[^99mTc]Tc-DGA1, a Promising CCK₂R-Antagonist-Based Tracer for Tumor Diagnosis with Single-Photon Emission Computed Tomography

Abstract

Radiolabeled gastrin analogues have been proposed for theranostics of cholecystokinin subtype 2 receptor (CCK 2 R)-positive cancer. Peptide radioligands based on other receptor antagonists have displayed superior pharmacokinetics and higher biosafety than agonists. Here, we present DGA1, a derivative of the nonpeptidic CCK 2 R antagonist Z-360 carrying an acyclic tetraamine, for [ 99m Tc]Tc labeling. Preclinical comparison of [ 99m Tc]Tc-DGA1 with [ 99m Tc]Tc-DG2 (CCK 2 R-agonist reference) was conducted in HEK293-CCK 2 R/CCK 2i4sv R cells and mice models, qualifying [ 99m Tc]Tc-DGA1 for further study in patients with CCK 2 R-positive tumors and singlephoton emission computed tomography/CT.

Preliminary Study of a 1,5-Benzodiazepine-Derivative Labelled with Indium-111 for CCK-2 Receptor Targeting

“…However, issues regarding in vivo stability, receptors affinity, and high kidney retention have hindered this approach so far. An alternative and less explored pathway is the labelling of small molecules such as 1,5-benzodiazepine derivatives, although, to the best of our knowledge, this has only been pursued with the diagnostic radionuclide technetium-99 and, despite promising preliminary results, only minor efforts have been devoted to this approach [ 16 , 17 ].…”

“…We acknowledge the fact that our results are only partially comparable to other studies reported thus far, but we would like to emphasize that non-transfected tumor cells represent a closer model to the real physio-pathological condition than transfected cancer cell lines. With this in mind, we ascertained that [ 111 In]In-IP-001 cell uptake in vitro was two-fold lower than what reported previously in AR4-2J rat pancreatic tumor cells for indium-111-labelled minigastrin derivatives [ 24 ] and four-fold lower than the total amount of technectium-99m nastorazepide-based derivatives accumulated by CCK-2R-transfected HEK293 cells [ 17 ].…”

“…The lungs, pancreas, and intestines exhibited a more rapid wash-out with tumor/organ ratios of 2.02, 5.85, and 2.76, respectively ( Figure 4 ). The slow kinetics of radiotracers based on the nastorazepide core was already reported, although a significantly more promising biodistribution was obtained in mice bearing tumors derived from transfected HEK293 cells [ 16 , 17 ], in which kidneys were the only organ with a comparable uptake with respect to the tumor at delayed times. As reported in Table 1 , the addition of a PEGylated spacer and a strongly hydrophilic chelator like DOTA to the hydrophobic Z-360 core imparted a quite hydrophilic nature to IP-001.…”

“…The usefulness of Z-360 as directing moiety for the preparation of radiopharmaceutical has already been demonstrated in the literature. For example, a series of nastorazepide-based derivatives have been synthesized and tethered to a N 3 S- or N 4 -system bifunctional chelator through different spacers [ 16 , 17 ]. The introduction of these chelators provided a suitable moiety for technetium-99m (t 1/2 = 6 h; E γ = 140 keV) complexation, while appropriate spacers were introduced to optimize affinity and water solubility for CCK-2R.…”

Benzodiazepines: Drugs with Chemical Skeletons Suitable for the Preparation of Metallacycles with Potential Pharmacological Activity

“…As mentioned above, BZDs are important drugs that are widely used in the treatment of a series of neurological pathologies. However, these drugs and derivatives have also demonstrated potential pharmacological activity and can act, for instance, against cancer [ 52 ], allergy [ 53 ], bacterial [ 54 ], fungal infections [ 55 ], and also as targeting agents for the cholecystokinin 2 receptor (CCK2R), which is overexpressed in some people [ 56 , 57 ]. Although reviews have been published on the different pharmacological activities of benzodiazepine-based compounds and their mechanism of action [ 4 , 5 ], studies in the field of drug discovery based on their metallo-derivatives are scarce.…”