¹⁷⁷Lu Labeled Cyclic Minigastrin Analogues with Therapeutic Activity in CCK2R Expressing Tumors: Preclinical Evaluation of a Kit Formulation

Minigastrin (MG) analogues specifically target cholecystokinin-2 receptors (CCK2R) expressed in different tumors and enable targeted radiotherapy of advanced and disseminated disease when radiolabeled with a beta emitter such as ¹⁷⁷Lu. Especially truncated MG analogues missing the penta-Glu sequence are associated with low kidney retention and seem therefore most promising for therapeutic use. Based on [d-Glu¹,desGlu^2–6]­MG (MG11) we have designed the two cyclic MG analogues cyclo^1,9[γ-d-Glu¹,desGlu^2–6,d-Lys⁹]­MG (cyclo-MG1) and cyclo^1,9[γ-d-Glu¹,desGlu^2–6,d-Lys⁹,Nle¹¹]­MG (cyclo-MG2). In the present work we have developed and preclinically evaluated a pharmaceutical kit formulation for the labeling with ¹⁷⁷Lu of the two DOTA-conjugated cyclic MG analogues. The stability of the kits during storage as well as the stability of the radiolabeled peptides was investigated. A cell line stably transfected with human CCK2R and a control cell line without receptor expression were used for <i>in vitro</i> and <i>in vivo</i> studies with the radioligands prepared from kit formulations. In terms of stability ¹⁷⁷Lu-DOTA-cyclo-MG2 showed advantages over ¹⁷⁷Lu-DOTA-cyclo-MG1. Still, for both radioligands a high receptor-mediated cell uptake and favorable pharmacokinetic profile combining receptor-specific tumor uptake with low unspecific tissue uptake and low kidney retention were confirmed. Investigating the therapy efficacy and treatment toxicity in xenografted BALB/c nude mice a receptor-specific and comparable therapeutic effect could be demonstrated for both radioligands. A 1.7- to 2.6-fold increase in tumor volume doubling time was observed for receptor-positive tumors in treated versus untreated animals, which was 39–73% higher when compared to receptor-negative tumors. The treatment was connected with transient bone marrow toxicity and minor signs of kidney toxicity. All together the obtained results support further studies for the clinical translation of this new therapeutic approach

A 75-years old male with suspicion of insulinoma—^99mTc-GLP1scintigraphy.

<p>^99mTc-GLP1scintigraphy revealed the focus of insulinoma in the pancreas—patient was disqualified from surgical excision of the tumor due to severe heart failure. The study was performed with dual-head, large field of view E.CAM gamma camera with low-energy high resolution (LEHR) collimators and images were evaluated with CT examination imposed by software fusion. A. Fusion of GLP-1 receptor imaging and CT—axial slice, B. CT—axial slice.</p

Blood glucose level versus time after injection of Lys⁴⁰(Ahx-HYNIC-^99mTc/EDDA)NH₂]-exendin-4—the group of patients with MTC.

<p>Blood glucose level versus time after injection of Lys⁴⁰(Ahx-HYNIC-^99mTc/EDDA)NH₂]-exendin-4—the group of patients with MTC.</p

A 77-year old female—^99mTc-GLP1-SPECT/CT.

<p>^99mTc-GLP1-SPECT/CT (Single Photo Emission Computed Tomography/Computed Tomography) revealed bifocal insulinoma (one focus is well visible on the border of the pancreatic body and tail, T/nT (Target/non-target) ratio 3.4; the second one is smaller, less visible in the pancreatic tail, T/nT ratio 1.7). Lesions were not detected by other diagnostic methods. Histopathology confirmed two foci of insulinoma: 9 mm and 2 mm in diameter. A. GLP-1 receptor imaging—MIP (<i>Maximum Intensity Projection</i>), B. Fusion of GLP-1 receptor imaging and CT—axial slice, C. CT—axial slice.</p

Information about patients and examinations performed.

<p>Information about patients and examinations performed.</p