Tc/Re-NODAGA/NOTA-peptides for SSTR targeting

Abstract Introduction The aim of this work was to develop diagnostic ( 99m Tc) and therapeutic ( 186 Re) agents for targeting somatostatin receptor (SSTR)-positive neuroendocrine tumors (NETs). In this regard, we evaluated in vitro complexes of the general formula [M(CO) 3 (L-sst 2 -ANT)] (M =  99m Tc, 186 Re), where L denotes NODAGA or NOTA and sst 2 -ANT denotes the potent SSTR2 antagonist 4-NO 2 -Phe-c(DCys-Tyr-DTrp-Lys-Thr-Cys)-DTyr-NH 2 . Moreover, we assessed the in vivo properties of the 99m Tc-complexes in an animal SSTR-tumor model. Methods The [ 99m Tc]/[ 186 Re][Tc/Re(OH 2 ) 3 (CO) 3 ] + precursors were utilized to prepare the 99m Tc/ 186 Re-complexes, which were identified by HPLC co-injection with their nat Re analogues. The tracers were challenged in vitro at 37 °C against cysteine and histidine in phosphate-buffered saline (pH 7.4) and in rat serum. Biodistribution and micro-SPECT/CT imaging studies of the 99m Tc-tracers were performed in AR42J tumor-bearing female ICR SCID mice. Results The 99m Tc-complexes were prepared in high radiochemical yield (RCY > 90%, by HPLC), with lower RCY (≤30%) obtained for 186 Re-complexes. Tracers remained intact in vitro and displayed low non-specific binding (10–25%) to rat serum proteins. Biodistribution of [ 99m Tc]Tc-NODAGA-sst 2 -ANT revealed low tumor uptake (2.78 ± 0.27 %ID/g) at 1 h, while high tumor uptake (16.70 ± 3.32 %ID/g) was found for [ 99m Tc]Tc-NOTA-sst 2 -ANT. Moderate to low tumor retention was observed for both tracers after 4 and 24 h. Tumor uptake for [ 99m Tc]Tc-NOTA-sst 2 -ANT was receptor-mediated, as demonstrated by parallel SSTR blocking studies. Rapid renal clearance was observed for both tracers, and SPECT/CT images clearly delineated the tumors, in agreement with the biodistribution data. Conclusions The [ 99m Tc]Tc-NOTA-sst 2 -ANT complex demonstrated high tumor uptake and rapid clearance in a SSTR-tumor mouse model, showing potential for further development. Advances in knowledge and implications for patient care Preclinical data support the feasibility of the [ 99m Tc]Tc/[ 186 Re]Re-NOTA/NODAGA labeling strategy for use in the development of theranostic radiopharmaceuticals for translation into the human clinic for targeting of SSTR-expressing NETs.