Abstract
[99mTc]Tc-HYNIC-TOC is the most widely used 99mTc-labeled somatostatin receptor (SST) agonist for the SPECT imaging of SST-expressing tumors, such as neuroendocrine tumors. Recently, radiolabeled SST antagonists have shown improved diagnostic efficacy over agonists. 99mTc-labeled SST antagonists are lacking in clinical practice. Surprisingly, when [99mTc]Tc-HYNIC was conjugated to the SST2 antagonist SS01, SST2 imaging was not feasible. This was not the case when [99mTc]Tc-N4 was conjugated to SS01. Here, we assessed the introduction of different spacers (X: β-Ala, Ahx, Aun and PEG4) among HYNIC and SS01 with the aim of restoring the affinity of HYNIC conjugates. In addition, we used the alternative antagonist JR11 for determining the suitability of HYNIC with 99mTc-labeled SST2 antagonists. We performed a head-to-head comparison of the N4 conjugates of SS01 and JR11. [99mTc]Tc-HYNIC-TOC was used as a reference, and HEK-SST2 cells were used for in vitro and in vivo evaluation. EDDA was used as a co-ligand for all [99mTc]Tc-HYNIC conjugates. The introduction of Ahx restored, to a great extent, the SST2-mediated cellular uptake of the [99mTc]Tc-HYNIC-X conjugates (X: spacer), albeit lower than the corresponding [99mTc]Tc-N4-conjugates. SPECT/CT images showed that all 99mTc-labeled conjugates accumulated in the tumor and kidneys with [99mTc]Tc-HYNIC-PEG4-SS01, [99mTc]Tc-N4-SS01 and [99mTc]Tc-N4-JR11 having notably higher kidney uptake. Biodistribution studies showed similar or better tumor-to-non-tumor ratios for the [99mTc]Tc-HYNIC-Ahx conjugates, compared to the [99mTc]Tc-N4 counterparts. The [99mTc]Tc-HYNIC-Ahx conjugates of SS01 and JR11 were comparable to [99mTc]Tc-HYNIC-TOC as imaging agents. HYNIC is a suitable chelator for the development of 99mTc-labeled SST2 antagonists when a spacer of appropriate length, such as Ahx, is used.
Highlights
We aimed to investigate whether: 1) the affinity of the HYNIC conjugate [99m Tc]Tc-HYNIC/EDDA-SS01 can be restored by incorporating spacers of different lengths and hydrophilicity, as we were aware that SST2 antagonists are extremely sensitive on the N-terminus modifications, often with unexpected outcomes [2]
All conjugates were synthesized with a maximum yield of 30–40% by following an Fmoc-based solid phase peptide synthesis
JR11 was coupled to HYNIC and HYNIC-Ahx (Figure 1)
Summary
Radiolabeled peptide analogs of somatostatin are used for diagnosis and for treatment of neuroendocrine tumors (NETs), given the high expression of somatostatin receptors (SST), especially of subtype 2 (SST2), on the surface of NET cells. The impact of PET imaging with 68 Ga-labeled SST agonists, such as DOTA-[Tyr3 ]-octreotide and DOTA[Tyr3 ,Thr8 ]-octreotide (DOTA-TOC and DOTA-TATE, respectively, where DOTA is the chelator 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), on the management of NET patients has been verified [1]. Preclinical [2,3] and clinical data [4,5] showed that SST antagonists can provide improved diagnostic efficacy over agonists
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