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  • Title: Somatostatin receptor targeting with hydrophilic [99mTc/186Re]Tc/Re-tricarbonyl NODAGA and NOTA complexes.
    Author: Makris G, Kuchuk M, Gallazzi F, Jurisson SS, Smith CJ, Hennkens HM.
    Journal: Nucl Med Biol; 2019 Apr; 71():39-46. PubMed ID: 31129499.
    Abstract:
    INTRODUCTION: The aim of this work was to develop diagnostic (99mTc) and therapeutic (186Re) 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-sst2-ANT)] (M = 99mTc, 186Re), where L denotes NODAGA or NOTA and sst2-ANT denotes the potent SSTR2 antagonist 4-NO2-Phe-c(DCys-Tyr-DTrp-Lys-Thr-Cys)-DTyr-NH2. Moreover, we assessed the in vivo properties of the 99mTc-complexes in an animal SSTR-tumor model. METHODS: The [99mTc]/[186Re][Tc/Re(OH2)3(CO)3]+ precursors were utilized to prepare the 99mTc/186Re-complexes, which were identified by HPLC co-injection with their natRe 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 99mTc-tracers were performed in AR42J tumor-bearing female ICR SCID mice. RESULTS: The 99mTc-complexes were prepared in high radiochemical yield (RCY > 90%, by HPLC), with lower RCY (≤30%) obtained for 186Re-complexes. Tracers remained intact in vitro and displayed low non-specific binding (10-25%) to rat serum proteins. Biodistribution of [99mTc]Tc-NODAGA-sst2-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 [99mTc]Tc-NOTA-sst2-ANT. Moderate to low tumor retention was observed for both tracers after 4 and 24 h. Tumor uptake for [99mTc]Tc-NOTA-sst2-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 [99mTc]Tc-NOTA-sst2-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 [99mTc]Tc/[186Re]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.
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