Elisa García-Garayoa

In vitro and in vivo evaluation of a 99mTc(I)-labeled bombesin analogue for imaging of gastrin releasing peptide receptor-positive tumors

A new radiolabeled bombesin analogue, [99mTc(I)-PADA-AVA]bombesin (7-14), was synthesized and in vitro and in vivo characterized. High affinity and rapid internalization were obtained in binding assays. A specific binding towards gastrin releasing peptide receptors-positive tissues, pancreas and tumor, was observed in CD-1 nu/nu mice bearing PC-3 prostate adenocarcinoma xenografts. We therefore conclude that [99mTc(I)-PADA-AVA]bombesin (7-14) might have promising characteristics for applications in nuclear medicine, namely for diagnosis of GRP receptor overexpressing tumors.

A click approach to structurally diverse conjugates containing a central di-1,2,3-triazole metal chelate.

Assemble & chelate: Click chemistry enables the efficient and selective synthesis of structurally diverse conjugates containing a central di‐1,2,3‐triazole chelator for complexation with [99mTc(CO)3]+. Use of appropriate building blocks allows the modulation of pharmacological relevant characteristics of the conjugate, or the introduction of secondary probes suitable for imaging modalities other than single photon emission computed tomography (SPECT).

Molecular Assembly of Multifunctional 99mTc Radiopharmaceuticals Using Clickable Amino Acid Derivatives

Synthetic strategies that enable the efficient and selective combination of different biologically active entities hold great promise for the development of multifunctional hybrid conjugates useful for biochemical and medical applications. Starting from side‐chain‐functionalized N(α)‐propargyl lysine derivatives, conjugates containing a 99mTc‐based imaging probe for SPECT and two different moieties (e.g., tumor‐targeting vectors, pharmacological modifiers, affinity tags, or second imaging probes) can be assembled using the CuI‐catalyzed alkyne–azide cycloaddition in efficient one‐pot protocols. This strategy was successfully applied to the preparation of a 99mTc‐labeled conjugate comprising a tumor‐targeting peptide sequence (bombesin(7–14)) and a low‐molecular‐weight albumin binder, a pharmacological modifier that prolongs the blood circulation time of the conjugate. Evaluation of the conjugate in vitro and in vivo provided promising results for its use as an imaging agent for the visualization of tumors positive for the gastrin‐releasing peptide receptor. The methodology presented herein provides an attractive synthetic tool for the preparation of multifunctional 99mTc‐based radiopharmaceuticals with significant potential for a multitude of applications.

Glycation Methods for Bombesin Analogs Containing the (NαHis)Ac chelator for 99mTc(CO)3 Radiolabeling

The overexpression of peptide receptors in a variety of human carcinomas has generated considerable interest in peptide‐based radiopharmaceuticals for peptide receptor imaging and peptide receptor radiotherapy. The gastrin‐releasing peptide receptor is overexpressed in human prostate‐, breast‐, colon‐ and small cell lung carcinoma cells. We have developed metabolically stable 99mTc‐radiolabeled bombesin ([Cha13, Nle14]BBS(7–14)) analogs, which bind with high affinity to the gastrin‐releasing peptide receptors. However, because of their lipophilicity, they showed unfavorable biodistribution with high hepatic accumulation and hepatobiliary excretion. We now report a study of different glycation methods for [Cha13, Nle14]BBS(7–14) analogs to improve their biodistribution profile. Whereas the glycation using the Maillard reaction was problematic, resulting in low yields, selective introduction of the glycomimetic shikimic acid to the side chain of a Lys residue was possible. A chemoselective ligation of α‐d‐glucose to an amino‐oxyacetylated [Cha13, Nle14]BBS(7–14) analog could be achieved, but was complicated by the co‐elution of starting peptide and glycopeptide. The best procedure consisted of the [1,3]‐cycloaddition of N3‐β‐d‐glucose to a propargylglycine‐containing [Cha13, Nle14]BBS(7–14) analog, using a catalytic amount of Cu(I)I. All glycated [Cha13, Nle14]BBS(7–14) analogs showed high affinity for the gastrin‐releasing peptide receptor and rapid accumulation into PC‐3 tumor cells.

Synthesis and Evaluation of Bombesin Analogues Conjugated to Two Different Triazolyl-Derived Chelators for 99mTc Labeling

Overexpression of the gastrin‐releasing peptide receptor (GRPR) in a variety of human carcinomas has provided a means of diagnosis and treatment. Previously we reported a metabolically stable (NαHis)Ac‐βAla‐βAla‐[Cha13,Nle14]BBS(7–14) analogue with high affinity for the GRPR. We have also shown that the biodistribution pattern of this fairly lipophilic, radiolabeled peptide can be enhanced by glycation, which is easily carried out by CuI‐catalyzed cycloaddition. Herein, we further elaborate this “click approach” in the synthesis of a new series of triazole‐based chelating systems as alternatives to the (NαHis)Ac chelator for labeling with the 99mTc(CO)3 core. The bombesin analogues, containing these new chelating systems, were evaluated with regard to their synthesis and in vitro and in vivo properties, and were compared with their (NαHis)Ac counterparts. The influence of the chelator on biodistribution properties was less than that of glycation, which clearly improved the tumor‐to‐background ratios.

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, Parkinsons 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.