Preclinical and Initial Clinical Evaluation of ⁶⁸ Ga/ ¹⁷⁷ Lu-Labeled Heterodimer Agents Targeting Somatostatin Receptors and Integrin α _V β ₃

Highly overexpressed somatostatin receptors (SSTRs), especially SSTR2, are frequently characterized in neuroendocrine tumors (NETs) and serve as a target for imaging and peptide receptor radionuclide therapy (PRRT). However, the SSTR2 expression decreases in higher-grade NETs, while the expression level of the integrin receptor α_Vβ₃ was increased. A reported heterodimer, [⁶⁸Ga]Ga-NOTA-3P-TATE-RGD, which targets both SSTR2 and integrin α_Vβ₃, has shown potential clinical value, but the high renal uptake limited its further development. The aim of this study is to evaluate [⁶⁸Ga]Ga/[¹⁷⁷Lu]Lu-DOTATATE-RGD ([⁶⁸Ga]Ga/[¹⁷⁷Lu]Lu-DTR) and [⁶⁸Ga]Ga-NOTA-TOC-RGD ([⁶⁸Ga]Ga-NCR) as potential SSTR and integrin α_vβ₃ heterodimer agents. Radiolabeling of both Ga-68 and Lu-177 was effectively accomplished with high yields and radiochemical purities. The three agents showed higher cell uptake compared with monomeric [⁶⁸Ga]Ga-RGD but reduced uptake compared with [⁶⁸Ga]Ga-DOTATATE. Results of biodistribution and small-animal positron emission tomography (PET) studies showed that the renal uptake of [⁶⁸Ga]Ga/[¹⁷⁷Lu]Lu-DTR decreased without affecting the tumor-binding ability compared to [⁶⁸Ga]Ga-NOTA-3P-TATE-RGD, but the tumor-to-kidney ratio of [⁶⁸Ga]Ga-NCR did not increase as desired. In initial clinical trials, [⁶⁸Ga]Ga-DTR PET/CT exhibited a lower uptake in the kidney and spleen than that of [⁶⁸Ga]Ga-NOTA-3P-TATE-RGD PET/CT (SUV_mean: 10.88 ± 3.27 <i>vs</i> 29.02 ± 8.89 and 3.41 ± 1.18 <i>vs</i> 8.16 ± 4.38, respectively), indicating that [⁶⁸Ga]Ga/[¹⁷⁷Lu]Lu-DTR may serve as a useful candidate ligand for theranostic agents in NET patients with a lower uptake of normal organs.