Radiochemical Synthesis and Evaluation of Novel Radioconjugates of Neurokinin 1 Receptor Antagonist Aprepitant Dedicated for NK1R-Positive Tumors

Abstract

Aprepitant, a lipophilic and small molecular representative of neurokinin 1 receptor antagonists, is known for its anti-proliferative activity on numerous cancer cell lines that are sensitive to Substance P mitogen action. In the presented research, we developed two novel structural modifications of aprepitant to create aprepitant conjugates with different radionuclide chelators. All of them were radiolabeled with 68Ga and 177Lu radionuclides and evaluated in terms of their lipophilicity and stability in human serum. Furthermore, fully stable conjugates were examined in molecular modelling with a human neurokinin 1 receptor structure and in a competitive radioligand binding assay using rat brain homogenates in comparison to the aprepitant molecule. This initial research is in the conceptual stage to give potential theranostic-like radiopharmaceutical pairs for the imaging and therapy of neurokinin 1 receptor-overexpressing cancers.

In Vivo, In Vitro and In Silico Studies of the Hybrid Compound AA3266, an Opioid Agonist/NK1R Antagonist with Selective Cytotoxicity

“…The opioid fragment extends towards the extracellular outlet of the receptor and the simulations suggest some mobility of this fragment, however an interaction between Tyr 1 amine and Glu193 is present for a great part of the collected trajectories. Notably, a polar interaction between Glu193 and small molecular ligand was also found in the experimental structure of aprepitant/NK1R complex [65] but SAR data suggest that it is not indispensable to high-affinity binding since the modification [73] or functionalization [74] of the interacting triazolinone ring results in relatively moderate affinity decreases. Moreover, E193A mutation has virtually no effect on aprepitant's affinity.…”

The Neurokinin-1 Receptor Antagonist Aprepitant: An Intelligent Bullet against Cancer?

“…The SP stimulus is crucial for the survival of tumor cells, and the overexpression of the NK-1R in cancer cells provides an excellent tool for its therapeutic use. Thus, due to this overexpression, NK-1R ligands (e.g., 213 Bi-DOTA-[Thi 8 ,Met(O2) 11 ] substance P and radioconjugates of aprepitant) have been developed and used in targeted radionuclide tumor therapy with promising results for selective irradiation to kill cancer cells [6,7,146]. DOTA-SP showed a lower uptake by normal cells than by tumor cells, and this has been related to the higher number of NK-1Rs expressed in the latter cells.…”

“…Moreover, the antitumor action of aprepitant/fosaprepitant has been confirmed (both compounds decreased the volume of the tumor) in experimental mouse models (MG-63 human-osteosarcoma and HuH6 human-hepatoblastoma xenografts). Finally, several studies have been reported on the use of aprepitant (in combination with radiotherapy) in a patient suffering from lung cancer [5] or in nuclear medicine for the diagnostic/treatment of tumors expressing the NK-1R [6,7]. Both therapeutic strategies have shown promising results.…”

“…In this line, a recent review has focused on the biological and chemical aspects of peptide and non-peptide NK-1R ligands (e.g., aprepitant) as radiopharmaceuticals and on the application of these compounds in targeted radionuclide cancer therapy [6]. Moreover, another recent study has been focused on the synthesis and evaluation of new radioconjugates of aprepitant [7]. Both studies have shown the potential use of aprepitant in nuclear medicine for the diagnosis/treatment of NK-1R-positive tumors.…”

Physicochemical and Biological Study of 99mTc and 68Ga Radiolabelled Ciprofloxacin and Evaluation of [99mTc]Tc-CIP as Potential Diagnostic Radiopharmaceutical for Diabetic Foot Syndrome Imaging

“…There is only one article on CIP labelled with Ga-68 in the literature [21], where the authors used either a macrocyclic DOTA (p-SCN-Bz-DOTA) or NOTA (p-SCN-Bz-NOTA) chelator, additionally attached to CIP via a propylamine (PA) linker. In our study, based on our own experience [22] and in order to avoid introducing into the radiopreparation molecule additional chemical fragments containing thiourea bonds [23], we used a DOTA-NHS chelator. The role of CIP in these radiopreparations is to act as a biologically active molecule (vector), which targets the radiopharmaceutical directly to the infected area with high specificity, allowing its precise visualisation by SPECT or PET.…”