[18F][natGa]rhTATE2.5

68 Ga- and 177 Lu-labeled theranostic companion tracers have become a mainstay in the clinical management of SST 2 overexpressing neuroendocrine tumors. Despite the excellent radionuclide characteristics of [ 18 F]fluorine for PET imaging, 18 F-labeled SST 2 -targeted tracers remain underrepresented. Novel radiohybrid SST 2 -tracers with DOTA as a bridging unit were designed, allowing radiolabeling with either 18 F or 68 Ga.

Seven DOTA-TATE derivatives (rhTATE1/2: N -SiFA lin - N , N -Me 2 -Gly- d -Dap/Lys( trans -DOTA-TATE)-OH and (rhTATE2.1-2.5: H-AA1-AA2-AA3- d -Dap( N -SiFA lin - N , N -Me 2 -Gly)- d -Lys( trans -DOTA-TATE)-OH) with different linkers and hydrophilic modifiers (AA1-AA3) were synthesized and compared to [ 18 F]SiTATE. Competitive binding studies (IC 50 ) were performed using hSST 2 -CHO cells and [ 125 I]TOC. Internalization was investigated using AR42J cells. Biodistribution and PET/CT studies were performed using AR42J xenograft bearing CD1 nu/nu mice. SST 2 specificity was confirmed in a blocking study (+/- co-injection of octreotide).

While the first-generation compounds showed good affinity (IC 50 : [ nat Ga]rhTATE1: 5.6 ± 1.4 n m , [ nat Ga]rhTATE2: 5.7 ± 0.2 n m ) but high lipophilicity (LogD pH=7.4 = -1.03 and − 1.19), the inclusion of hydrophilic modifiers ([ nat Ga]rhTATE2.1-[ nat Ga]rhTATE2.5) improved affinity (IC 50 : 2.6 to 3.7 n m ) and hydrophilicity (LogD pH=7.4 = -2.30 to -2.12). The compounds demonstrated efficient internalization (357% to 841% compared to [ 125 I]TOC), and variable human serum albumin affinity (84.8% to 98.8%). [ 18 F][ nat Ga]rhTATE2.2 showed the highest tumor accumulation (27.9 ± 4.8%iD/g), while [ 18 F][ nat Ga]rhTATE2.5 showed lower tumor uptake (18.6 ± 6.2%iD/g), but substantially lower background accumulation, providing improved tumor-to-organ ratios.

This study demonstrates a SST 2 -targeted radiohybrid concept using bifunctionalized DOTA as a bridging unit. N -terminal modifications with hydrophilic tripeptides improved the pharmacokinetic properties. [ 18 F][ nat Ga]rhTATE2.5 ( d -Glu- d -Glu- d -Glu) compares particularly well to [ 18 F]SiTATE regarding background clearance and tumor accumulation, with the additional advantage of radiohybrid radiolabeling.