Publications (100)346.7 Total impact
- [Show abstract] [Hide abstract] ABSTRACT: Peptide receptor radionuclide therapy (PRRT) is commonly performed in the treatment of neuroendocrine tumours (NET), where somatostatin analogs (DOTATATE) are radiolabeled with 90Y, 68Ga or 111In for pre-therapeutic and therapeutic purposes. Quantitative evaluation of the biokinetic data can be performed by using physiologically based pharmacokinetic (PBPK) models. Knowledge about the biodistribution in a pre-clinical setting would allow optimizing the translation from bench to bedside. The aim of this study was to develop a PBPK model to describe the biodistribution of a novel sst2-targeting radiotracer.
- [Show abstract] [Hide abstract] ABSTRACT: Unorthodox 18F-labeling strategies not employing the formation of a carbon-18F bond are seldom found in radiochemistry. Historically the formation of a boron- or silicon-18F bond has been introduced very early on into the repertoire of labeling chemistries but is without translation into any clinical radiotracer besides inorganic B[18F]F4- for brain tumor diagnosis. For many decades these labeling methodologies have been forgotten and have just recently been revived by a handful of researchers thinking outside the box. When breaking with established paradigms such as the inability to obtain labeled compounds of high specific activity via isotopic exchange or performing radiofluorination in aqueous media, the research community often reacts skeptically. In 2005 and 2006 two novel labeling methodologies were introduced into radiochemistry for positron emission tomography (PET) tracer development: RBF3- labeling reported by Perrin et al. and the SiFA methodology by Schirrmacher, Jurkschat and Waengler et al. which is based on isotopic exchange (IE). Both labeling methodologies have been complemented by other non-canonical strategies to introduce 18F into biomolecules of diagnostic importance, thus profoundly enriching the landscape of 18F radiolabeling. B and Si based labeling strategies finally revealed that IE is a viable alternative to established and traditional radiochemistry with the advantage of simplifying both the labeling effort as well as the necessary purification of the radiotracer. Hence IE will be the focus of this contribution in favor over other non-canonical labeling methods. Peptides for tumor imaging especially lend themselves favorably towards one-step labeling via IE but small molecules have been described as well taking advantage of these new approaches and have been used successfully for brain imaging. This review gives an account on both radiochemistries centered on boron and silicon, describing the very beginnings of their basic research, the path that led to optimization of their chemistries and the first encouraging pre-clinical results paving the way to their clinical use. This side by side approach will give the reader the opportunity to follow the development of a new basic discovery into a clinically applicable radiotracer including all the hurdles that have had to be overcome.
- [Show abstract] [Hide abstract] ABSTRACT: The Silicon-Fluoride-Acceptor (SiFA)-18F-labeling strategy has been shown before to enable the straightforward and efficient 18F-labeling of complex biologically active substances such as proteins and peptides. Especially in case of peptides, the radiolabeling proceeds kit-like in short reaction times and without need of complex product workup. SiFA-derivatized, 18F-labeled Tyr3-octreotate (TATE) derivatives demonstrated before strong somatostatin receptor (SSTR) binding, favorable in vivo pharmacokinetics as well as an excellent tumor visualization by PET imaging. In this study, we intended to determine the influence of the underlying molecular design and used molecular scaffolds of SiFAlin-TATE derivatives on SSTR binding as well as on the in vivo pharmacokinetics of the resulting 18F-labeled peptides. For this purpose, new SiFAlin-(Asp)n-PEG1-TATE analogs (where n = 1 - 4) were synthesized, efficiently radiolabeled with 18F in a kit-like manner and obtained in radiochemical yields of 70 - 80%, radiochemical purities of ≥97% and non-optimized specific activities of 20.1 - 45.2 GBq/µmol within 20-25 minutes starting from 0.7 - 1.5 GBq of 18F. In the following, the radiotracer's lipophilicities and stabilities in human serum were determined. Furthermore, the SSTR-specific binding affinities were evaluated by a competitive displacement assay on SSTR-positive AR42J cells. The obtained in vitro results support the assumption that aspartic acids are able to considerably increase the radiotracer's hydrophilicity and that their number does not affect the SSTR binding potential of the TATE derivatives. The most promising tracer 18F-SiFAlin-Asp3-PEG1-TATE [18F]6 (LogD = -1.23 ± 0.03, IC50 = 20.7 ± 2.5 nM) was further evaluated in vivo in AR42J tumor-bearing nude mice via PET/CT imaging against the clinical gold standard 68Ga-DOTATATE as well as the earlier developed SiFAlin-TATE derivative [18F]3. The results of these evaluations showed that [18F]6 - although showing very similar chemical and in vitro properties to [18F]3 - exhibits a slowed renal clearance compared to [18F]3 but also a higher absolute tumor uptake compared to 68Ga-DOTATATE and furthermore enables an excellent tumor visualization with high image resolution. These results emphasize the importance to systematically study the influence of molecular design and applied structure elements of peptidic radiotracers as these may considerably influence in vivo pharmacokinetics while not affecting other parameters such as radiochemistry, lipophilicity, serum stability or receptor binding potential.
- [Show abstract] [Hide abstract] ABSTRACT: Peptidic radiotracers are highly potent substances for the specific in vivo imaging of various biological targets with Single Photon Emission Computed Tomography and Positron Emission Tomography. However, some radiolabeled peptides such as bombesin analogs were shown to exhibit only a limited stability, hampering a successful target visualization. One option to positively influence the stability of radiolabeled peptides is the introduction of certain artificial molecular scaffolds. In order to comparatively assess the influence of different structure elements on the stability of radiolabeled peptides and to identify those structure elements being most useful for peptide radiotracer stabilization, several monomeric and dimeric bombesin derivatives were synthesized, exhibiting differing molecular designs and the chelator NODAGA for (68) Ga-labeling. The radiolabeled peptides were evaluated regarding their in vitro stability in human serum to determine the influence of the introduced molecular scaffolds on the peptides' serum stabilities. The results of the evaluations showed that the introduction of scaffold structures and the overall molecular design have a substantial impact on the stabilities of the resulting peptidic radiotracers. But besides some general trends found using certain scaffold structures, the obtained results point to the necessity to empirically assess their influence on stability for each susceptible peptidic radiotracer individually. Copyright © 2015 John Wiley & Sons, Ltd.
- [Show abstract] [Hide abstract] ABSTRACT: As the gastrin releasing peptide receptor (GRPR) is overexpressed on several tumor types, it represents a promising target for the specific in vivo imaging of these tumors using positron emission tomography (PET). We were able to show that PESIN-based peptide multimers can result in substantially higher GRPR avidities, highly advantageous in vivo pharmacokinetics and tumor imaging properties compared to the respective monomers. However, the minimal distance between the peptidic binders, resulting in the lowest possible system entropy while enabling a concomitant GRPR binding and thus optimized receptor avidities, has not been determined so far. Thus, we aimed here to identify the minimal distance between two GRPR-binding peptides in order to provide the basis for the development of highly avid GRPR-specific PET imaging agents. We therefore synthesized dimers of the GRPR-binding bombesin analogue BBN(7-14) on a dendritic scaffold, exhibiting different distances between both peptide binders. The homodimers were further modified with the chelator NODAGA, radiolabeled with (68)Ga, and evaluated in vitro regarding their GRPR avidity. We found that the most potent of the newly developed radioligands exhibits GRPR avidity twice as high as the most potent reference compound known so far, and that a minimal distance of 62 bond lengths between both peptidic binders within the homodimer can result in concomitant peptide binding and optimal GRPR avidities. These findings answer the question as to what molecular design should be chosen when aiming at the development of highly avid homobivalent peptidic ligands addressing the GRPR.
- [Show abstract] [Hide abstract] ABSTRACT: An efficient method to prepare the 18F-labeled tetrazine-derivative 18F-SiFA-OTz for bioorthogonal radiochemistry was developed. 18F-SiFA-OTz can be synthesized with a radiochemical yield of 78 ± 5 % within 25 min and can quantitatively react with a model strained dienophile, trans-cyclooctenol.
- [Show abstract] [Hide abstract] ABSTRACT: Hintergrund Gastrointestinale Stromatumoren (GIST) sind die häufigste mesenchymale Neoplasie des Gastrointestinaltraktes. Sie unterscheiden sich hinsichtlich Tumorbiologie, Behandlungsstrategie und insbesondere Indikationsstellung zum chirurgischen Vorgehen in wesentlichen Aspekten von gastrointestinalen Karzinomen. Jeder an der Behandlung von GIST beteiligte Chirurg sollte mit diesen Aspekten vertraut sein. Ziel der Arbeit In dieser Arbeit wird der Stellenwert der Positronenemissionstomographie (PET) in der chirurgischen Behandlung von Patienten mit GIST diskutiert und ein Ausblick auf die Entwicklung von auf GIST maßgeschneiderten molekularen Tracern gegeben. Ergebnisse In verschiedenen klinischen Szenarien ist die PET eine wertvolle Hilfe für die Therapieplanung und insbesondere chirurgische Indikationsstellung in der multimodalen Behandlung von GIST. Hervorzuheben sind das Primärstaging, das Monitoring unter neoadjuvanter Therapie sowie das Staging und die Verlaufskontrolle in der metastasierten Situation. Der routinemäßig eingesetzte Tracer ist 18F-FDG, der zuverlässig den Metabolismus von GIST-Läsionen abbildet. Verglichen mit Computertomographie/Magnetresonanztomographie erlaubt das 18F-FDG-PET häufig eine frühere und genauere Responsebeurteilung. GIST-spezifische molekulare Tracer, die eine direkte Prognose zum Therapieansprechen und frühzeitige Informationen zur Resistenzentwicklung liefern könnten, befinden sich in der präklinischen Entwicklung. Hier sind aber noch pharmakokinetische und immunologische Hürden zu überwinden. Fernziel ist die Entwicklung von „theranostics“, also Substanzen, die zugleich diagnostische und therapeutische Zwecke erfüllen. Diskussion In der multimodalen Therapie von GIST und der Indikationsstellung zum chirurgischen Vorgehen hat die PET einen festen Stellenwert.
- [Show abstract] [Hide abstract] ABSTRACT: For (64) Cu radiolabeling of biomolecules to be used as in vivo positron emission tomography (PET) imaging agents, various chelators are commonly applied. It has not yet been determined which of the most potent chelators-NODA-GA ((1,4,7-triazacyclononane-4,7-diyl)diacetic acid-1-glutaric acid), CB-TE2A (2,2'-(1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4,11-diyl)diacetic acid), or CB-TE1A-GA (1,4,8,11-tetraazabicyclo[6.6.2]hexadecane-4,11-diyl-8-acetic acid-1-glutaric acid)-forms the most stable complexes resulting in PET images of highest quality. We determined the (64) Cu complex stabilities for these three chelators by a combination of complex challenge and an in vivo approach. For this purpose, bioconjugates of the chelating agents with the gastrin-releasing peptide receptor (GRPR)-affine peptide PESIN and an integrin αv β3 -affine c(RGDfC) tetramer were synthesized and radiolabeled with (64) Cu in excellent yields and specific activities. The (64) Cu-labeled biomolecules were evaluated for their complex stabilities in vitro by conducting a challenge experiment with the respective other chelators as challengers. The in vivo stabilities of the complexes were also determined, showing the highest stability for the (64) Cu-CB-TE1A-GA complex in both experimental setups. Therefore, CB-TE1A-GA is the most appropriate chelating agent for *Cu-labeled radiotracers and in vivo imaging applications. © 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.
- [Show abstract] [Hide abstract] ABSTRACT: Radiolabeled peptides for tumor imaging with positron emission tomography (PET) that can be produced with kits are currently in the spot light of radiopharmacy as well as nuclear medicine. The diagnosis of neuroendocrine tumors in particular has been a prime example for the usefulness of peptides labeled with a variety of different radionuclides. Among those, (68)Ga and (18)F stand out because of the ease of radionuclide introduction (e.g. (68)Ga isotope) or optimal nuclide properties for PET imaging (slightly favoring (18)F isotope). In vivo properties of GMP-compliant, newly developed kit-like producible (18)F-SiFA- and (18)F-SiFAlin- (SiFA = silicon-fluoride acceptor) modified TATE derivatives were compared to the current clinical gold standard (68)Ga-DOTATATE for high quality imaging of somatostatin receptor-bearing tumors. SiFA- and SiFAlin-derivatized somatostatin analogs were synthesized and radiolabeled using cartridge-based dried (18)F and purified via a C18 cartridge (RCY 49.8 ± 5.9% within 20-25 min) without HPLC purification. Tracer lipophilicity and stability in human serum were tested in vitro. Competitive receptor binding affinity studies were performed using AR42J cells. The most promising tracers were evaluated in vivo in an AR42J xenograft mouse model by ex vivo biodistribution as well as in vivo PET/CT imaging studies for evaluation of their pharmacokinetic profiles and the results were compared to those of the current clinical gold standard (68)Ga-DOTATATE. Synthetically easily accessible (18)F-labeled silicon-fluoride acceptor modified somatostatin analogs were developed. They exhibited high binding affinities to somatostatin receptor-positive tumor cells (1.88-14.82 nM). The most potent compound demonstrated comparable pharmacokinetics and an even slightly higher absolute tumor accumulation level in ex vivo biodistribution studies as well as higher tumor SUVs in PET/CT imaging than (68)Ga-DOTATATE in vivo. The radioactivity uptake in non tumor tissue was higher than for (68)Ga-DOTATATE. The introduction of the novel SiFA building block SiFAlin as well as of hydrophilic auxiliaries enables a favorable in vivo biodistribution profile of the modified TATE peptides, resulting in high tumor-to-background ratios however still lower than those observed with (68)Ga-DOTATATE. Moreover, the SiFA-methodology enables a kit-like labeling procedure for (18)F-labeled peptides advantageous for routine clinical application. Copyright © 2015 by the Society of Nuclear Medicine and Molecular Imaging, Inc.
- [Show abstract] [Hide abstract] ABSTRACT: Modern imaging techniques that can provide functional information on tumor vascularization, metabolic activity, or cellularity have seen significant improvements over the past decade. However, most of these techniques are currently not broadly utilized neither in clinical trials nor in clinical routine, although there is a large agreement on the fact that conventional approaches for therapy response assessment such as Response Evaluation Criteria in Solid Tumors or World Health Organization criteria-that exclusively focus on the change in tumor size-are of less value for response assessment in modern thoracic oncology. The aim of this article comprises two parts: a short review of the most promising state-of-the-art imaging techniques that have the potential to play a larger role in thoracic oncology within the near future followed by a meeting report including recommendations of an interdisciplinary expert panel that discussed the potential of the different techniques during the Dresden 2013 Post World Congress of Lung Cancer (WCLC) - International Association for the Study of Lung Cancer (IASLC) meeting. It is intended to provide a comprehensive summary about ongoing trends and future perspectives on functional imaging in thoracic oncology.
Conference Paper: Receptor Binding studies of 68Ga-labelled Peptides on GIST tumour cells[Show abstract] [Hide abstract] ABSTRACT: Introduction: Gastrointestinal stromal tumour (GIST) is a rare disease and frequently affects young patients, which often results in a short life expectancy of less than 3 years once diagnosed. The MITIGATE project aims to develop new approaches to diagnose and treat patients with metastatic GIST resistant to the Tyrosin Kinase Inhibitor (TK) treatment. Within this project we investigated binding of various 68Ga-labelled peptides, targeting receptors reported to be overexpressed in GIST, in different cell lines. Methods: 3 GIST cell lines were established: T1, 882 (Imatinib sensitive) and 430 (Imatinib resistant). Different DOTA-derivatized peptides were included: DOTA-NT 8-13 (targeting NTR1), DOTA-TATE (targeting SSTR2), CP04 (Targeting CCK2), VIP-DOTA (targeting VPAC1/2) and 2 DOTA-Bombesin derivatives (targeting GRP1). The peptide conjugates were radiolabelled with 68Ga under standardized conditions and characterized by HPLC. 68Ga-peptides were incubated with the respective tumour cell lines in 6-well plates including control by blocking with 1µM excess peptide and membrane bound activity (by Glycine buffer acid wash). The internalized activity was measured after the different incubation times. Additional controls included binding assays in receptor expressing control cells (AR42J, PC-3, HT-29) Results: Very low or no specific binding to GIST tumour cells was found for all 68Ga-DOTA labelled peptides except, for Bombesin derivatives indicating no or very low expression of respective receptors. For 68Ga-labelled Bombesin a pronounced specific binding to all GIST cell lines was found, for the agonist (DOTA-AMBA) a high percentage of internalized activity, whereas for an antagonist specific binding was mainly associated with membrane bound activity (with up to >80% bound/mg protein). Binding of DOTA-Bombesin was in the following order T1<430~882. Conclusion: Our results in the tumour cells indicate that radiolabelled Bombesin analogs may be a good candidate for targeting TK-resistant GIST for molecular imaging but also for potential radionuclide therapy approaches. The difference in binding found between TK resistant and TK sensitive tumour still cells needs to be verified. Characterisation of the tumour cells by FACS is currently ongoing and in vivo studies in GIST bearing tumour models are planned. This work is part of MITIGATE, co-funded by EU FP7 Programme, grant agreement no 602306
- [Show abstract] [Hide abstract] ABSTRACT: Background: Over the recent years, radiopharmaceutical chemistry has experienced a wide variety of innovative pushes towards finding both novel and unconventional radiochemical methods to introduce fluorine-18 into radiotracers for positron emission tomography (PET). These "nonclassical" labeling methodologies based on silicon-, boron-, and aluminium-(18)F chemistry deviate from commonplace bonding of an [(18)F]fluorine atom ((18)F) to either an aliphatic or aromatic carbon atom. One method in particular, the silicon-fluoride-acceptor isotopic exchange (SiFA-IE) approach, invalidates a dogma in radiochemistry that has been widely accepted for many years: the inability to obtain radiopharmaceuticals of high specific activity (SA) via simple IE. Methodology: The most advantageous feature of IE labeling in general is that labeling precursor and labeled radiotracer are chemically identical, eliminating the need to separate the radiotracer from its precursor. SiFA-IE chemistry proceeds in dipolar aprotic solvents at room temperature and below, entirely avoiding the formation of radioactive side products during the IE. Scope of review: A great plethora of different SiFA species have been reported in the literature ranging from small prosthetic groups and other compounds of low molecular weight to labeled peptides and most recently affibody molecules. Conclusions: The literature over the last years (from 2006 to 2014) shows unambiguously that SiFA-IE and other silicon-based fluoride acceptor strategies relying on (18)F(-) leaving group substitutions have the potential to become a valuable addition to radiochemistry.
- [Show abstract] [Hide abstract] ABSTRACT: Purpose: The aim of this study is to non-invasively assess early, irradiation-induced normal tissue alterations via metabolic imaging with 3'-deoxy-3'-[(18) F]fluorothymidine ([(18) F]FLT). Procedures: Twenty-nine male C57BL/6 mice were investigated by [(18) F]FLT positron emission tomography for 7 days after total body irradiation (1, 4, and 8 Gy) versus 'sham' irradiation (0 Gy). Target/background ratios were determined. The imaging results were validated by histology and immunohistochemistry (Thymidine kinase 1, Ki-67). Results: [(18) F]FLT demonstrated a dose-dependent intestinal accumulation post irradiation. Mean target/background ratio (±standard error) 0 Gy: 1.4 (0.2), 1 Gy: 1.7 (0.1), 4 Gy: 3.1 (0.3), 8 Gy: 4.2 (0.6). Receiver operating characteristic analysis (area under the curve, p value): 0 vs. 1 Gy: 0.81, 0.049; 0 vs. 4 Gy: 1.0, 0.0016; and 0 vs. 8 Gy: 1.0, 0.0020. Immunohistochemistry confirmed the results. Conclusions: [(18) F]FLT seems to provide dose-dependent information on radiation-induced proliferation in the bowel. This opens the perspective for monitoring therapy-related side-effects as well as assessing, e.g., radiation accident victims.
- [Show abstract] [Hide abstract] ABSTRACT: Dendritic structures, being highly homogeneous and symmetric, represent ideal scaffolds for the multimerization of bioactive molecules and thus enable the synthesis of compounds of high valency which are e.g., applicable in radiolabeled form as multivalent radiotracers for in vivo imaging. As the commonly applied solution phase synthesis of dendritic scaffolds is cumbersome and time-consuming, a synthesis strategy was developed that allows for the efficient assembly of acid amide bond-based highly modular dendrons on solid support via standard Fmoc solid phase peptide synthesis protocols. The obtained dendritic structures comprised up to 16 maleimide functionalities and were derivatized on solid support with the chelating agent DOTA. The functionalized dendrons furthermore could be efficiently reacted with structurally variable model thiol-bearing bioactive molecules via click chemistry and finally radiolabeled with 68Ga. Thus, this solid phase-assisted dendron synthesis approach enables the fast and straightforward assembly of bioactive multivalent constructs for example applicable as radiotracers for in vivo imaging with Positron Emission Tomography (PET).
- [Show abstract] [Hide abstract] ABSTRACT: For many years, the main application of [18F]F-DOPA has been the PET imaging of neuropsychiatric diseases, movement disorders, and brain malignancies. Recent findings however point to very favorable results of this tracer for the imaging of other malignant diseases such as neuroendocrine tumors, pheochromocytoma, and pancreatic adenocarcinoma expanding its application spectrum. With the application of this tracer in neuroendocrine tumor imaging, improved radiosyntheses have been developed. Among these, the no-carrier-added nucleophilic introduction of fluorine-18, especially, has gained increasing attention as it gives [18F]F-DOPA in higher specific activities and shorter reaction times by less intricate synthesis protocols. The nucleophilic syntheses which were developed recently are able to provide [18F]F-DOPA by automated syntheses in very high specific activities, radiochemical yields, and enantiomeric purities. This review summarizes the developments in the field of [18F]F-DOPA syntheses using electrophilic synthesis pathways as well as recent developments of nucleophilic syntheses of [18F]F-DOPA and compares the different synthesis strategies regarding the accessibility and applicability of the products for human in vivo PET tumor imaging.
- [Show abstract] [Hide abstract] ABSTRACT: Gastrointestinal stromal tumor (GIST) is the most common mesenchymal neoplasm of the digestive tract. The GIST differ substantially from gastrointestinal carcinomas regarding tumor biology, treatment strategies and indications for surgery. Every surgeon involved in the treatment of GIST should be acquainted with these aspects. The aims of this article are to discuss the value of positron emission tomography (PET) in the surgical treatment of patients with GIST and to provide an outlook on the development of molecular tracers specifically tailored for GIST. PET is an invaluable decision aid in the multimodal therapy of GIST and particularly for deciding on surgical indications. Specific scenarios in which PET is used are primary staging monitoring during neoadjuvant therapy and staging and response assessment in the metastatic setting. The routinely used tracer is 18F-fluorodeoxyglucose (18F-FDG) and uptake reliably correlates with the metabolism of GIST lesions. Compared to computed tomography and magnetic resonance imaging (CT/MRI), 18F-FDG-PET often allows a more timely and accurate response assessment. GIST-specific molecular tracers, which could provide a direct prognosis regarding response and development of resistance to treatment, are currently in preclinical development. However, pharmacokinetic and immunological issues still need to be resolved. A distant aim is the development of "theranostics", i.e. substances which serve both diagnostic and therapeutic purposes. PET has an established value in the multimodal treatment of GIST and is particularly useful for deciding on surgical indications.
- [Show abstract] [Hide abstract] ABSTRACT: Water soluble 3nm maleimide-terminated PEGylated gold nanoparticles (maleimide-AuNP) were synthesized in both partially hydrolyzed and non-hydrolyzed forms. Both of these maleimide-AuNPs, when reacted with the silicon-fluorine prosthetic group [18F]SiFA-SH, resulted in radiolabelled AuNPs. These NPs were readily purified with high radiochemical yields (RCY) of 60-80% via size exclusion chromatography. Preliminary small animal positron emission tomography (PET) in healthy rats gave information about the pathway of excretion and the stability of the radioactive label in vivo. The partially hydrolyzed [18F]SiFA-maleimide-AuNPs showed uptake in the brain region of interest (ROI) (> 0.13 % ID/g) which was confirmed by ex vivo examination of the thoroughly perfused rat brain. The multiple maleimide end groups on the AuNP surface also allowed for the simultaneous incorporation of [18F]SiFA-SH and a bioactive peptide (cysteine-modified octreotate, cys-TATE, which can bind to somatostatin receptor subtypes 2 and 5) in a proof of concept study. The well-defined Michael addition reaction between various thiol containing molecules and the multi-functionalized maleimide-AuNPs thus offers an opportunity to develop a new bio-conjugation platform for new diagnostics as well as therapeutics.
- [Show abstract] [Hide abstract] ABSTRACT: To determine if the conjugation of a small receptor ligand to a peptidic carrier potentially facilitating the transport across the BBB by "Molecular Trojan Horse" transcytosis is feasible, we synthesized several transport peptide-fallypride-fusion molecules as model systems and determined their binding affinities to the hD2 receptor. Although being affected by conjugation, the binding affinities were found to be still in the nM range (between 1.5nM and 64.2nM). In addition, a homology modeling of the receptor and docking studies for the most potent compounds were performed elucidating the binding modes of the fusion molecules and the structure elements contributing to the observed high receptor binding. Furthermore, no interaction of the hybrid compounds and P-gp, the main excretory transporter of the BBB, were found. From these results it can be inferred that the approach to deliver small neuroreceptor ligands across the BBB by transport peptide carriers is feasible.
Universität MannheimMannheim, Baden-Württemberg, Germany
Heidelburg, Baden-Württemberg, Germany
- • Institute of Clinical Radiology
- • Faculty of Medicine Mannheim and Clinic Mannheim
German Cancer Research CenterHeidelburg, Baden-Württemberg, Germany
Technische Universität MünchenMünchen, Bavaria, Germany
Ludwig-Maximilians-University of Munich
München, Bavaria, Germany
- Department of Nuclear Medicine
Johannes Gutenberg-Universität Mainz
Mayence, Rheinland-Pfalz, Germany
- • Klinik und Poliklinik für Nuklearmedizin
- • Institute for Nuclear Chemistry