Scandium(iii) complexes of monophosphorus acid DOTA analogues: a thermodynamic and radiolabelling study with⁴⁴Sc from cyclotron and from a⁴⁴Ti/⁴⁴Sc generator

Abstract

The complexation ability of DOTA analogs bearing one methylenephosphonic (DO3AP) or methylenephosphinic (DO3AP(PrA) and DO3AP(ABn)) acid pendant arm toward scandium was evaluated. Stability constants of their scandium(iii) complexes were determined by potentiometry combined with (45)Sc NMR spectroscopy. The stability constants of the monophosphinate analogues are somewhat lower than that of the Sc-DOTA complex. The phosphorus acid moiety interacts with trivalent scandium even in very acidic solutions forming out-of-cage complexes; the strong affinity of the phosphonate group to Sc(iii) precludes stability constant determination of the Sc-DO3AP complex. These results were compared with those obtained by the free-ion selective radiotracer extraction (FISRE) method which is suitable for trace concentrations. FISRE underestimated the stability constants but their relative order was preserved. Nonetheless, as this method is experimentally simple, it is suitable for a quick relative comparison of stability constant values under trace concentrations. Radiolabelling of the ligands with (44)Sc was performed using the radioisotope from two sources, a (44)Ti/(44)Sc generator and (44m)Sc/(44)Sc from a cyclotron. The best radiolabelling conditions for the ligands were pH = 4, 70 °C and 20 min which were, however, not superior to those of the parent DOTA. Nonetheless, in vitro behaviour of the Sc(iii) complexes in the presence of hydroxyapatite and rat serum showed sufficient stability of (44)Sc complexes of these ligands for in vivo applications. PET images and ex vivo biodistribution of the (44)Sc-DO3AP complex performed on healthy Wistar male rats showed no specific bone uptake and rapid clearance through urine.

Antibody Fragment and Affibody ImmunoPET Imaging Agents: Radiolabelling Strategies and Applications

“…Scandium‐44 is receiving current interest owing to its intermediate 3.97 h half‐life, high positron yield, route of production and coordination chemistry . It is typically produced from 44 Ca in a cyclotron, but has the potential to be more conveniently produced via a 44 Ti/ 44 Sc generator system . 44 Sc, which is considered to be a potential alternative to 68 Ga, displays similar coordination chemistry to 68 Ga and could be used to extend the PET scanning window which may result in better images for certain probes .…”

“…[89] It is typically produced from 44 Ca in ac yclotron, [90] but hast he potential to be more conveniently produced via a 44 Ti/ 44 Sc generators ystem. [91] 44 Sc, which is considered to be ap otential alternative to 68 Ga,d isplays similar coordination chemistry to 68 Ga and could be used to extend the PET scanning window which may resulti nb etter images for certain probes. [92] The longer 3.97 hh alf-life is particularly well matched for antibody fragment imaging studies.…”

AAZTA: An Ideal Chelating Agent for the Development of 44Sc PET Imaging Agents

“…The 44 Sc(AAZTA) À complex was observed to be stable over 12 hinp lasma similarly to 44 Sc(DOTA) À . [14] To gain more insight into the in vivo properties,t he biodistribution of 44 Sc 3+ , 44 Sc(AAZTA) À , 44 Sc(CNAAZTAc(RGDfK)), and 44 Sc(CNAAZTA-BSA) was investigated in healthy control and 4T1 tumor-bearing BALB/c mice.P ET/ MRI images of healthy BALB/c mice obtained 90 min after i.v.i njection of 44 Sc 3+ and 44 Sc(AAZTA) À show am oderate accumulation of free 44 Sc 3+ in the liver,l ung, and spleen (Supporting Information, Figure S13A), whereas no radiotracer uptake of 44 Sc(AAZTA) À was found in thoracic and abdominal regions (Supporting Information, Figure S13B). PET/MRI images of healthy control BALB/c mice at 30 min (Supporting Information, Figure S14A) and 90 min (Supporting Information, Figure S14B) after i.v.a dministration of 44 Sc(CNAAZTA-BSA) remains practically unchanged with accumulations in the liver, heart, and bladder.T he long halflife of 44 Sc provides opportunity for delayed imaging so that 44 Sc(CNAAZTA-c(RGDfK)) could clear from non-targeted background organs while at the same time keep accumulating in the tumor region, as shown by comparing the whole body PET/MR images of healthy control vs.4 T1 tumor-bearing BALB/c mice 90 min after tracer injection (Figure 3).…”

“…[12] DOTA( Scheme 1) and its derivatives are still the workhorse for the preparation of stable chelates, but their slow formation kinetics requires long reaction times at 70-95 8 8C, which is hardly compatible with the labeling of antibodies and other biomolecules. [13][14][15] NOTA [16] and selected acyclic ligands (for example,D TPA, [17] EGTA, [17] CHX-A"-DTPA [18] )b ind Sc 3+ more rapidly than DOTA, but with am arkedly reduced stability of the corresponding chelates.…”

“…70 8 8C), therefore limiting its application for temperature-and pH-sensitive biomolecules,proteins,and so on. [14] We compared the labeling efficiency of the AAZTA and DOTAligand with 44 Sc separately over abroad range of pH, temperature,r eaction times,a nd ligand concentrations. Theinfluence of these parameters on the RCY is summarized in the Supporting Information, Figures S5 and S6.…”