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Synthesis and Evaluation of Novel 68Ga-Labeled [D-Phe6,Leu13ψThz14]bombesin(6-14) Analogs for Cancer Imaging with Positron Emission Tomography Wang, Lei; Chen, Chao-Cheng; Zhang, Zhengxing; Kuo, Hsiou-Ting; Zhang, Chengcheng; Colpo, Nadine; Merkens, Helen; Bénard, François; Lin, Kuo-Shyan

Abstract

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, [⁶⁸Ga]Ga-TacsBOMB2 ([⁶⁸Ga]Ga-DOTA-Pip-D-Phe⁶-Gln⁷-Trp⁸-Ala⁹-Val¹⁰-Gly¹¹-His¹²-Leu¹³ψThz¹⁴-NH₂), which showed a minimal pancreas uptake in a preclinical mouse model. In this study, we synthesized four derivatives with unnatural amino acid substitutions (Tle¹⁰-derived Ga-LW01158, NMe-His¹²-derived Ga-LW01160, α-Me-Trp⁸- and Tle¹⁰-derived Ga-LW01186, and Tle¹⁰- and N-Me-Gly¹¹-derived Ga-LW02002) and evaluated their potential for detecting GRPR-expressing tumors with positron emission tomography (PET). The binding affinities (Ki(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. [⁶⁸Ga]Ga-LW01158, [⁶⁸Ga]Ga-LW01186, and [⁶⁸Ga]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 [⁶⁸Ga]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 [⁶⁸Ga]Ga-LW01158, [⁶⁸Ga]Ga-LW01186, and [⁶⁸Ga]Ga-LW02002 (76.5–80.7% remaining intact in mouse plasma at 15 min post-injection). In summary, the Tle¹⁰ substitution, either alone or combined with α-Me-Trp⁸ or NMe-Gly¹¹ 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, [⁶⁸Ga]Ga-LW01158 is promising for detecting GRPR-expressing lesions with PET.

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