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

Abstract

The cholecystokinin-2 receptor (CCK-2R) is overexpressed in several human cancers but displays limited expression in normal tissues. For this reason, it is a suitable target for developing specific radiotracers. In this study, a nastorazepide-based ligand functionalized with a 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) chelator (IP-001) was synthesized and labelled with indium-111. The radiolabeling process yielded >95% with a molar activity of 10 MBq/nmol and a radiochemical purity of >98%. Stability studies have shown a remarkable resistance to degradation (>93%) within 120 h of incubation in human blood. The in vitro uptake of [111In]In-IP-001 was assessed for up to 24 h on a high CCK-2R-expressing tumor cell line (A549) showing maximal accumulation after 4 h of incubation. Biodistribution and single photon emission tomography (SPECT)/CT imaging were evaluated on BALB/c nude mice bearing A549 xenograft tumors. Implanted tumors could be clearly visualized after only 4 h post injection (2.36 ± 0.26% ID/cc), although a high amount of radiotracer was also found in the liver, kidneys, and spleen (8.25 ± 2.21%, 6.99 ± 0.97%, and 3.88 ± 0.36% ID/cc, respectively). Clearance was slow by both hepatobiliary and renal excretion. Tumor retention persisted for up to 24 h, with the tumor to organs ratio increasing over-time and ending with a tumor uptake (1.52 ± 0.71% ID/cc) comparable to liver and kidneys.

Nonpeptidic Z360-Analogs Tagged with Trivalent Radiometals as Anti-CCK2R Cancer Theranostic Agents: A Preclinical Study

“…Although a hitherto restricted number of other Z360 analogs carrying the DOTA-chelator through different linkers was developed [ 55 ], animal data was only reported for [ 111 In]In-IP-001, but in a mice model different to ours [ 56 ]. Thus, an A549 non-small cell lung cancer xenograft was implanted in the shoulder of homozygous female BALB/c nude mice.…”

Update on Preclinical Development and Clinical Translation of Cholecystokinin-2 Receptor Targeting Radiopharmaceuticals

“…However, this was accompanied by a higher kidney retention, impairing the tumor-to-kidney ratios for both radioligands. Furthermore, DOTA-conjugated CCK2R antagonists for possible theranostic use have recently been developed [ 31 , 51 ]. Z-360 conjugated to DOTA through a combination of a tripeptide linker and PEG spacers of different length yielded derivatives with retained CCK2R affinity and antagonistic properties.…”

“…Z-360 conjugated to DOTA through a combination of a tripeptide linker and PEG spacers of different length yielded derivatives with retained CCK2R affinity and antagonistic properties. The DOTA-conjugates radiolabeled with indium-111, lutetium-177 and gallium-68 further showed improved hydrophilicity [ 31 , 51 , 52 ]. [ 111 In]In-IP-001, containing Z-360 conjugated to DOTA through a short alkyl chain followed by a PEGylated portion, has been evaluated in a human cell line with physiological CCK2R expression.…”

“…Small animal SPECT/CT imaging with [ 111 In]In-IP-001 resulted in overall high background activity, combined with low tumor uptake. However, specificity of the tumor uptake could not be confirmed in an additional blocking experiment [ 51 ].…”

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.…”