Synthesis and Evaluation of Novel 68 Ga-Labeled [D-Phe 6 ,Leu 13 ψThz 14 ]bombesin(6-14) Analogs for Cancer Imaging with Positron Emission Tomography.

Gastrin-releasing peptide receptor (GRPR) is overexpressed in various cancers and is a promising target for cancer diagnosis and therapy. However, the high pancreas uptake and/or metabolic instability observed for most reported GRPR-targeted radioligands might limit their clinical applications. Our group recently reported a GRPR-targeted antagonist tracer, [ 68 Ga]Ga-TacsBOMB2 ([ 68 Ga]Ga-DOTA-Pip-D-Phe 6 -Gln 7 -Trp 8 -Ala 9 -Val 10 -Gly 11 -His 12 -Leu 13 ψThz 14 -NH 2 ), which showed a minimal pancreas uptake in a preclinical mouse model. In this study, we synthesized four derivatives with unnatural amino acid substitutions (Tle 10 -derived Ga-LW01158, NMe-His 12 -derived Ga-LW01160, α-Me-Trp 8 - and Tle 10 -derived Ga-LW01186, and Tle 10 - and N-Me-Gly 11 -derived Ga-LW02002) and evaluated their potential for detecting GRPR-expressing tumors with positron emission tomography (PET). The binding affinities (K i (GRPR)) of Ga-LW01158, Ga-LW01160, Ga-LW01186, and Ga-LW02002 were 5.11 ± 0.47, 187 ± 17.8, 6.94 ± 0.95, and 11.0 ± 0.39 nM, respectively. [ 68 Ga]Ga-LW01158, [ 68 Ga]Ga-LW01186, and [ 68 Ga]Ga-LW02002 enabled clear visualization of subcutaneously implanted human prostate cancer PC-3 tumor xenografts in mice in PET images. Ex vivo biodistribution studies showed that [ 68 Ga]Ga-LW01158 had the highest tumor uptake (11.2 ± 0.65 %ID/g) and good tumor-to-background uptake ratios at 1 h post-injection. Comparable in vivo stabilities were observed for [ 68 Ga]Ga-LW01158, [ 68 Ga]Ga-LW01186, and [ 68 Ga]Ga-LW02002 (76.5-80.7% remaining intact in mouse plasma at 15 min post-injection). In summary, the Tle 10 substitution, either alone or combined with α-Me-Trp 8 or NMe-Gly 11 substitution, in Ga-TacsBOMB2 generates derivatives that retained good GRPR binding affinity and in vivo stability. With good tumor uptake and tumor-to-background imaging contrast, [ 68 Ga]Ga-LW01158 is promising for detecting GRPR-expressing lesions with PET.