Selection of the First 99mTc-Labelled Somatostatin Receptor Subtype 2 Antagonist for Clinical Translation—Preclinical Assessment of Two Optimized Candidates

Abstract

Recently, radiolabelled antagonists targeting somatostatin receptors subtype 2 (SST2) in neuroendocrine neoplasms demonstrated certain superior properties over agonists. Within the ERA-PerMED project “TECANT” two 99mTc-Tetramine (N4)-derivatized SST2 antagonists (TECANT-1 and TECANT-2) were studied for the selection of the best candidate for clinical translation. Receptor-affinity, internalization and dissociation studies were performed in human embryonic kidney-293 (HEK293) cells transfected with the human SST2 (HEK-SST2). Log D, protein binding and stability in human serum were assessed. Biodistribution and SPECT/CT studies were carried out in nude mice bearing HEK-SST2 xenografts, together with dosimetric estimations from mouse-to-man. [99mTc]Tc-TECANT-1 showed higher hydrophilicity and lower protein binding than [99mTc]-TECANT-2, while stability was comparable. Both radiotracers revealed similar binding affinity, while [99mTc]Tc-TECANT-1 had higher cellular uptake (>50%, at 2 h/37 °C) and lower dissociation rate (<30%, at 2 h/37 °C). In vivo, [99mTc]Tc-TECANT-1 showed lower blood values, kidney and muscles uptake, whereas tumour uptake was comparable to [99mTc]Tc-TECANT-2. SPECT/CT imaging confirmed the biodistribution results, providing the best tumour-to-background image contrast for [99mTc]Tc-TECANT-1 at 4 h post-injection (p.i.). The estimated radiation dose amounted to approximately 6 µSv/MBq for both radiotracers. This preclinical study provided the basis of selection of [99mTc]Tc-TECANT-1 for clinical translation of the first 99mTc-based SST2 antagonist.

Synthesis and preclinical evaluation of novel 99mTc-labeled PSMA ligands for radioguided surgery of prostate cancer

“…To retain high affinity, while ensuring low lipophilicity of the new tracers, a less lipophilic SiOH-moiety (formally a hydrolyzed SiFA) was preferred. For complexation of technetium-99m a tetraamine (N4) chelator was chosen, as this chelating system exhibits excellent in vivo stability and confers high hydrophilicity to peptidic radioligands [ 29 , 30 ]. A further advantage over N 3 S-based chelating systems such as mercaptoacetyltriserine is the absence of chemically reactive thiol-groups which might limit the shelf-live of radioligand precursors, an oftentimes neglected aspect in early radioligand development.…”

Radiolabeled Somatostatin Analogs—A Continuously Evolving Class of Radiopharmaceuticals

“…Nevertheless, the alternative chelating system 6-carboxy-1,4,8,11-tetraazaundecane (N4) seems to be better suited to 99m Tc-based SST 2 antagonists. In fact, 99m Tc-labeled LM3 via N4 ([ 99m Tc]Tc-TECANT-1) has been selected as the first 99m Tc-based antagonist for clinical translation [ 48 ] under the ERAPerMED project “TECANT” (Ref No. ERAPERMED2018-125).…”

Effect of Peptide Length on <em>in Vitro</em> and <em>in Vivo</em> Properties of ¹⁷⁷Lu-labeled Peptide Analogs Targeting CCK2R

“…For this purpose, the % IA/g determined in mice was extrapolated to humans using the following equation: % IA per organ in humans = ([%IA/g in mice × mass of mice (kg)] × mass of human organ (g))/(total body mass (kg)). Time scaling was additionally applied to account for the faster kinetics in mice versus humans using the following equation: time in humans = time in mice × [mass of human (kg)/mass of mice] 1/4 [25]. The uptake values in mice were decay corrected for the adopted time points.…”