Synthesis and evaluation of a Tc tricarbonyl-labeled somatostatin receptor-targeting antagonist peptide for imaging of neuroendocrine tumors.

Introduction: A somatostatin receptor (SSTR)-targeting antagonist peptide (sst-ANT) was radiolabeled with Tc tricarbonyl via a tridentate [N,S,N]-type ligand (L) to develop a radiodiagnostic agent, TcL-sst-ANT, for imaging of SSTR-expressing neuroendocrine tumors.

Methods: Receptor affinity was assessed in vitro with the nonradioactive analogue, ReL-sst-ANT, via a challenge experiment in AR42J cells with I-SS-14 as the competing radioligand. Preparation of TcL-sst-ANT was achieved via reaction of [Tc(CO)(HO)] with L-sst-ANT. To test the stability of the radiolabeled complex, challenge experiments were performed in phosphate-buffered saline solutions containing cysteine or histidine and also in mouse serum. Biodistribution and micro-SPECT/CT imaging studies were performed in AR42J tumor-bearing female ICR SCID mice.

Results: The half maximal inhibitory concentration (IC value) of ReL-sst-ANT in AR42J cells was 15nM. Preparation of TcL-sst-ANT was achieved with ≥97% radiochemical yield (RCY) and was verified by HPLC co-elution with the ReL-sst-ANT analogue. The radiolabeled complex remained intact for up to 24h in high concentration solutions of cysteine and histidine at 37°C. Furthermore, the radiotracer was 90% stable for 1h at 37°C in mouse serum. Micro-SPECT/CT images showed clear uptake in tumors and were supported by the biodistribution data, in which the 3.2% ID/g tumor uptake at 4h was significantly blocked by co-administration of nonradioactive SS-14.

Conclusions: A [Tc(CO)(N,S,N)] chelate was employed for radiolabeling of an SSTR-targeting antagonist peptide. Synthesis of TcL-sst-ANT was achieved in high RCY, and the resulting complex displayed high in vitro stability. Somatostatin receptor affinity was retained in both cells and in tumor-bearing mice, where the complex successfully targeted SSTR-positive tumors via a receptor-mediated process. Advances in Knowledge and Implications for Patient Care. This first Tc-tricarbonyl-labeled SSTR antagonist peptide showed promising in vivo tumor targeting in mice. Future studies may lead to translation of a similar design into the clinic.