The Effect of Albumin-Binding Moiety on Tumor Targeting and Biodistribution Properties of Ga-67-Labeled Albumin Binder-Conjugated Alpha-Melanocyte-Stimulating Hormone Peptides

The purpose of this study was to examine the effect of 4-p-(tolyl)butyric acid as an albumin-binding (ALB) moiety on tumor targeting and biodistribution properties of Ga-67-labeled albumin binder-conjugated alpha-melanocyte-stimulating hormone peptides.

Methods: DOTA-Lys(ALB)-G/GG/GGG-Nle-CycMSH(hex) {1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-Lys(ALB)-Gly/GlyGly/GlyGlyGly-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH2} were synthesized with 4-p-(tolyl)butyric acid serving as an ALB moiety. The melanocortin-1 receptor (MC1R)-binding affinities of the peptides were determined on B16/F10 melanoma cells. The biodistribution of Ga-67-DOTA-Lys(ALB)-G/GG/GGG-Nle-CycMSH(hex) was examined on B16/F10 melanoma-bearing C57 mice at 2 h postinjection to select a lead peptide for further evaluation. The melanoma targeting and imaging properties of Ga-67-DOTA-Lys(ALB)-GGNle-CycMSH(hex) {Ga-67-ALB-G2} were determined on B16/F10 melanoma-bearing C57 mice.

Results: The IC50 value of DOTA-Lys(ALB)-G/GG/GGG-Nle-CycMSH(hex) {ALB-G1, ALB-G2, ALB-G3} was 0.67 +/- 0.07, 0.5 +/- 0.09 and 0.51 +/- 0.03 nM on B16/F10 cells, respectively. Ga-67-ALB-G2 was further evaluated as a lead peptide because of its higher tumor uptake (30.25 +/- 3.24%ID/g) and lower kidney uptake (7.09 +/- 2.22%ID/g) than Ga-67-ALB-G1 and Ga-67-ALB-G3 at 2 h postinjection. The B16/F10 melanoma uptake of Ga-67-ALB-G2 was 15.64 +/- 4.55, 30.25 +/- 3.24, 26.76 +/- 3.23, and 10.71 +/- 1.21%ID/g at 0.5, 2, 4, and 24 h postinjection, respectively. The B16/F10 melanoma lesions were clearly visualized by SPECT/CT using Ga-67-ALB-G2 as an imaging probe at 2 h postinjection.

Conclusions: The introduction of 4-p-(tolyl)butyric acid as an ALB moiety increased the blood retention, and resulted in higher tumor/kidney ratio of Ga-67-ALB-G2 as compared with its counterpart without an albumin binder. However, the resulting high uptake of Ga-67-ALB-G2 in blood and liver need to be further reduced to facilitate its therapeutic application when replacing Ga-67 with therapeutic radionuclides.