A stable neurotensin-based radiopharmaceutical for targeted imaging and therapy of neurotensin receptor-positive tumours

Purpose: Neurotensin (NT) and its high affinity receptor (NTR1) are involved in several neoplastic processes. Thus, NT-based radiopharmaceuticals are potential tracers for targeted diagnosis and therapy of NTR-positive tumours. A new analogue based on NT(8-13), NT-XIX, with the three enzymatic cleavage sites stabilised, was synthesised and tested. Methods: The synthesis was performed by Boc strategy. Labelling with 99mTc/188Re was performed using the tricarbonyl technique. Metabolic stability was tested in vitro and in vivo. NT-XIX was further characterised in vitro in HT-29 cells and in vivo in nude mice with HT-29 xenografts. Results: NT-XIX showed much longer half-lives than non-stabilised analogues. Binding to NTR1 was highly specific, although the affinity was lower than that of natural NT. Bound activity rapidly internalised into HT-29 cells and 50% remained trapped after 24h. In the time-course biodistribution, the highest uptake was found in the tumour at all p.i. times. In vivo uptake was specific, and accumulation of activity in the kidneys was low. Radioactivity clearance from healthy organs was faster than that from the tumour, resulting in improved tumour-to-tissue ratios and good SPECT/CT imaging. Treatment with 188Re-NT-XIX (30MBq, in three or four fractions) decreased tumour growth by 50% after 3weeks. Conclusion: The high in vivo stability and the favourable in vivo behaviour makes NT-XIX an excellent candidate for the imaging and therapy of NTR1-positive tumour

A stable neurotensin-based radiopharmaceutical for targeted imaging and therapy of neurotensin receptor-positive tumors

ISSN:1619-7070ISSN:1619-708

Evaluation of a Novel Tc-99m Labelled Vitamin B12 Derivative for Targeting Escherichia coli and Staphylococcus aureus In Vitro and in an Experimental Foreign-Body Infection Model

Purpose: Vitamin B12 (cyanocobalamin, Cbl) is accumulated by rapidly replicating prokaryotic and eukaryotic cells. We investigated the potential of a Tc-99m labelled Cbl derivative ([99mTc]PAMA(4)-Cbl) for targeting infections caused by Escherichia coli and Staphylococcus aureus. In vitro binding assays were followed by biodistribution studies in a mouse model of foreign body infection. Procedures: E. coli (ATCC 25922) and S. aureus (ATCC 43335) were used as test strains. [57Co]Cbl, [67Ga]citrate and [99mTc]DTPA served as reference compounds. The in vitro competitive binding of [57Co]Cbl or [99mTc]PAMA(4)-Cbl, and unlabeled Cbl, to viable or killed bacteria, was evaluated at 37 and 4 °C. A cage mouse model of infection was used for biodistribution of intravenous [57Co]Cbl and [99mTc]PAMA(4)-Cbl in cage and dissected tissues of infected and non-infected mice. Results: Maximum binding (mean ± SD) of [57Co]Cbl to viable E. coli was 81.7 ± 2.6 % and to S. aureus 34.0 ± 6.7 %, at 37 °C; no binding occurred to heat-killed bacteria. Binding to both test strains was displaced by 100- to 1000-fold excess of unlabeled Cbl. The in vitro binding of [99mTc]PAMA(4)-Cbl was 100-fold and 3-fold lower than the one of [57Co]Cbl for E. coli and S. aureus, respectively. In vivo, [99mTc]PAMA(4)-Cbl showed peak percentage of injected dose (% ID) values between 1.33 and 2.3, at 30 min post-injection (p.i.). Significantly higher retention occurred in cage fluids infected with S. aureus at 4 h and with E. coli at 8 h p.i. than in non-infected animals. Accumulation into infected cages was also higher than the one of [99mTc]DTPA, which showed similar biodistribution in infected and sterile mice. [57Co]Cbl gradually accumulated in cages with peaks % ID between 3.58 and 4.83 % achieved from 24 to 48 h. Discrimination for infection occurred only in E. coli-infected mice, at 72 h p.i. [67Ga]citrate, which showed a gradual accumulation into cage fluids during 12 h, was discriminative for infection from 48 to 72 h p.i. (P < 0.05). Conclusion: Cbl displayed rapid and specific in vitro binding to test strains. [99mTc]PAMA(4)-Cbl was rapidly cleared from most tissues and discriminated between sterile and infected cages, being a promising candidate for imaging infections in humans

Radiopharmaceuticals: From Molecular Imaging to Targeted Radionuclide Therapy

The research and development of smart radiodrugs is the goal of the Center of Radiopharmaceutical Science of ETH, PSI, and USZ. Positron Emission Tomography (PET) allows the non-invasive visualization of biochemical processes within the body. Radiolabeled PET-tracers allow the study of neurophysiological diseases like Alzheimer, Parkinson's disease or the imaging of metastatic tumors. PET-techniques are nowadays an important part of routine nuclear medicine diagnosis. Tumor-cell targeting biomolecules (e.g. antibodies or peptides) coupled to therapeutic radionuclides can sterilize the malignant cells while sparing healthy tissue. This so-called targeted radionuclide therapy has made tremendous progress in the recent years and the first approved radiotherapeutics are available for clinical use

Radiopharmaceuticals for Targeted Tumor Diagnosis and Therapy

Radiopharmaceutical research and development is carried out by the Center for Radiopharmaceutical Science as part of the PSI Life Science Department, the Department of Applied BioSciences at the Swiss Federal Institute of Technology Zürich and the University Hospital Zürich. The common theme is the search for radioactive-labeled tracer molecules, which bind to specific targets in the body. Such radiopharmaceuticals are applied either systemically into the blood stream or locally to patients. Due to their specific molecular binding properties combined with the emitted radiation, they can be used for non-invasive imaging of tumors and the destruction of tumor cells. In this first of two articles, we will present exemplified topics from the research activities of the groups involved with tumor targeting