Development of the Tc-Labelled SST Antagonist TECANT-1 for a First-in-Man Multicentre Clinical Study.

Broad availability and cost-effectiveness of Mo/Tc generators worldwide support the use, and thus the development, of novel Tc-labelled radiopharmaceuticals. In recent years, preclinical and clinical developments for neuroendocrine neoplasms patient management focused on somatostatin receptor subtype 2 (SST) antagonists, mainly due to their superiority in SST-tumour targeting and improved diagnostic sensitivity over agonists. The goal of this work was to provide a reliable method for facile preparation of a Tc-labelled SST antagonist, [Tc]Tc-TECANT-1, in a hospital radiopharmacy setting, suitable for a multi-centre clinical trial.

Radiolabelled CCK R Antagonists Containing PEG Linkers: Design, Synthesis and Evaluation.

The cholecystokinin-2/gastrin receptor (CCK R) is considered a suitable target for the development of radiolabelled antagonists, due to its overexpression in various tumours, but no such compounds are available in clinical use. Therefore, we designed novel 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-conjugated ligands based on CCK R antagonist Z360/nastorazepide. As a proof of concept that CCK R antagonistic activity can be retained by extending the Z360/nastorazepide structure using suitable linker, we present herein three compounds containing various PEG linkers synthesised on solid phase and in solution.

Preclinical pharmacokinetics, biodistribution, radiation dosimetry and toxicity studies required for regulatory approval of a phase I clinical trial with (111)In-CP04 in medullary thyroid carcinoma patients.

Introduction: From a series of radiolabelled cholecystokinin (CCK) and gastrin analogues, (111)In-CP04 ((111)In-DOTA-(DGlu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2) was selected for further translation as a diagnostic radiopharmaceutical towards a first-in-man study in patients with medullary thyroid carcinoma (MTC). A freeze-dried kit formulation for multicentre application has been developed. We herein report on biosafety, in vivo stability, biodistribution and dosimetry aspects of (111)In-CP04 in animal models, essential for the regulatory approval of the clinical trial.

From preclinical development to clinical application: Kit formulation for radiolabelling the minigastrin analogue CP04 with In-111 for a first-in-human clinical trial.

Introduction: A variety of radiolabelled minigastrin analogues targeting the cholecystokinin 2 (CCK2) receptor were developed and compared in a concerted preclinical testing to select the most promising radiotracer for diagnosis and treatment of medullary thyroid carcinoma (MTC). DOTA-DGlu-DGlu-DGlu-DGlu-DGlu-DGlu-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2 (CP04) after labelling with (111)In displayed excellent characteristics, such as high stability, receptor affinity, specific and persistent tumour uptake and low kidney retention in animal models. Therefore, it was selected for further clinical evaluation within the ERA-NET project GRAN-T-MTC.

A novel, self-shielded modular radiosynthesis system for fully automated preparation of PET and therapeutic radiopharmaceuticals.

Objective: With the vast development of theranostics and, recently, (68)Ga-radiolabeled molecules, there is also a need for novel, smaller, flexible, safe, and efficient modular automated synthesis systems in different clinical settings. The aim of our study was to determine the shielding properties of the modular self-shielded automated radiosynthesis box and determine its suitability for routine preparation of different radiopharmaceuticals to be used for diagnosis and therapy.

Methods: To evaluate shielding properties, shielding factors were determined using two different radiation sources: (137)Cs and (68)Ga.

Stereochemistry of amino acid spacers determines the pharmacokinetics of (111)In-DOTA-minigastrin analogues for targeting the CCK2/gastrin receptor.

The metabolic instability and high kidney retention of minigastrin (MG) analogues hamper their suitability for use in peptide-receptor radionuclide therapy of CCK2/gastrin receptor-expressing tumors. High kidney retention has been related to N-terminal glutamic acids and can be substantially reduced by coinjection of polyglutamic acids or gelofusine. The aim of the present study was to investigate the influence of the stereochemistry of the N-terminal amino acid spacer on the enzymatic stability and pharmacokinetics of (111)In-DOTA-(d-Glu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2 ((111)In-PP11-D) and (111)In-DOTA-(l-Glu)6-Ala-Tyr-Gly-Trp-Met-Asp-Phe-NH2 ((111)In-PP11-L).

Influence of radiation source geometry on determination of (111)In and (90)Y activity of radiopharmaceuticals.

Objective: Yttrium-90 (Y)-labelled peptides such as DOTATOC and antibodies such as Zevalin are widely used in radionuclide therapy. Indium-111 (In) is used as a Y surrogate for imaging and dosimetry purposes. We aimed to investigate accuracy, geometry (vials and syringes) and volume dependencies for both radionuclides in several different radionuclide calibrators.