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In order to optimize elevated kidney retention of previously reported minigastrin derivatives, we substituted ( R )-DOTAGA by DOTA in ( R )-DOTAGA-rhCCK-16/-18. CCK-2R-mediated internalization and affinity of the new compounds were determined using AR42J cells. Biodistribution and µ SPECT/CT imaging studies at 1 and 24 h p.i. were carried out in AR42J tumor-bearing CB17-SCID mice. Both DOTA-containing minigastrin analogs exhibited 3- to 5-fold better IC  50 values than their ( R )-DOTAGA-counterparts. nat Lu-labeled peptides revealed higher CCK-2R affinity than their nat Ga-labeled analogs. In vivo, tumor uptake at 24 h p.i. of the most affine compound, [ 19 F]F-[ 177 Lu]Lu-DOTA-rhCCK-18, was 1.5- and 13-fold higher compared to its ( R )-DOTAGA derivative and the reference compound, [ 177 Lu]Lu-DOTA-PP-F11N, respectively. However, activity levels in the kidneys were elevated as well. At 1 h p.i., tumor and kidney accumulation of [ 19 F]F-[ 177 Lu]Lu-DOTA-rhCCK-18 and [ 18 F]F-[ nat Lu]Lu-DOTA-rhCCK-18 was high. We could demonstrate that the choice of chelators and radiometals has a significant impact on CCK-2R affinity and thus tumor uptake of minigastrin analogs. While elevated kidney retention of [ 19 F]F-[ 177 Lu]Lu-DOTA-rhCCK-18 has to be further addressed with regard to radioligand therapy, its radiohybrid analog, [ 18 F]F-[ nat Lu]Lu-DOTA-rhCCK-18, might be ideal for positron emission tomography (PET) imaging due to its high tumor accumulation at 1 h p.i. and the attractive physical properties of fluorine-18.

pharmaceutics

Development of the First 18F-Labeled Radiohybrid-Based Minigastrin Derivative with High Target Affinity and Tumor Accumulation by Substitution of the Chelating Moiety