DOTA-PSMA-617 were higher than those of the SA.KuE conjugates. In particular, [ 44 Sc]Sc-PSMA-617 seems to display high PSMA-binding affinity as published by several groups [41,42]. Since PSMA-617 was not commercially available at the time this study was performed, PSMA-11 was used as reference.…”

Section: Discussionmentioning

confidence: 83%

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Hybrid Chelator-Based PSMA Radiopharmaceuticals: Translational Approach

et al. 2021

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(1) Background: Prostate-specific membrane antigen (PSMA) has been extensively studied in the last decade. It became a promising biological target in the diagnosis and therapy of PSMA-expressing cancer diseases. Although there are several radiolabeled PSMA inhibitors available, the search for new compounds with improved pharmacokinetic properties and simplified synthesis is still ongoing. In this study, we developed PSMA ligands with two different hybrid chelators and a modified linker. Both compounds have displayed a promising pharmacokinetic profile. (2) Methods: DATA5m.SA.KuE and AAZTA5.SA.KuE were synthesized. DATA5m.SA.KuE was labeled with gallium-68 and radiochemical yields of various amounts of precursor at different temperatures were determined. Complex stability in phosphate-buffered saline (PBS) and human serum (HS) was examined at 37 °C. Binding affinity and internalization ratio were determined in in vitro assays using PSMA-positive LNCaP cells. Tumor accumulation and biodistribution were evaluated in vivo and ex vivo using an LNCaP Balb/c nude mouse model. All experiments were conducted with PSMA-11 as reference. (3) Results: DATA5m.SA.KuE was synthesized successfully. AAZTA5.SA.KuE was synthesized and labeled according to the literature. Radiolabeling of DATA5m.SA.KuE with gallium-68 was performed in ammonium acetate buffer (1 M, pH 5.5). High radiochemical yields (>98%) were obtained with 5 nmol at 70 °C, 15 nmol at 50 °C, and 60 nmol (50 µg) at room temperature. [68Ga]Ga-DATA5m.SA.KuE was stable in human serum as well as in PBS after 120 min. PSMA binding affinities of AAZTA5.SA.KuE and DATA5m.SA.KuE were in the nanomolar range. PSMA-specific internalization ratio was comparable to PSMA-11. In vivo and ex vivo studies of [177Lu]Lu-AAZTA5.SA.KuE, [44Sc]Sc-AAZTA5.SA.KuE and [68Ga]Ga-DATA5m.SA.KuE displayed specific accumulation in the tumor along with fast clearance and reduced off-target uptake. (4) Conclusions: Both KuE-conjugates showed promising properties especially in vivo allowing for translational theranostic use.

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Section: Discussionmentioning

confidence: 66%

Section: Discussionmentioning

confidence: 83%

Hybrid Chelator-Based PSMA Radiopharmaceuticals: Translational Approach

et al. 2021

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“…The most appropriate theranostic AAZTA-derived chelators would certainly be 44 Sc/ 47 Sc, although this has not be reported in the literature. The [ 44 Sc]Sc-AAZTA 5 -PSMA-617 derivative was later evaluated in vivo after an indepth study of the radiolabeling reaction conditions [73]. Although its amount in radiopharmaceuticals is strictly limited by European Pharmacopoeia [74], HEPES 0.1 M was found to be a particularly suitable buffer to reach high RCY and excellent molar activity (average of 39.4 GBq/µmol) at pH 4.…”

Section: Prostate-specific Antigen Ligandsmentioning

confidence: 99%

AAZTA-Derived Chelators for the Design of Innovative Radiopharmaceuticals with Theranostic Applications

et al. 2022

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With the development of 68Ga and 177Lu radiochemistry, theranostic approaches in modern nuclear medicine enabling patient-centered personalized medicine applications have been growing in the last decade. In conjunction with the search for new relevant molecular targets, the design of innovative chelating agents to easily form stable complexes with various radiometals for theranostic applications has gained evident momentum. Initially conceived for magnetic resonance imaging applications, the chelating agent AAZTA features a mesocyclic seven-membered diazepane ring, conferring some of the properties of both acyclic and macrocyclic chelating agents. Described in the early 2000s, AAZTA and its derivatives exhibited interesting properties once complexed with metals and radiometals, combining a fast kinetic of formation with a slow kinetic of dissociation. Importantly, the extremely short coordination reaction times allowed by AAZTA derivatives were particularly suitable for short half-life radioelements (i.e., 68Ga). In view of these particular characteristics, the scope of this review is to provide a survey on the design, synthesis, and applications in the nuclear medicine/radiopharmacy field of AAZTA-derived chelators.

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“…The desirable biological properties confirmed suitability of 44 Sc-PSMA-617 for clinical use. By comparing the 44 Sc-PSMA-617 and 44 Sc-B28110, 44 Sc-B28110 could be a better radiotracer for PET scan to detect prostate cancer compared to 44 Sc-PSMA-617 due to higher uptake and retention in tumor (Eppard et al, 2017;Ghiani et al, 2021). (The results of radiolabeled PSMA ligands for targeting prostate cancer are summarized in Table 1).…”

Section: Sc-psmamentioning

confidence: 99%