Novel [99mTc]-Tricarbonyl-NOTA-Conjugated Lactam-Cyclized Alpha-MSH Peptide with Enhanced Melanoma Uptake and Reduced Renal Uptake

The purpose of this study was to examine the melanoma targeting and imaging properties of 99m Tc(CO) 3 -NOTA-GGNle-CycMSH hex {1,4,7-triazacyclononane-1,4,7-triyl-triacetic acid-GlyGlyNle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH 2 } and 99m Tc(CO) 3 -NODAGA-GGNle-CycMSH hex {1,4,7-triazacyclononane,1-gluteric acid-4,7-acetic acid-GlyGlyNle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH 2 } on B16/F10 melanoma-bearing C57 mice to demonstrate the feasibility of NOTA/NODAGA as metal chelators for 99m Tc(CO) 3 + radiolabeling. NOTA/NODAGA-GGNle-CycMSH hex were synthesized using fluorenylmethoxycarbonyl (Fmoc) chemistry. The melanocortin-1 (MC1) receptor binding affinities of the peptides were determined on B16/F10 melanoma cells. The biodistribution of 99m Tc(CO) 3 -NOTA-GGNle-CycMSH hex and 99m Tc(CO) 3 -NODAGA-GGNle-CycMSH hex were determined 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 99m Tc(CO) 3 -NOTA-GGNle-CycMSH hex and 99m Tc(CO) 3 -NODAGA-GGNle-CycMSH hex were determined on B16/F10 melanoma-bearing C57 mice. The IC 50 values of NOTA/NODAGA-GGNle-CycMSH hex were 0.8 ± 0.1 and 0.9 ± 0.1 nM on B16/F10 cells. 99m Tc(CO) 3 -NOTA-GGNle-CycMSH hex and 99m Tc(CO) 3 -NODAGA-GGNle-CycMSH hex were readily prepared via the [ 99m Tc(CO) 3 (OH 2 ) 3 ] + intermediate and displayed MC1R-specific binding on B16/F10 cells. 99m Tc(CO) 3 -NOTA-GGNle-CycMSH hex was further evaluated as a lead peptide because of its higher tumor uptake (19.76 ± 3.62% ID/g) and lower kidney uptake (1.59 ± 0.52% ID/g) at 2 h postinjection than 99m Tc(CO) 3 -NODAGA-GGNle-CycMSH hex . The B16/F10 melanoma uptake of 99m Tc(CO) 3 -NOTA-GGNle-CycMSH hex was 16.07 ± 4.47, 19.76 ± 3.62, 11.30 ± 2.81, and 3.16 ± 2.28% ID/g at 0.5, 2, 4, and 24 h postinjection, respectively. 99m Tc(CO) 3 -NOTA-GGNle-CycMSH hex showed high tumor to normal organ uptake ratios after 2 h postinjection. The B16/F10 melanoma lesions were clearly visualized by SPECT/CT using 99m Tc(CO) 3 -NOTA-GGNle-CycMSH hex as an imaging probe at 2 h postinjection. High tumor uptake, low kidney uptake, and fast urinary clearance of 99m Tc(CO) 3 -NOTA-GGNle-CycMSH hex highlighted its potential for melanoma imaging and facilitated the evaluation of 188 Re(CO) 3 -NOTA-GGNle-CycMSH hex for melanoma therapy.