In vivo Evaluation of ¹⁸F-SiFAlin modified TATE: A Potential Challenge for ⁶⁸Ga- DOTATATE, the Clinical Gold Standard for Somatostatin Receptor Imaging with Positron Emission Tomography (PET)

Abstract

Radiolabeled peptides for tumor imaging with positron emission tomography (PET) that can be produced with kits are currently in the spot light of radiopharmacy as well as nuclear medicine. The diagnosis of neuroendocrine tumors in particular has been a prime example for the usefulness of peptides labeled with a variety of different radionuclides. Among those, ⁶⁸Ga and ¹⁸F stand out because of the ease of radionuclide introduction (e.g. ⁶⁸Ga isotope) or optimal nuclide properties for PET imaging (slightly favoring ¹⁸F isotope). In vivo properties of GMP-compliant, newly developed kit-like producible ¹⁸F-SiFA- and ¹⁸F-SiFAlin- (SiFA = silicon-fluoride acceptor) modified TATE derivatives were compared to the current clinical gold standard ⁶⁸Ga-DOTATATE for high quality imaging of somatostatin receptor-bearing tumors. Methods: SiFA- and SiFAlin-derivatized somatostatin analogs were synthesized and radiolabeled using cartridge-based dried ¹⁸F and purified via a C18 cartridge (RCY 49.8 ± 5.9% within 20-25 min) without HPLC purification. Tracer lipophilicity and stability in human serum were tested in vitro. Competitive receptor binding affinity studies were performed using AR42J cells. The most promising tracers were evaluated in vivo in an AR42J xenograft mouse model by ex vivo biodistribution as well as in vivo PET/CT imaging studies for evaluation of their pharmacokinetic profiles and the results were compared to those of the current clinical gold standard ⁶⁸Ga-DOTATATE. Results: Synthetically easily accessible ¹⁸F-labeled silicon-fluoride acceptor modified somatostatin analogs were developed. They exhibited high binding affinities to somatostatin receptor-positive tumor cells (1.88-14.82 nM). The most potent compound demonstrated comparable pharmacokinetics and an even slightly higher absolute tumor accumulation level in ex vivo biodistribution studies as well as higher tumor SUVs in PET/CT imaging than ⁶⁸Ga-DOTATATE in vivo. The radioactivity uptake in non tumor tissue was higher than for ⁶⁸Ga-DOTATATE. Conclusion: The introduction of the novel SiFA building block SiFAlin as well as of hydrophilic auxiliaries enables a favorable in vivo biodistribution profile of the modified TATE peptides, resulting in high tumor-to-background ratios however still lower than those observed with ⁶⁸Ga-DOTATATE. Moreover, the SiFA-methodology enables a kit-like labeling procedure for ¹⁸F-labeled peptides advantageous for routine clinical application.