In this work we utilized the integrated labeling approach for the design of novel radiometal-cyclized somatostatin receptor (SSTR) antagonists with potential applications in imaging (99mTc) or therapy (186Re) of neuroendocrine tumors (NETs). In particular, we report the synthesis and in vitro evaluation of 99mTc/186Re-cyclized peptides, employing the potent SSTR2 antagonist sequence X-4-NO2-Phe-DCys-Tyr-DTrp-Lys-Thr-Cys-DTyr-NH2, where X = Ac (peptide 1) or DOTA (peptide 2). The 99mTc-cyclized analogues were prepared by reacting 99mTc-glucoheptonate with 40 μΜ linear (SH) 1 or 2, promoting ligand exchange on the 99mTcO3+ core and affording 99mTc-1 and 99mTc-2 in quantitative radiochemical yields (RCY &gt;95%). The 186Re-1 analogue was synthesized by reacting 186ReOCl3(PPh3)2 with 130 μΜ linear 1 in moderate RCY (&gt;50%). Radiotracers consisted of isomeric products, two isomers for 99mTc/186Re-1 and three isomers for 99mTc-2. Comparative HPLC studies revealed similar elution patterns to the previously-characterized non-radioactive Re-1 and Re-2 analogues of known nanomolar SSTR affinity. Lipophilicity was measured via the “shake-flask” method (PBS/n-octanol) and logD7.4 values were 0.81 for 99mTc-1, 0.76 for 186Re-1 and -1.46 for 99mTc-2. In vitro stability studies were performed at 37 °C in PBS (pH 7.4), against 1 mM L-cysteine and in rat serum, and percent stability was determined with radioTLC and HPLC analyses. The 99mTc-tracers were sufficiently stable in vitro at 4 h in PBS (82% for 99mTc-1 and 99% for 99mTc-2), in L-cysteine (71% for 99mTc-1 and 65% for 99mTc-2) and in rat serum (77% for 99mTc-1 and 99% for 99mTc-2, with low non-specific protein binding of 18% for 99mTc-1 and 21% for 99mTc-2). The 186Re-1 tracer exhibited moderate in vitro stability (&gt;57% in PBS at 1 h); efforts are underway to prepare and evaluate the 186Re-2 tracer. These findings indicate that direct 99mTc/186Re-cyclization of SSTR-targeting peptide antagonists is feasible and may be further applied as an alternative approach (to the traditional use of bifunctional chelates) in the design of 99mTc/186Re-radiolabeled biomolecules for targeting SSTR-expressing NETs.

Synthesis and in vitro evaluation of 99mTc/186Re-cyclized somatostatin receptor-targeting peptides for the diagnosis/therapy of neuroendocrine tumors

255th National Meeting (2018)

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.