Abstract
BackgroundThe AAZTA chelator and in particular its bifunctional derivative AAZTA5 was recently investigated to demonstrate unique capabilities to complex diagnostic and therapeutic trivalent radiometals under mild conditions. This study presents a comparison of 68Ga, 44Sc and 177Lu-labeled AAZTA5-PSMA-617 with DOTA-PSMA-617 analogues. We evaluated the radiolabeling characteristics, in vitro stability of the radiolabeled compounds and evaluated their binding affinity and internalization behavior on LNCaP tumor cells in direct comparison to the radiolabeled DOTA-conjugated PSMA-617 analogs.ResultsAAZTA5 was synthesized in a five-step synthesis and coupled to the PSMA-617 backbone on solid phase. Radiochemical evaluation of AAZTA5-PSMA-617 with 68Ga, 44Sc and 177Lu achieved quantitative radiolabeling of > 99% after less than 5 min at room temperature. Stabilities against human serum, PBS buffer and EDTA and DTPA solutions were analyzed. While there was a small degradation of the 68Ga complex over 2 h in human serum, PBS and EDTA/DTPA, the 44Sc and 177Lu complexes were stable at 2 h and remained stable over 8 h and 1 day. For all three compounds, i.e. [natGa]Ga-AAZTA5-PSMA-617, [natSc]Sc-AAZTA5-PSMA-617 and [natLu]Lu-AAZTA5-PSMA-617, in vitro studies on PSMA-positive LNCaP cells were performed in direct comparison to radiolabeled DOTA-PSMA-617 yielding the corresponding inhibition constants (Ki). Ki values were in the range of 8–31 nM values which correspond with those of [natGa]Ga-DOTA-PSMA-617, [natSc]Sc-DOTA-PSMA-617 and [natLu]Lu-DOTA-PSMA-617, i.e. 5–7 nM, respectively. Internalization studies demonstrated cellular membrane to internalization ratios for the radiolabeled 68Ga, 44Sc and 177Lu-AAZTA5-PSMA-617 tracers (13–20%IA/106 cells) in the same range as the ones of the three radiolabeled DOTA-PSMA-617 tracers (17–20%IA/106 cells) in the same assay.ConclusionsThe AAZTA5-PSMA-617 structure proved fast and quantitative radiolabeling with all three radiometal complexes at room temperature, excellent stability with 44Sc, very high stability with 177Lu and medium stability with 68Ga in human serum, PBS and EDTA/DTPA solutions. All three AAZTA5-PSMA-617 tracers showed binding affinities and internalization ratios in LNCaP cells comparable with that of radiolabeled DOTA-PSMA-617 analogues. Therefore, the exchange of the chelator DOTA with AAZTA5 within the PSMA-617 binding motif has no negative influence on in vitro LNCaP cell binding characteristics. In combination with the faster and milder radiolabeling features, AAZTA5-PSMA-617 thus demonstrates promising potential for in vivo application for theranostics of prostate cancer.
Highlights
The AAZTA chelator and in particular its bifunctional derivative AAZTA5 was recently investigated to demonstrate unique capabilities to complex diagnostic and therapeutic trivalent radiometals under mild conditions
The new era of radio-theranostics in medicine is driven in a significant way by potent radiolabeled Prostate-specific membrane antigen (PSMA) inhibitors based on the KuE motif binding to prostate cancer cells
One of the relevant features of the diagnostic tracer [68Ga]Ga-HBED-PSMA is its easy labeling under mild conditions (Eder et al 2012a), which later was paralleled by DATA (2,2′-(6-((carboxymethyl)amino)-1,4-diazepane-1, 4-diyl) diacetic acid)- and THP-conjugated KuE motifs (Tsionou et al 2017; Seemann et al 2015a; Nagy et al 2017; Pfister et al 2015)
Summary
The AAZTA chelator and in particular its bifunctional derivative AAZTA5 was recently investigated to demonstrate unique capabilities to complex diagnostic and therapeutic trivalent radiometals under mild conditions. The new era of radio-theranostics in (nuclear) medicine is driven in a significant way by potent radiolabeled PSMA (prostate-specific membrane antigen) inhibitors based on the KuE (lysine-urea-glutamate) motif binding to prostate cancer cells This success was initiated by [68Ga]Ga-HBED-PSMA ([68Ga]Ga-PSMA-11) for PET/CT imaging, while the important therapeutic compounds are DOTA (1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid)-conjugated KuE derivatives with varying linker and spacer moieties, ready for labelling with 90Y, 177Lu and other radiolanthanides, as well as alpha emitters such as 225Ac. One of the relevant features of the diagnostic tracer [68Ga]Ga-HBED-PSMA is its easy labeling under mild conditions (Eder et al 2012a), which later was paralleled by DATA (2,2′-(6-((carboxymethyl)amino)-1,4-diazepane-1, 4-diyl) diacetic acid)- and THP-conjugated KuE motifs (Tsionou et al 2017; Seemann et al 2015a; Nagy et al 2017; Pfister et al 2015). AAZTA5-TOC was recently described and evaluated in terms of radiolabeling capabilities and stabilities of the complexes with 68Ga, 44Sc and 177Lu (Sinnes et al 2019)
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