Introduction of a SiFA Moiety into the D-Glutamate Chain of DOTA-PP-F11N Results in Radiohybrid-Based CCK-2R-Targeted Compounds with Improved Pharmacokinetics In Vivo

Abstract

In order to enable ¹⁸F- and ¹⁷⁷Lu-labelling within the same molecule, we introduced a silicon-based fluoride acceptor (SiFA) into the hexa-D-glutamate chain of DOTA-PP-F11N. In addition, minigastrin analogues with a prolonged as well as <i>γ</i>-linked D-glutamate chain were synthesised and evaluated. CCK-2R affinity (<i>IC</i>₅₀, AR42J cells) and lipophilicity (log<i>D</i>_7.4) were determined. Biodistribution studies at 24 h post-injection (p.i.) and <i>µ</i>SPECT/CT imaging at 1, 4 and 24 h p.i. were carried out in AR42J tumour-bearing CB17-SCID mice. CCK-2R affinity of (<i>R</i>)-DOTAGA-rhCCK-1 to 18 was enhanced with increasing distance between the SiFA building block and the binding motif. Lipophilicity of [¹⁷⁷Lu]Lu-(<i>R</i>)-DOTAGA-rhCCK-1 to 18 was higher compared to that of [¹⁷⁷Lu]Lu-DOTA-PP-F11N and [¹⁷⁷Lu]Lu-CP04. The respective <i>α</i>- and <i>γ</i>-linked rhCCK derivatives revealing the highest CCK-2R affinity were further evaluated in vivo. In comparison with [¹⁷⁷Lu]Lu-DOTA-PP-F11N, [¹⁷⁷Lu-]Lu-(<i>R</i>)-DOTAGA-rhCCK-9 and -16 exhibited three- to eight-fold increased activity levels in the tumour at 24 h p.i. However, activity levels in the kidneys were elevated as well. We could show that the introduction of a lipophilic SiFA moiety into the hydrophilic backbone of [¹⁷⁷Lu]Lu-DOTA-PP-F11N led to a decelerated blood clearance and thus improved tumour retention. However, elevated kidney retention has to be addressed in future studies.