Publications by authors named "Frank Rösch"

107 Publications

AAZTA-squaramide ester competing with DOTA-, DTPA- and CHX-A-DTPA-analogues: Promising tool for Lu-labeling of monoclonal antibodies under mild conditions.

Nucl Med Biol 2021 Mar 26;96-97:80-93. Epub 2021 Mar 26.

Department of Chemistry - TRIGA site, Johannes Gutenberg University, Mainz, Germany. Electronic address:

Background: Combining the advantages of both cyclic and acyclic chelator systems, AAZTA (1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)]amino-6-methylperhydro-1,4-diazepine) is well suited for complexation of various diagnostic and therapeutic radiometals such as gallium-68, scandium-44 and lutetium-177 under mild conditions. Due to its specificity for primary amines and pH dependent binding properties, squaric acid (SA) represents an excellent tool for selective coupling of the appropriate chelator to different target vectors. Therefore, the aim of this study was to evaluate radiolabeling properties of the novel bifunctional AAZTA-SA being coupled to a model antibody (bevacizumab) in comparison to DOTA-SA, DTPA-p-Bn-SA and CHX-A″-DTPA-p-Bn-SA using the therapeutic nuclide lutetium-177.

Methods And Results: As proof-of-concept, bevacizumab was first functionalized with AAZTA-SA, DOTA-SA, DTPA-p-Bn-SA or CHX-A″-DTPA-p-Bn-SA. After purification via fractionated size exclusion chromatography (SEC), the corresponding immunoconjugates were subsequently radiolabeled with lutetium-177 at pH 7 and room temperature (RT) as well as 37 °C. After 90 min, labeling of AAZTA-SA-mAb resulted in almost quantitative radiochemical yields (RCY) of >98% and >99%, respectively. Formation of [Lu]Lu-DTPA-p-Bn-SA-mAb indicated rapid labeling kinetics reaching similar yields at RT already after 30 min. Fast but incomplete radiolabeling of the CHX-A″-analogue could be observed with a yield of 74% after 10 min and no further significant increase. In contrast, Lu-labeling of DOTA-SA-mAb showed negligible radiochemical yields of <2% both at room temperature and 37 °C. In vitro complex stability measurements of [Lu]Lu-AAZTA-SA-mAb at 37 °C indicated >94% protein bound activity in human serum and >92% in phosphate buffered saline (PBS), respectively within 15 days. [Lu]Lu-DTPA-p-Bn-SA-mAb and [Lu]Lu-CHX-A″-DTPA-p-Bn-SA-mAb revealed similar to even slightly higher in vitro stability in both media.

Conclusion: Coupling of AAZTA-SA to the monoclonal antibody bevacizumab allowed for Lu-labeling with almost quantitative radiochemical yields both at room temperature and 37 °C. Within 15 days, the resulting radioconjugate indicated very high in vitro complex stability both in human serum and PBS. Therefore, AAZTA-SA is a promising tool for Lu-labeling of sensitive biomolecules such as antibodies for theranostic applications.
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http://dx.doi.org/10.1016/j.nucmedbio.2021.03.007DOI Listing
March 2021

Impact of prompt gamma emission of Sc on quantification in preclinical and clinical PET systems.

Appl Radiat Isot 2021 Apr 21;170:109599. Epub 2021 Jan 21.

Dep. of Nuclear Medicine, Saarland University, Homburg, Germany.

Sc is an increasingly investigated positron emitter for use in positron emission tomography (PET) imaging. However, Sc is a non-pure positron emitter, since prompt photons are co-emitted during the decay process. This study investigates coincidence energy spectra of Sc and its impact on PET quantification on a preclinical and clinical PET system in comparison with F. The raw data of the coincidence events revealed characteristic differences comparing the photon energy distribution of Sc and F. Due to prompt gamma emission of Sc, activity recovery is underestimated on PET systems. However, clinical PET imaging of Sc with acceptable quantitative accuracy appears feasible by using a single, constant correction factor.
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http://dx.doi.org/10.1016/j.apradiso.2021.109599DOI Listing
April 2021

[18F]PR04.MZ PET/CT Imaging for Evaluation of Nigrostriatal Neuron Integrity in Patients With Parkinson Disease.

Clin Nucl Med 2021 Feb;46(2):119-124

Institute of Nuclear Chemistry, Johannes Gutenberg-University, Mainz, Germany.

Introduction: Degeneration of dopaminergic, nigrostriatal neurons is the hallmark of Parkinson disease (PD), and PET quantification of dopamine transporters is a widely accepted method for differential diagnosis between idiopathic PD and essential tremor. [18F]PR04.MZ is a new PET tracer with excellent imaging properties allowing for precise quantification of striatal and extrastriatal dopamine transporter. Here we describe our initial experience with [18F]PR04.MZ PET/CT in a larger cohort of healthy controls and PD patients as a proof-of-concept study for this tracer.

Methods: Eighteen healthy subjects, 19 early PD patients (Hoehn-Yahr I-II), and 13 moderate-advanced PD patients (Hoehn-Yahr III-IV) underwent static PET/CT scans 60 to 90 minutes after injection of 5.16 ± 1.03 mCi (191 ± 38 MBq) [18F]PR04.MZ. Specific binding ratios (SBRs) were calculated for caudate nucleus, anterior putamen, posterior putamen, substantia nigra (SNpc), compared between different groups and correlated with clinical ratings.

Results: [18F]PR04.MZ showed very high and specific uptake in the putamen, caudate, and substantia nigra pars compacta and very low nonspecific binding in other brain regions, and SBR values for the control group were 22.3 ± 4.1, 19.1 ± 3.5, and 5.4 ± 1.2, respectively. A reduction of SBR values was observed in all regions and in both initial and moderate PD, ranging from 35% to 89% (P < 0.001). The observed pattern of reduction was posterior putamen > anterior putamen > substantia nigra pars compacta > caudate, with contralateral posterior putamen being the most affected region. Rostrocaudal depletion gradient was evident in all PD patients and progression correlated with motor manifestations.

Conclusions: [18F]PR04.MZ PET/CT is a highly sensitive imaging modality for the detection of dopaminergic deficit in nigrostriatal pathways in PD.
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http://dx.doi.org/10.1097/RLU.0000000000003430DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7774816PMC
February 2021

Effect of the versatile bifunctional chelator AAZTA on the radiometal labelling properties and the in vitro performance of a gastrin releasing peptide receptor antagonist.

EJNMMI Radiopharm Chem 2020 Nov 30;5(1):29. Epub 2020 Nov 30.

Department of Nuclear Medicine, Inselspital, Bern University Hospital, Freiburgstr. 18, 3010, Bern, Switzerland.

Background: Gastrin Releasing Peptide receptor (GRPr)-based radioligands have shown great promise for diagnostic imaging of GRPr-positive cancers, such as prostate and breast. The present study aims at developing and evaluating a versatile GRPr-based probe for both PET/SPECT imaging as well as intraoperative and therapeutic applications. The influence of the versatile chelator AAZTA on the radiometal labelling properties and the in vitro performance of the generated radiotracers were thoroughly investigated. The GRPr-based antagonist D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH was functionalized with the chelator 6-[Bis (carboxymethyl)amino]-1,4-bis (carboyxmethyl)-6-methyl-1,4-diazepane (AAZTA) through the spacer 4-amino-1-carboxymethyl-piperidine (Pip) to obtain AAZTA-Pip-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH (LF1). LF1 was radiolabelled with gallium-68 (PET), indium-111 (SPECT, intraoperative applications) and lutetium-177 (therapy, SPECT). In vitro evaluation included stability studies, determination of lipophilicity, protein-binding studies, determination of K and B as well as internalization studies using the epithelial human prostate cancer cell line PC3. In vitro monotherapy as well as combination therapy studies were further performed to assess its applicability as a theranostic compound.

Results: LF1 was labelled with gallium-68, indium-111 and lutetium-177 within 5 min at room temperature (RT). The apparent molar activities (A) were ranging between 50 and 60 GBq/μmol for the Ga-labelled LF1, 10-20 GBq/μmol for the In- and Lu-labelled LF1. The radiotracers were stable for a period of 4 h post labeling exhibiting a hydrophilic profile with an average of a LogD of - 3, while the bound activity to the human serum protein was approximately 10%. Ga-LF1, Lu-LF1 and In-LF1 exhibited high affinity for the PC3 cells, with K values of 16.3 ± 2.4 nM, 10.3 ± 2.73 nM and 5.2 ± 1.9 nM, respectively, and the required concentration of the radiotracers to saturate the receptors (B) was between 0.5 and 0.8 nM which corresponds to approximately 4 × 10 receptors per cell. Low specific internalization rate was found in cell culture, while the total specific cell surface bound uptake always exceeded the internalized activity. In vitro therapy studies showed that inhibition of PC3 cells growth is somewhat more efficient when combination of Lu-labelled LF1 with rapamycin is applied compared to Lu-laballed LF1 alone.

Conclusion: Encouraged by these promising in vitro data, preclinical evaluation of the LF1 precursor are planned in tumour models in vivo.
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http://dx.doi.org/10.1186/s41181-020-00115-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7704979PMC
November 2020

Ga-Labelled Tropane Analogues for the Visualization of the Dopaminergic System.

ChemMedChem 2021 Mar 10;16(5):804-808. Epub 2020 Dec 10.

Institute of Nuclear Chemistry, Johannes Gutenberg-University Mainz, Fritz-Strassmann-Weg 2, 55128, Mainz, Germany.

The development of radiometal-labelled pharmaceuticals for neuroimaging could offer great potential due to easier handling during labelling and availability through radionuclide generator systems. Nonetheless, to date, no such tracers are available for positron emission tomography, primarily owing to the challenge of crossing the blood-brain barrier (BBB) and loss of affinity through chelator attachment. We have prepared a variety of Ga-labelled phenyltropanes showing that, through a simple hydrocarbon-linker, it is possible to introduce a chelator onto the lead structure while maintaining its high affinity for hDAT (human dopamine transporter) and simultaneously achieving adequate lipophilicity. One of the candidates, [ Ga]Ga-HBED-hexadiyne-tropane, showed an IC value of 66 nM, together with a log D of 0.96. A μPET study in a hemi-parkinsonian rat model showed a fast wash-out of the tracer, and no specific uptake in the brain, thus implying an inability to penetrate the BBB.
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http://dx.doi.org/10.1002/cmdc.202000820DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7984292PMC
March 2021

Ga, Sc and Lu-labeled AAZTA-PSMA-617: synthesis, radiolabeling, stability and cell binding compared to DOTA-PSMA-617 analogues.

EJNMMI Radiopharm Chem 2020 Nov 26;5(1):28. Epub 2020 Nov 26.

Johannes Gutenberg-University Mainz, Department of Chemistry/ TRIGA, Fritz-Strassmann-Weg 2, 55128, Mainz, Germany.

Background: The AAZTA chelator and in particular its bifunctional derivative AAZTA was recently investigated to demonstrate unique capabilities to complex diagnostic and therapeutic trivalent radiometals under mild conditions. This study presents a comparison of Ga, Sc and Lu-labeled AAZTA-PSMA-617 with DOTA-PSMA-617 analogues. We evaluated the radiolabeling characteristics, in vitro stability of the radiolabeled compounds and evaluated their binding affinity and internalization behavior on LNCaP tumor cells in direct comparison to the radiolabeled DOTA-conjugated PSMA-617 analogs.

Results: AAZTA was synthesized in a five-step synthesis and coupled to the PSMA-617 backbone on solid phase. Radiochemical evaluation of AAZTA-PSMA-617 with Ga, Sc and Lu achieved quantitative radiolabeling of > 99% after less than 5 min at room temperature. Stabilities against human serum, PBS buffer and EDTA and DTPA solutions were analyzed. While there was a small degradation of the Ga complex over 2 h in human serum, PBS and EDTA/DTPA, the Sc and Lu complexes were stable at 2 h and remained stable over 8 h and 1 day. For all three compounds, i.e. [Ga]Ga-AAZTA-PSMA-617, [Sc]Sc-AAZTA-PSMA-617 and [Lu]Lu-AAZTA-PSMA-617, in vitro studies on PSMA-positive LNCaP cells were performed in direct comparison to radiolabeled DOTA-PSMA-617 yielding the corresponding inhibition constants (K). K values were in the range of 8-31 nM values which correspond with those of [Ga]Ga-DOTA-PSMA-617, [Sc]Sc-DOTA-PSMA-617 and [Lu]Lu-DOTA-PSMA-617, i.e. 5-7 nM, respectively. Internalization studies demonstrated cellular membrane to internalization ratios for the radiolabeled Ga, Sc and Lu-AAZTA5-PSMA-617 tracers (13-20%IA/10 cells) in the same range as the ones of the three radiolabeled DOTA-PSMA-617 tracers (17-20%IA/10 cells) in the same assay.

Conclusions: The AAZTA-PSMA-617 structure proved fast and quantitative radiolabeling with all three radiometal complexes at room temperature, excellent stability with Sc, very high stability with Lu and medium stability with Ga in human serum, PBS and EDTA/DTPA solutions. All three AAZTA-PSMA-617 tracers showed binding affinities and internalization ratios in LNCaP cells comparable with that of radiolabeled DOTA-PSMA-617 analogues. Therefore, the exchange of the chelator DOTA with AAZTA within the PSMA-617 binding motif has no negative influence on in vitro LNCaP cell binding characteristics. In combination with the faster and milder radiolabeling features, AAZTA-PSMA-617 thus demonstrates promising potential for in vivo application for theranostics of prostate cancer.
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http://dx.doi.org/10.1186/s41181-020-00107-8DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7691401PMC
November 2020

On the consensus nomenclature rules for radiopharmaceutical chemistry - Reconsideration of radiochemical conversion.

Nucl Med Biol 2021 02 18;93:19-21. Epub 2020 Nov 18.

Department of Chemistry, Hunter College of the City University of New York, New York, NY, USA; Department of Radiology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.

Radiochemical conversion is an important term to be included in the "Consensus nomenclature rules for radiopharmaceutical chemistry". Radiochemical conversion should be used to define reaction efficiency by measuring the transformation of components in a crude reaction mixture at a given time, whereas radiochemical yield is better suited to define the efficiency of an entire reaction process including, for example, separation, isolation, filtration, and formulation.
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http://dx.doi.org/10.1016/j.nucmedbio.2020.11.003DOI Listing
February 2021

[Ga]Ga-THP-Pam: A Bisphosphonate PET Tracer with Facile Radiolabeling and Broad Calcium Mineral Affinity.

Bioconjug Chem 2020 Aug 27. Epub 2020 Aug 27.

School of Biomedical Engineering & Imaging Sciences, King's College London, St Thomas' Hospital, London SE1 7EH, U.K.

Calcium minerals such as hydroxyapatite (HAp) can be detected noninvasively using nuclear imaging agents such as [F]NaF (available from cyclotrons), for positron emission tomography (PET) and Tc-radiolabeled bisphosphonates (BP; available from Tc generators for single photon emission computed tomography (SPECT) or scintigraphy). These two types of imaging agents allow detection of bone metastases (based on the presence of HAp) and vascular calcification lesions (that contain HAp and other calcium minerals). With the aim of developing a cyclotron-independent PET radiotracer for these lesions, with broad calcium mineral affinity and simple one-step radiolabeling, we developed [Ga]Ga-THP-Pam. Radiolabeling with Ga is achieved using a mild single-step kit (5 min, room temperature, pH 7) to high radiochemical yield and purity (>95%). NMR studies demonstrate that Ga binds via the THP chelator, leaving the BP free to bind to its biological target. [Ga]Ga-THP-Pam shows high stability in human serum. The calcium mineral binding of [Ga]Ga-THP-Pam was compared to two other Ga-BPs which have been successfully evaluated in humans, [Ga]Ga-NO2AP and [Ga]Ga-BPAMD, as well as [F]NaF. Interestingly, we found that all Ga-BPs have a high affinity for a broad range of calcium minerals implicated in vascular calcification disease, while [F]NaF is selective for HAp. Using healthy young mice as a model of metabolically active growing calcium mineral , we compared the pharmacokinetics and biodistribution of [Ga]Ga-THP-Pam with [F]NaF as well as [Ga]NO2AP. These studies revealed that [Ga]Ga-THP-Pam has high affinity for bone tissue (high bone/muscle and bone/blood ratios) and fast blood clearance ( < 10 min) comparable to both [Ga]NO2AP and [F]NaF. Overall, [Ga]Ga-THP-Pam shows high potential for clinical translation as a cyclotron-independent calcium mineral PET radiotracer, with simple and efficient radiochemistry that can be easily implemented in any radiopharmacy.
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http://dx.doi.org/10.1021/acs.bioconjchem.0c00401DOI Listing
August 2020

Targeting fibroblast activation protein (FAP): next generation PET radiotracers using squaramide coupled bifunctional DOTA and DATA chelators.

EJNMMI Radiopharm Chem 2020 Jul 29;5(1):19. Epub 2020 Jul 29.

Department of Chemistry - TRIGA Site, Johannes Gutenberg University Mainz, 55128, Mainz, Germany.

Background: Fibroblast activation protein (FAP) is a proline selective serine protease that is overexpressed in tumor stroma and in lesions of many other diseases that are characterized by tissue remodeling. In 2014, a most potent FAP-inhibitor (referred to as UAMC1110) with low nanomolar FAP-affinity and high selectivity toward related enzymes such as prolyl oligopeptidase (PREP) and the dipeptidyl-peptidases (DPPs): DPP4, DPP8/9 and DPP2 were developed. This inhibitor has been adopted recently by other groups to create radiopharmaceuticals by coupling bifunctional chelator-linker systems. Here, we report squaric acid (SA) containing bifunctional DATA and DOTA chelators based on UAMC1110 as pharmacophor. The novel radiopharmaceuticals DOTA.SA.FAPi and DATA.SA.FAPi with their non-radioactive derivatives were characterized for in vitro inhibitory efficiency to FAP and PREP, respectively and radiochemical investigated with gallium-68. Further, first proof-of-concept in vivo animal study followed by ex vivo biodistribution were determined with [Ga]Ga-DOTA.SA.FAPi.

Results: [Ga]Ga-DOTA.SA.FAPi and [Ga]Ga-DATA.SA.FAPi showed high complexation > 97% radiochemical yields after already 10 min and high stability over a period of 2 h. Affinity to FAP of DOTA.SA.FAPi and DATA.SA.FAPi and its Ga and Lu-labeled derivatives were excellent resulting in low nanomolar IC values of 0.7-1.4 nM. Additionally, all five compounds showed low affinity for the related protease PREP (high IC with 1.7-8.7 μM). First proof-of-principle in vivo PET-imaging animal studies of the [Ga]Ga-DOTA.SA.FAPi precursor in a HT-29 human colorectal cancer xenograft mouse model indicated promising results with high accumulation in tumor (SUV of 0.75) and low background signal. Ex vivo biodistribution showed highest uptake in tumor (5.2%ID/g) at 60 min post injection with overall low uptake in healthy tissues.

Conclusion: In this work, novel PET radiotracers targeting fibroblast activation protein were synthesized and biochemically investigated. Critical substructures of the novel compounds are a squaramide linker unit derived from the basic motif of squaric acid, DOTA and DATA bifunctional chelators and a FAP-targeting moiety. In conclusion, these new FAP-ligands appear promising, both for further research and development as well as for first human application.
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http://dx.doi.org/10.1186/s41181-020-00102-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391456PMC
July 2020

A prospective intra-individual comparison of [Ga]Ga-PSMA-11 PET/CT, [Ga]Ga-NODAGA PET/CT, and [Tc]Tc-MDP bone scintigraphy for radionuclide imaging of prostate cancer skeletal metastases.

Eur J Nucl Med Mol Imaging 2021 Jan 18;48(1):134-142. Epub 2020 May 18.

Department of Nuclear Medicine, University of Pretoria & Steve Biko Academic Hospital, Private Bag X169, Pretoria, 0001, South Africa.

Purpose: Prostate cancer (PCa) commonly metastasizes to the bones. There are several radionuclide techniques for imaging PCa skeletal metastases. We aimed to compare the lesion detection rate of [Ga]Ga-PSMA-11 PET/CT, [Ga]Ga-NODAGA-zoledronate ([Ga]Ga-NODAGA) PET/CT, and [Tc]Tc-MDP bone scan in the assessment of bone metastases in patients with advanced PCa.

Methods: We prospectively recruited two cohorts of patients (staging and re-staging cohorts) with advanced prostate cancer. The staging cohort was treatment-naïve PCa patients who showed skeletal metastases on bone scan. These patients were subsequently imaged with [Ga]Ga-PSMA-11 PET/CT and [Ga]Ga-NODAGA PET/CT. Re-staging cohort was patients who were previously treated with PSMA-based radioligand therapy and were experiencing PSA progression. The re-staging cohort was imaged with [Ga]Ga-PSMA-11 PET/CT and [Ga]Ga-NODAGA PET/CT. We performed a per-patient and per-lesion analysis of skeletal metastases in both cohorts and made a comparison between scan findings.

Results: Eighteen patients were included with a median age of 68 years (range = 48-80) and a median Gleason score of 8. There were ten patients in the staging cohort with a median PSA of 119.26 ng/mL (range = 4.63-18,948.00) and eight patients in the re-staging cohort with a median PSA of 48.56 ng/mL (range = 6.51-3175.00). In the staging cohort, skeletal metastases detected by [Ga]Ga-PSMA-11 PET/CT, [Ga]Ga-NODAGA PET/CT, and bone scan were 322, 288, and 261, respectively, p = 0.578. In the re-staging cohort, [Ga]Ga-PSMA-11 PET/CT and [Ga]Ga-NODAGA PET/CT detected 152 and 191 skeletal metastases, respectively, p = 0.529. In two patients with negative [Ga]Ga-PSMA-11 PET/CT findings, [Ga]Ga-NODAGA detected one skeletal metastasis in one patient and 12 skeletal metastases in the other.

Conclusion: In patients with advanced prostate cancer, [Ga]Ga-PSMA-11 PET/CT may detect more lesions than [Ga]Ga-NODAGA PET/CT and [Tc]Tc-MDP bone scan for the staging of skeletal metastases. In patients who experience PSA progression on PSMA-based radioligand therapy, [Ga]Ga-NODAGA PET/CT is a more suitable imaging modality for the detection of skeletal lesions not expressing PSMA. In the setting of re-staging, [Ga]Ga-NODAGA PET/CT may detect more lesions than [Ga]Ga-PSMA-11 PET/CT.
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http://dx.doi.org/10.1007/s00259-020-04867-yDOI Listing
January 2021

Image quality analysis of Sc on two preclinical PET scanners: a comparison to Ga.

EJNMMI Phys 2020 Mar 12;7(1):16. Epub 2020 Mar 12.

Department of Nuclear Medicine, University Medical Center of the Johannes Gutenberg-University Mainz, Mainz, Germany.

Background: Sc has been increasingly investigated as a potential alternative to Ga in the development of tracers for positron emission tomography (PET). The lower mean positron energy of Sc (0.63 MeV) compared to Ga (0.83 MeV) can result in better spatial image resolutions. However, high-energy γ-rays (1157 keV) are emitted at high rates (99.9%) during Sc decay, which can reduce image quality. Therefore, we investigated the impact of these physical properties and performed an unbiased performance evaluation of Sc and Ga with different imaging phantoms (image quality phantom, Derenzo phantom, and three-rod phantom) on two preclinical PET scanners (Mediso nanoScan PET/MRI, Siemens microPET Focus 120).

Results: Despite the presence of high-energy γ-rays in Sc decay, a higher image resolution of small structures was observed with Sc when compared to Ga. Structures as small as 1.3 mm using the Mediso system, and as small as 1.0 mm using the Siemens system, could be visualized and analyzed by calculating full width at half maximum. Full widths at half maxima were similar for both isotopes. For image quality comparison, we calculated recovery coefficients in 1-5 mm rods and spillover ratios in either air, water, or bone-equivalent material (Teflon). Recovery coefficients for Sc were significantly higher than those for Ga. Despite the lower positron energy, Sc-derived spillover ratio (SOR) values were similar or slightly higher to Ga-derived SOR values. This may be attributed to the higher background caused by the additional γ-rays. On the Siemens system, an overestimation of scatter correction in the central part of the phantom was observed causing a virtual disappearance of spillover inside the three-rod phantom.

Conclusion: Based on these findings, Sc appears to be a suitable alternative to Ga. The superior image resolution makes it an especially strong competitor in preclinical settings. The additional γ-emissions have a small impact on the imaging resolution but cause higher background noises and can effect an overestimation of scatter correction, depending on the PET system and phantom.
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http://dx.doi.org/10.1186/s40658-020-0286-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7067939PMC
March 2020

Synthesis, Labeling and Preclinical Evaluation of a Squaric Acid Containing PSMA Inhibitor Labeled with Ga: A Comparison with PSMA-11 and PSMA-617.

ChemMedChem 2020 04 19;15(8):695-704. Epub 2020 Mar 19.

Institute of Nuclear Chemistry, Johannes Gutenberg University, Fritz-Strassmann-Weg 2, 55128, Mainz, Germany.

The L-lysine urea-L-glutamate (KuE) represents a key motif in recent diagnostic and therapeutic radiopharmaceuticals targeting the prostate specific membrane antigen (PSMA). Using a squaric acid moiety for coupling of KuE with a radioactive label, the squaric acid as a linker in the PSMA ligand seems to mimic the aromatic structure of the naphthylalanine unit on PSMA-617. In this work, we investigate the influence of squaric acid moiety on the biological activity of the compound carrying a KuE motif and three typical chelates. The derivatives TRAM.SA.KuE, DOTAGA.SA.KuE and NODAGA.SA.KuE were all synthesized in straightforward organic reactions and purified by HPLC afterward. Different amounts of tracer were labeled at different temperatures with Ga. PET examinations were performed on NMRInu/nu nude mice with an LNCaP tumor on the right hind leg including ex vivo investigations of the organs. For comparison, Ga-derivatives of PSMA-11 and PSMA-617, the derivatives most commonly used in clinics, were investigated in the same animal model.
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http://dx.doi.org/10.1002/cmdc.201900559DOI Listing
April 2020

Synthesis and labeling of a squaric acid containing PSMA-inhibitor coupled to AAZTA for versatile labeling with Sc, Cu, Ga and Lu.

Appl Radiat Isot 2020 Feb 16;156:108867. Epub 2019 Aug 16.

Institute of Nuclear Chemistry, Johannes Gutenberg University, Mainz, Germany, Fritz-Strassmann-Weg 2, 55128, Mainz. Electronic address:

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http://dx.doi.org/10.1016/j.apradiso.2019.108867DOI Listing
February 2020

Gallium-68 and scandium-44 labelled radiotracers based on curcumin structure linked to bifunctional chelators: Synthesis and characterization of potential PET radiotracers.

J Inorg Biochem 2020 03 5;204:110954. Epub 2019 Dec 5.

Radiopharmaceutical Chemistry Section, Nuclear Medicine Unit, Azienda USL-IRCCS Reggio Emilia, via Amendola 2, 42122 Reggio Emilia, Italy.

Curcumin metal complexes showed widespread applications in medicine and can be exploited as a lead structure for developing new tracers for nuclear medicine application. Herein, the synthesis, chemical characterization and radiolabelling with gallium-68 and scandium-44 of two new targeting vectors based on curcumin scaffolds and linked to the chelators 1,4,7-triazacyclononane,1-glutaric acid-4,7-acetic acid (NODAGA) and 1,4-bis(carboxymethyl)-6-[bis(carboxymethyl)]amino-6-methylperhydro-1,4-diazepine (AAZTA) are reported. Synthesis of the precursors could be achieved with a 13% and 11% yield and radiolabelling generally afforded rapid incorporation under mild conditions (>95%). Stability in physiological media (~75% after 2 h in human blood for [Ga]Ga-/[Sc]Sc-AAZTA-PC21 and ~60% for [Ga]Ga-NODAGA-C21, respectively) are generally enhanced if compared to the previously radiolabelled analogues. MS fragmentation experiments showed high stability of the AAZTA-PC21 structure mainly due to the pyrazole derivatization of the curcumin keto-enol moiety and a more feasible radiolabelling was noticed both with gallium-68 and scandium-44 mainly due to the AAZTA-chelator properties. [Ga]Ga-NODAGA-C21 showed the most favorable lipophilicity value (logD = 1.3). Due to these findings, both compounds appear to be promising candidates for the imaging of colorectal cancer, but further studies such as in vitro uptake and in vivo biodistribution experiments are needed.
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http://dx.doi.org/10.1016/j.jinorgbio.2019.110954DOI Listing
March 2020

Pharmacokinetic evaluation of [F]PR04.MZ for PET/CT imaging and quantification of dopamine transporters in the human brain.

Eur J Nucl Med Mol Imaging 2020 07 1;47(8):1927-1937. Epub 2019 Dec 1.

Center for Nuclear Medicine & PET/CT Positronmed, Julio Prado 714, Santiago, Chile.

Purpose: Dopamine transporters (DAT) modulate pre-synaptic dopamine and physiological functions such as movement and reward. DAT also mirrors disease state in neurological disorders, rendering it an essential diagnostic target. [F]PR04.MZ is a new PET imaging agent for DAT with an improved affinity and selectivity profile, for which we here describe the complete pharmacokinetic evaluation in healthy controls.

Methods: Thirty-two healthy subjects underwent T1-weighted MRI and dynamic PET scans for 180 min with arterial blood sampling (n = 5) or 90 min without blood sampling (n = 25) after injection of 197.6 ± 12.2 MBq [F]PR04.MZ. Blood and plasma metabolite analysis were performed. MRI-based normalization of brain images, delineation of VOIs, and kinetic modeling was conducted to determine distribution volumes (V) and binding potentials (BP). The impact of scan duration was evaluated and repeated PET scans were performed to assess test-retest variability (n = 5). A static imaging protocol has been validated for clinical applications.

Results: [F]PR04.MZ showed rapid metabolization in circulation, very high uptake in striatum and midbrain, and very low non-specific binding. The two-tissue compartment model 2TCM provided best fits for measured time-activity-curves and calculated Vs in putamen, caudate, substantia nigra pars compacta (SNpc), and cerebellar cortex were 11.83, 9.73, 2.12, and 0.57, respectively. All non-invasive models correlated well with BP values derived from 2TCM but underestimated DAT availability by about 28-33%. Of those, simplified reference tissue model (SRTM) provided the best fits, lowest Akaike Information Criteria values, and BP values of 14.82, 11.95, and 2.63 in putamen, caudate, and SNpc, respectively. BP estimates for striatal regions and SNpc were stable between 90 and 130 min post-injection. Test-retest results were excellent, showing low variability in all and excellent reliability in most relevant regions. Static imaging from 60 to 90-min post-injection is a viable alternative for quantification.

Conclusions: [F]PR04.MZ is a PET tracer with very high affinity, selectivity, and specific uptake in striatum and midbrain. 2TCM and SRTM provide good fits, high and stable Vs or BPs, and good test-retest reliability for precise quantification of DAT in human subjects.
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http://dx.doi.org/10.1007/s00259-019-04594-zDOI Listing
July 2020

AAZTA/AAZTA-TOC: synthesis and radiochemical evaluation with Ga, Sc and Lu.

EJNMMI Radiopharm Chem 2019 Aug 1;4(1):18. Epub 2019 Aug 1.

Johannes Gutenberg-University Mainz, Institute of Nuclear Chemistry, Fritz-Strassmann-Weg 2, 55128, Mainz, Germany.

Purpose: AAZTA (1,4-bis (carboxymethyl)-6-[bis (carboxymethyl)]amino-6-methylperhydro-1,4-diazepine) based chelators were initially developed in the context of magnetic resonance imaging. First radiochemical studies showed the capability of AAZTA to form stable complexes with radiolanthanides and moderately stable complexes with Ga. For a systematic comparison of the labelling capabilities with current diagnostic and therapeutic trivalent radiometals, AAZTA (1,4-bis (carboxymethyl)-6-[bis (carboxymethyl)]amino-6-[pentanoic-acid]perhydro-1,4-diazepine) was synthesized representing a bifunctional version with a pentanoic acid at the carbon-6 atom. To evaluate the effect of adding a targeting vector (TV) to the bifunctional chelator on the complex formation, AAZTA-TOC was synthesized, radiolabeled and tested in comparison to the uncoupled AAZTA.

Methods: AAZTA was synthesized in a 5-step synthesis. It was coupled to the cyclic peptide TOC (Phe-Tyr octreotide) via amide bound formation. AAZTA and AAZTA-TOC complex formations with Ga, Sc and Lu were investigated at different pH, temperature and precursor amounts. Stability studies against human serum, PBS buffer, EDTA and DTPA were performed.

Results: AAZTA and AAZTA-TOC achieved quantitative labelling (> 95%) at room temperature in less than 5 min with all three nuclides at pH ranges from 4 to 5.5 with low precursor amounts of 1 to 10 nmol. [Sc]Sc-AAZTA complexes as well as [Sc]Sc-AAZTA-TOC were completely stable. The Lu complexes of AAZTA and AAZTA-TOC showed high stability comparable to the Sc complexes. In contrast, the [Ga]Ga-AAZTA complex stability was rather low, but interestingly, [Ga]Ga-AAZTA-TOC was completely stable.

Conclusion: AAZTA appears to be a promising bifunctional chelator for Ga, Sc and Lu with outstanding labelling capabilities at room temperature. Complex stabilities are high in the case of Sc and Lu. While [Ga]Ga-AAZTA complexes alone lacking stability, [Ga]Ga-AAZTA-TOC demonstrated high stability. The latter indicates an interesting feature of [Ga]Ga-AAZTA-labelled radiopharmaceuticals.
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http://dx.doi.org/10.1186/s41181-019-0068-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6675801PMC
August 2019

Characterization of the serotonin 2A receptor selective PET tracer (R)-[F]MH.MZ in the human brain.

Eur J Nucl Med Mol Imaging 2020 02 12;47(2):355-365. Epub 2019 Oct 12.

Department of Drug Design and Pharmacology, University of Copenhagen, Jagtvej 160, 2100, Copenhagen, Denmark.

Purpose: The serotonin receptor subtype 2A antagonist (5-HTR) (R)-[F]MH.MZ has in preclinical studies been identified as a promising PET imaging agent for quantification of cerebral 5-HTRs. It displays a very similar selectivity profile as [C]MDL 100907, one of the most selective compounds identified thus far for the 5-HTR. As [C]MDL 100907, (R)-[F]MH.MZ also displays slow brain kinetics in various animal models; however, the half-life of fluorine-18 allows for long scan times and consequently, a more precise determination of 5-HTR binding could still be feasible. In this study, we aimed to evaluate the potential of (R)-[F]MH.MZ PET to image and quantify the 5-HTR in the human brain in vivo.

Methods: Nine healthy volunteers underwent (R)-[F]MH.MZ PET at baseline and four out of these also received a second PET scan, after ketanserin pretreatment. Regional time-activity curves of 17 brain regions were analyzed before and after pretreatment. We also investigated radiometabolism, time-dependent stability of outcomes measures, specificity of (R)-[F]MH.MZ 5-HTR binding, and performance of different kinetic modeling approaches.

Results: Highest uptake was determined in 5-HTR rich regions with a BP of approximately 1.5 in cortex regions. No radiometabolism was observed. 1TCM and 2TCM resulted in similar outcome measure, whereas reference tissue models resulted in a small, but predictable bias. (R)-[F]MH.MZ binding conformed to the known distribution of 5-HTR and could be blocked by pretreatment with ketanserin. Moreover, outcomes measures were stable after 100-110 min.

Conclusion: (R)-[F]MH.MZ is a suitable PET tracer to image and quantify the 5-HTR system in humans. In comparison with [C]MDL 100907, faster and more precise outcome measure could be obtained using (R)-[F]MH.MZ. We believe that (R)-[F]MH.MZ has the potential to become the antagonist radiotracer of choice to investigate the human 5-HTR system.
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http://dx.doi.org/10.1007/s00259-019-04527-wDOI Listing
February 2020

From Bench to Bedside-The Bad Berka Experience With First-in-Human Studies.

Semin Nucl Med 2019 09 6;49(5):422-437. Epub 2019 Jul 6.

THERANOSTICS Center for Molecular Radiotherapy and Precision Oncology, Zentralklinik Bad Berka, Bad Berka, Germany. Electronic address:

Precision oncology is being driven by rapid advances in novel diagnostics and therapeutic interventions, with treatments targeted to the needs of individual patients on the basis of genetic, biomarker, phenotypic, or psychosocial characteristics that distinguish a given patient from other patients with similar clinical presentations. Inherent in the theranostics paradigm is the assumption that diagnostic test results can precisely determine whether an individual is likely to benefit from a specific treatment. As part and integral in the current era of precision oncology, theranostics in the context of nuclear medicine aims to identify the appropriate molecular targets in neoplasms (diagnostic tool), so that the optimal ligands and radionuclides (therapeutic tool) with favorable labeling chemistry can be selected for personalized management of a specific disease, taking into consideration the specific patient, and subsequently monitor treatment response. Over the past two decades, the use of gallium-68 labeled peptides for somatostatin receptor (SSTR)-targeted PET/CT (or PET/MRI) imaging followed by lutetium-177 and yttrium-90 labeled SSTR-agonist for peptide receptor radionuclide therapy has demonstrated remarkable success in the management of neuroendocrine neoplasms, and paved the way to other indications of theranostics. Rapid advances are being made in the development of other peptide-based radiopharmaceuticals, small molecular-weight ligands and with newer radioisotopes with more favorable kinetics, potentially useful for theranostics strategies for the clinical application. The present review features the Bad Berka experience with first-in-human studies of new radiopharmaceuticals, for example, prostate-specific membrane antigen ligand, gastrin-releasing peptide receptor, neurotensin receptor 1 ligand, novel SSTR-targeting peptides and nonpeptide, and bone-seeking radiopharmaceuticals. Also new radioisotopes, for example, actinium (Ac), copper (Cu), scandium (Sc), and terbium (Tb/Tb) will be discussed briefly demonstrating the development from basic science to precision oncology in the clinical setting.
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http://dx.doi.org/10.1053/j.semnuclmed.2019.06.002DOI Listing
September 2019

Evaluation of the inverse electron demand Diels-Alder reaction in rats using a scandium-44-labelled tetrazine for pretargeted PET imaging.

EJNMMI Res 2019 May 28;9(1):49. Epub 2019 May 28.

Department of Clinical Physiology, Nuclear Medicine & PET, Rigshospitalet, Blegdamsvej 9, 2100, Copenhagen, Denmark.

Background: Pretargeted imaging allows the use of short-lived radionuclides when imaging the accumulation of slow clearing targeting agents such as antibodies. The biotin-(strept)avidin and the bispecific antibody-hapten interactions have been applied in clinical pretargeting studies; unfortunately, these systems led to immunogenic responses in patients. The inverse electron demand Diels-Alder (IEDDA) reaction between a radiolabelled tetrazine (Tz) and a trans-cyclooctene (TCO)-functionalized targeting vector is a promising alternative for clinical pretargeted imaging due to its fast reaction kinetics. This strategy was first applied in nuclear medicine using an In-labelled Tz to image TCO-functionalized antibodies in tumour-bearing mice. Since then, the IEDDA has been used extensively in pretargeted nuclear imaging and radiotherapy; however, these studies have only been performed in mice. Herein, we report the Sc labelling of a Tz and evaluate it in pretargeted imaging in Wistar rats.

Results: Sc was obtained from an in house Ti/Sc generator. A 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA)-functionalized tetrazine was radiolabelled with Sc resulting in radiochemical yields of 85-95%, a radiochemical purity > 99% at an apparent molar activity of 1 GBq/mmol. The Sc-labelled Tz maintained stability in solution for up to 24 h. A TCO-functionalized bisphosphonate, which accumulates in skeletal tissue, was used as a targeting vector to evaluate the Sc-labelled Tz. Biodistribution data of the Sc-labelled Tz showed specific uptake (0.9 ± 0.3% ID/g) in the bones (humerus and femur) of rats pre-treated with the TCO-functionalized bisphosphonate. This uptake was not present in rats not receiving pre-treatment (< 0.03% ID/g).

Conclusions: We have prepared a Sc-labelled Tz and used it in pretargeted PET imaging with rats treated with TCO-functionalized bisphosponates. This allowed for the evaluation of the IEDDA reaction in animals larger than a typical mouse. Non-target accumulation was low, and there was a 30-fold higher bone uptake in the pre-treated rats compared to the non-treated controls. Given its convenient half-life and the ability to perform positron emission tomography with a previously studied DOTA-functionalized Tz, scandium-44 (t = 3.97 h) proved to be a suitable radioisotope for this study.
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http://dx.doi.org/10.1186/s13550-019-0520-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6538705PMC
May 2019

Instant kit preparation of Ga-radiopharmaceuticals via the hybrid chelator DATA: clinical translation of [Ga]Ga-DATA-TOC.

EJNMMI Res 2019 May 23;9(1):48. Epub 2019 May 23.

Institute of Nuclear Chemistry, Johannes Gutenberg-University Mainz, Mainz, Germany.

Purpose: The widespread use of Ga for positron emission tomography (PET) relies on the development of radiopharmaceutical precursors that can be radiolabelled and dispensed in a simple, quick, and convenient manner. The DATA (6-amino-1,4-diazapine-triacetate) scaffold represents a novel hybrid chelator architecture possessing both cyclic and acyclic character that may allow for facile access to Ga-labelled tracers in the clinic. We report the first bifunctional DATA chelator conjugated to [Tyr]octreotide (TOC), a somatostatin subtype 2 receptor (SST)-targeting vector for imaging and functional characterisation of SSTR expressing tumours.

Methods: The radiopharmaceutical precursor, DATA-TOC, was synthesised as previously described and used to complex Ga(III) and Ga(III). Competition binding assays of [Ga]Ga-DATA-TOC or [Ga]Ga-DOTA-TOC against [I-Tyr]LTT-SS28 were conducted in membranes of HEK293 cells transfected to stably express one of the hSST receptor subtypes (HEK293-hSST cells). First in vivo studies were performed in female NMRI-nude mice bearing SST-positive mouse phaeochromocytoma mCherry (MPC-mCherry) tumours to compare the in vivo SST-specific tumour-targeting of [Ga]Ga-DATA-TOC and its overall pharmacokinetics versus the [Ga]Ga-DOTA-TOC reference. A direct comparison of [Ga]Ga-DATA-TOC with the well-established PET radiotracer [Ga]Ga-DOTA-TOC was additionally performed in a 46-year-old male patient with a well-differentiated NET (neuroendocrine tumour), representing the first in human administration of [Ga]Ga-DATA-TOC.

Results: DATA-TOC was labelled with Ga with a radiolabelling efficiency of > 95% in less than 10 min at ambient temperature. A molar activity up to 35 MBq/nmol was achieved. The hSST-affinities of [Ga]Ga-DATA-TOC and [Ga]Ga-DOTA-TOC were found similar with only sub-nanomolar differences in the respective IC values. In mice, [Ga]Ga-DATA-TOC was able to visualise the tumour lesions, showing standardised uptake values (SUVs) similar to [Ga]Ga-DOTA-TOC. Direct comparison of the two PET tracers in a NET patient revealed very similar tumour uptake for the two Ga-radiotracers, but with a higher tumour-to-liver contrast for [Ga]Ga-DATA-TOC.

Conclusion: [Ga]Ga-DATA-TOC was prepared, to a quality appropriate for in vivo use, following a highly efficient kit type process. Furthermore, the novel radiopharmaceutical was comparable or better than [Ga]Ga-DOTA-TOC in all preclinical tests, achieving a higher tumour-to-liver contrast in a NET-patient. The results illustrate the potential of the DATA-chelator to facilitate the access to and preparation of Ga-radiotracers in a routine clinical radiopharmacy setting.
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http://dx.doi.org/10.1186/s13550-019-0516-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6533321PMC
May 2019

Ga[Ga]-, In[In]-oxine: a novel strategy of radiolabeling of HPMA-based micelles.

Am J Nucl Med Mol Imaging 2019 15;9(1):67-83. Epub 2019 Feb 15.

Institute of Nuclear Chemistry, Johannes Gutenberg-University Fritz-Straßmann-Weg 2, Mainz 55128, Germany.

Polymeric micelles are of increasing interest as drug delivery vehicles since they can accumulate in tumor tissue through EPR effect and deliver their hydrophobic cargo. The pharmacology can be visualized and quantified noninvasively by molecular imaging techniques. Here, a novel, fast and efficient technique for radiolabeling various HPMA-LMA based micellar aggregates with hydrophobic oxine-complexes of the trivalent radiometals Ga and In was investigated. The radiometal-oxine complexes resemble the hydrophobic drug In[In]-oxine considered for the diagnosis of infection and inflammation. Promising stability lead to evaluation in healthy mice in terms of quantitative organ distribution. The results show that while the hydrophobic radiometal-oxine complexes were safely encapsulated in aqueous saline, they left the polymeric micelles slowly in contact with blood serum and more rapidly . Due to the similarity between the radiometal complexes and hydrophobic drugs transported in the polymeric micelles this has significant implications for further strategies on transport mechanisms of hydrophobically encapsulated drugs.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6420711PMC
February 2019

Evaluation of [Ac]Ac-DOTA for α-Therapy of Bone Metastases.

Curr Radiopharm 2018 ;11(3):223-230

Institute of Nuclear Chemistry, Johannes Gutenberg University, Mainz, Germany.

Background: Conjugates of bisphosphonates with macrocyclic chelators possess high potential in bone targeted radionuclide imaging and therapy. DOTAZOL, zoledronic acid conjugated to DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid), demonstrated promising results in vivo in small animals as well as in first patient applications using 68Ga for diagnosis via PET and the lowenergy β-emitter 177Lu for therapy of painful bone metastases. In consideration of the fact that targeted α-therapy probably offers various advantages over the use of β--emitters, the 225Ac-labelled derivative [225Ac]Ac-DOTAZOL was synthesized and evaluated in vivo. Here, we report on radiolabelling and biodistribution of [225Ac]Ac-DOTAZOL in healthy Wistar rats.

Methods: DOTAZOL was labelled with 225Ac and injected without further purification into the tail vein with activities of 404 ± 47 kBq per animal. Ex vivo biodistribution studies were performed in healthy Wistar rats at 1 hour, 24 hours, 5 days and 10 days post injection. The accumulation of [225Ac]Ac- DOTAZOL on healthy bone and soft tissue organs was determined in terms of SUV. The results were compared to those of other radiolabelled bisphosphonates such as [68Ga]Ga-DOTAZOL and [177Lu]Lu- DOTAZOL. A group of 7 animals was observed over a period of 3 month after application of 394 kBq ± 10 kBq of [225Ac]Ac-DOTAZOL for signs of toxicity. After 3 months, kidneys were microscopically analysed for signs of chronic kidney damage.

Results: Radiolabelling of DOTAZOL with 225Ac at 98 °C provided radiochemical yields ≥98 % within 30 minutes. [225Ac]Ac-DOTAZOL showed high femur uptake (SUVfemur = 4.99 ± 0.97, 10 d p.i.), which was comparable to that of other Me(III)-DOTAZOL derivatives. Ratios between bone uptake and blood pool activity reached levels of 5, 940, 2181 and 2409 at 1 hour, 24 hours, 5 days and 10 days post injection. During the observation period of the first two month no toxicity was observed clinically. Histopathology of kidneys after 3 month revealed significant tubular damage in most of the animals.

Conclusion: [225Ac]Ac-DOTAZOL repeats the well-known pharmacology of DOTAZOL derivatives in preclinical evaluations. It thus may be considered for translational application together with strategies to reduce renal toxicity.
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http://dx.doi.org/10.2174/1874471011666180604083911DOI Listing
January 2019

Improved Efficacy of Synthesizing *M-Labeled DOTA Complexes in Binary Mixtures of Water and Organic Solvents. A Combined Radio- and Physicochemical Study.

Inorg Chem 2018 May 10;57(10):6107-6117. Epub 2018 May 10.

Institute of Nuclear Chemistry , Johannes Gutenberg-University of Mainz , Fritz-Strassmann-Weg 2 , D-55128 Mainz , Germany.

Typically, the synthesis of radiometal-based radiopharmaceuticals is performed in buffered aqueous solutions. We found that the presence of organic solvents like ethanol increased the radiolabeling yields of [Ga]Ga-DOTA (DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacatic acid). In the present study, the effect of organic cosolvents [ethanol (EtOH), isopropyl alcohol, and acetonitrile] on the radiolabeling yields of the macrocyclic chelator DOTA with several trivalent radiometals (gallium-68, scandium-44, and lutetium-177) was systematically investigated. Various binary water (HO)/organic solvent mixtures allowed the radiolabeling of DOTA at a significantly lower temperature than 95 °C, which is relevant for the labeling of sensitive biological molecules. Simultaneously, much lower amounts of the chelators were required. This strategy may have a fundamental impact on the formulation of trivalent radiometal-based radiopharmaceuticals. The equilibrium properties and formation kinetics of [M(DOTA)] (M= Ga, Ce, Eu, Y, and Lu) complexes were investigated in HO/EtOH mixtures (up to 70 vol % EtOH). The protonation constants of DOTA were determined by pH potentiometry in HO/EtOH mixtures (0-70 vol % EtOH, 0.15 M NaCl, 25 °C). The log K and log K values associated with protonation of the ring N atoms decreased with an increase of the EtOH content. The formation rates of [M(DOTA)] complexes increase with an increase of the pH and [EtOH]. Complexation occurs through rapid formation of the diprotonated [M(HDOTA)] intermediates, which are in equilibrium with the kinetically active monoprotonated [M(HDOTA)] intermediates. The rate-controlling step is deprotonation (and rearrangement) of the monoprotonated intermediate, which occurs through HO ( k) and OH ( k) assisted reaction pathways. The rate constants are essentially independent of the EtOH concentration, but the k values increase from Ce to Lu. However, the log K protonation constants, analogous to the log K value, decrease with increasing [EtOH], which increases the concentration of the monoprotonated M(HDOTA) intermediate and accelerates formation of the final complexes. The overall rates of complex formation calculated by the obtained rate constants at different EtOH concentrations show a trend similar to that of the complexation rates determined with the use of radioactive isotopes.
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http://dx.doi.org/10.1021/acs.inorgchem.8b00669DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6121814PMC
May 2018

Comparison of Linear and Hyperbranched Polyether Lipids for Liposome Shielding by F-Radiolabeling and Positron Emission Tomography.

Biomacromolecules 2018 07 27;19(7):2506-2516. Epub 2018 Apr 27.

Institute of Nuclear Chemistry , Johannes Gutenberg University , Fritz-Strassmann-Weg 2 , D-55128 Mainz , Germany.

Multifunctional and highly biocompatible polyether structures play a key role in shielding liposomes from degradation in the bloodstream, providing also multiple functional groups for further attachment of targeting moieties. In this work hyperbranched polyglycerol ( hbPG) bearing lipids with long alkyl chain anchor are evaluated with respect to steric stabilization of liposomes. The branched polyether lipids possess a hydrophobic bis(hexadecyl)glycerol membrane anchor for the liposomal membrane. hbPG was chosen as a multifunctional alternative to PEG, enabling the eventual linkage of multiple targeting vectors. Different hbPG lipids ( M = 2900 and 5200 g mol) were examined. A linear bis(hexadecyl)glycerol-PEG lipid ( M = 3000 g mol) was investigated as well, comparing hbPG and PEG with respect to shielding properties. Radiolabeling of the polymers was carried out using 1-azido-2-(2-(2-[F]fluoroethoxy)ethoxy)ethane ([F]F-TEG-N) via copper-catalyzed alkyne-azide cycloaddition with excellent radiochemical yields exceeding 95%. Liposomes were prepared by the thin-film hydration method followed by repeated extrusion. Use of a custom automatic extrusion device gave access to reproducible sizes of the liposomes (hydrodynamic radius of 60-94 nm). The in vivo fate of the bis(hexadecyl)glycerol polyethers and their corresponding assembled liposome structures were evaluated via noninvasive small animal positron emission tomography (PET) imaging and biodistribution studies (1 h after injection and 4 h after injection) in mice. Whereas the main uptake of the nonliposomal polyether lipids was observed in the kidneys and in the bladder after 1 h due to rapid renal clearance, in contrast, the corresponding liposomes showed uptake in the blood pool as well as in organs with good blood supply, that is, heart and lung over the whole observation period of 4 h. The in vivo behavior of all three liposomal formulations was comparable, albeit with remarkable differences in splenic uptake. Overall, liposomes shielded by the branched polyglycerol lipids show a favorable biodistribution with greatly prolonged blood circulation times, rendering them promising novel nanovesicles for drug transport and targeting.
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http://dx.doi.org/10.1021/acs.biomac.8b00115DOI Listing
July 2018

Comparison Study of Two Differently Clicked F-Folates-Lipophilicity Plays a Key Role.

Pharmaceuticals (Basel) 2018 Mar 17;11(1). Epub 2018 Mar 17.

Hannover Medical School, Department of Nuclear Medicine, Radiopharmaceutical Chemistry, Carl-Neuberg-Str. 1, 30625 Hannover, Germany.

Within the last decade, several folate-based radiopharmaceuticals for Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) have been evaluated; however, there is still a lack of suitable F-folates for clinical PET imaging. Herein, we report the synthesis and evaluation of two novel F-folates employing strain-promoted and copper-catalyzed click chemistry. Furthermore, the influence of both click-methods on lipophilicity and pharmacokinetics of the F-folates was investigated. F-Ala-folate and F-DBCO-folate were both stable in human serum albumin. In vitro studies proved their high affinity to the folate receptor (FR). The lipophilic character of the strain-promoted clicked F-DBCO-folate (logD = 0.6) contributed to a higher non-specific binding in cell internalization studies. In the following in vivo PET imaging studies, FR-positive tumors could not be visualized in a maximum intensity projection images. Compared with F-DBCO-folate, F-Ala-folate (logD = -1.4), synthesized by the copper-catalyzed click reaction, exhibited reduced lipophilicity, and as a result an improved in vivo performance and a clear-cut visualization of FR-positive tumors. In view of high radiochemical yield, radiochemical purity and favorable pharmacokinetics, F-Ala-folate is expected to be a promising candidate for FR-PET imaging.
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http://dx.doi.org/10.3390/ph11010030DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5874726PMC
March 2018

Labeling of DOTA-conjugated HPMA-based polymers with trivalent metallic radionuclides for molecular imaging.

EJNMMI Res 2018 Feb 27;8(1):16. Epub 2018 Feb 27.

Institute of Nuclear Chemistry, Johannes Gutenberg University Mainz, Mainz, Germany.

Background: In this work, the in vitro and in vivo stabilities and the pharmacology of HPMA-made homopolymers were studied by means of radiometal-labeled derivatives. Aiming to identify the fewer amount and the optimal DOTA-linker structure that provides quantitative labeling yields, diverse DOTA-linker systems were conjugated in different amounts to HPMA homopolymers to coordinate trivalent radiometals Me(III)* = gallium-68, scandium-44, and lutetium-177.

Results: Short linkers and as low as 1.6% DOTA were enough to obtain labeling yields > 90%. Alkoxy linkers generally exhibited lower labeling yields than alkane analogues despite of similar chain length and DOTA incorporation rate. High stability of the radiolabel in all examined solutions was observed for all conjugates. Labeling with scandium-44 allowed for in vivo PET imaging and ex vivo measurements of organ distribution for up to 24 h.

Conclusions: This study confirms the principle applicability of DOTA-HPMA conjugates for labeling with different trivalent metallic radionuclides allowing for diagnosis and therapy.
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http://dx.doi.org/10.1186/s13550-018-0372-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5829281PMC
February 2018

Structure-Function Evaluation of Imidazopyridine Derivatives Selective for δ-Subunit-Containing γ-Aminobutyric Acid Type A (GABA) Receptors.

J Med Chem 2018 03 26;61(5):1951-1968. Epub 2018 Feb 26.

Department of Psychiatry and Psychotherapy, Faculty of Health and Medical Sciences , University Medical Center Mainz , D-55131 Mainz , Germany.

δ-Selective compounds 1 and 2 (DS1, compound 22; DS2, compound 16) were introduced as functionally selective modulators of δ-containing GABA type A receptors (GABAR). In our hands, [H]EBOB-binding experiments with recombinant GABAR and compound 22 showed no proof of δ-selectivity, although there was a minimally higher preference for the α4β3δ and α6β2/3δ receptors with respect to potency. In order to delineate the structural determinants of δ preferences, we synthesized 25 derivatives of DS1 and DS2, and investigated their structure-activity relationships (SAR). Four of our derivatives showed selectivity for α6β3δ receptors (29, 38, 39, and 41). For all of them, the major factors that distinguished them from compound 22 were variations at the para-positions of their benzamide groups. However, two compounds (29 and 39), when tested in the presence of GABA, revealed effects at several additional GABAR. The newly synthesized compounds will still serve as useful tools to investigate α6β3δ receptors.
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http://dx.doi.org/10.1021/acs.jmedchem.7b01484DOI Listing
March 2018

Long-term biodistribution study of HPMA-ran-LMA copolymers in vivo by means of I-labeling.

Nucl Med Biol 2018 03 16;58:59-66. Epub 2017 Dec 16.

Institute of Nuclear Chemistry, Johannes Gutenberg University, Fritz-Strassmann-Weg 2, 55128 Mainz, Germany. Electronic address:

Background: For the evaluation of macromolecular drug delivery systems suitable pre-clinical monitoring of potential nanocarrier systems is needed. In this regard, both short-term as well as long-term in vivo tracking is crucial to understand structure-property relationships of polymer carrier systems and their resulting pharmacokinetic profile. Based on former studies revealing favorable in vivo characteristics for F-labeled random (ran) copolymers consisting of N-(2-hydroxypropyl)methacrylamide (HPMA) and lauryl methacrylate (LMA) - including prolonged plasma half-life as well as enhanced tumor accumulation - the presented work focuses on their long-term investigation in the living organism.

Methods: In this respect, four different HPMA-based polymers (homopolymers as well as random copolymers with LMA as hydrophobic segment) were synthesized and subsequent radioactive labeling was accomplished via the longer-lived radioisotope I. In vivo results, concentrating on the pharmacokinetics of a high molecular weight HPMA-ran-LMA copolymer, were obtained by means of biodistribution and metabolism studies in the Walker 256 mammary carcinoma model over a time-span of up to three days. Besides, a direct comparison with the F-radiolabeled polymer was drawn. To consider physico-chemical differences between the differently labeled polymer (F or I) on the critical micelle concentration (CMC) and the size of the polymeric micelles, those properties were determined using the F- or I-functionalized polymer. Special emphasis was laid on the time-dependent correlation between blood circulation properties and corresponding tumor accumulation, particularly regarding the enhanced permeability and retention (EPR) effect.

Results: Studies revealed, at first, differences in the short time (2h) body distribution, despite the very similar properties (molecular structure, CMC and size of the micellar aggregates) of the non-radioactive F- and I-functionalized polymers. Long-term investigations with the I-labeled polymer demonstrated that, despite a polymer clearance from the blood within 72h, there was still an increase in tumor uptake observed over time. Regarding the stability of the I-label, ex vivo biodistribution experiments, considering the uptake in the thyroid, indicated low metabolism rates.

Conclusion: The observed in vivo characteristics strongly underline the EPR effect. The findings illustrate the need to combine information of different labeling approaches and in vivo evaluation techniques to generate an overall pharmacokinetic picture of potential nanocarriers in the pre-clinical setting.

Advances In Knowledge And Implications For Patients: The in vivo behavior of the investigated HPMA-ran-LMA copolymer demonstrates great potential in terms of an effective accumulation in the tumor.
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http://dx.doi.org/10.1016/j.nucmedbio.2017.12.002DOI Listing
March 2018

Clinical Translation and First In-Human Use of [Sc]Sc-PSMA-617 for PET Imaging of Metastasized Castrate-Resistant Prostate Cancer.

Theranostics 2017 26;7(18):4359-4369. Epub 2017 Sep 26.

Institute of Nuclear Chemistry, Johannes Gutenberg University, 55128 Mainz, Germany.

Background: Various trivalent radiometals are well suited for labeling of DOTA-conjugated variants of Glu-ureido-based prostate-specific membrane antigen (PSMA) inhibitors. The DOTA-conjugate PSMA-617 has proven high potential in PSMA radioligand therapy (PSMA-RLT) of prostate cancer as well as PET imaging when labeled with lutetium-177 and gallium-68 respectively. Considering the relatively short physical half-life of gallium-68 this positron emitter precludes prolonged acquisition periods, as required for pre-therapeutic dosimetry or intraoperative applications. In this context, the positron emitter scandium-44 is an attractive alternative for PET imaging. We report the synthesis of [Sc]Sc-PSMA-617 as radiopharmaceutical with generator produced scandium-44, its characterization and clinical translation as part of a first in-human study.

Methods: Scandium-44 was obtained from a Ti/Sc radionuclide generator. PSMA-617 was labeled with 142.4±12.7 MBq of scandium-44 in analogy to [Ga]Ga-PSMA-617 and evaluated and in cell studies using PSMA+ LNCaP cells. A first-in-human investigation was subsequently carried out in a cohort of 4 patients (mean age 70±1.8 a) registered for [Lu]Lu-PSMA-617 therapy. 50.5±9.3 MBq (40 µg, 38.4 nmol) [Sc]Sc-PSMA-617 were applied via intravenous injection (i.v.), respectively. A Siemens Biograph 2 PET/CT system was used to acquire initial dynamic PET data (30 min) of abdomen in list mode followed by static PET/CT data (skull to mid-thigh) at 45 min, 2 and 18 h post-injection (p.i.). For quantitative analysis, dynamic images were reconstructed as 6 data sets of 300 s each. The noise ratio was measured in liver, lung and an additional region outside the body. SUV values in different organs and lesions were measured and compared to [Ga]Ga-PSMA-11 data of the same patients. Residence times and organ absorbed doses were calculated using OLINDA/EXM software.

Results: Quantitative radiochemical yields of ≥98 % were achieved using 18 nmol of PSMA-617 after 20 min at 95 °C with apparent molar activity of 6.69±0.78 MBq/nmol. Following purification, >99 % radiochemical purity was obtained. [Sc]Sc-PSMA-617 showed high stability (>95 %) in serum for 24 h. The binding affinity and internalization fraction were determined in PSMA+ LNCaP cells (IC = 4.72±0.7 nM and internalization fraction: 15.78±2.14 % IA/10 LNCaP cells) and compared to [Ga]Ga-PSMA-11 (12.0±2.8 nM and 9.47±2.56 % IA/10 LNCaP cells). Physiological tracer uptake was observed in kidneys, liver, spleen, small intestine, urinary bladder, and salivary glands and pathological uptake in both soft and skeletal metastases. SUV values were significantly lower in the kidneys (14.0) compared to [Ga]Ga-PSMA-11 OET (30.5). All other measured SUV values did not show a statistically significant difference. Tumor to liver ratios were found to lie between 1.9 and 8.3 for [Ga]Ga-PSMA-11 and between 2.5 and 8.8 for [Sc]Sc-PSMA-617 after 120 min. For [Sc]Sc-PSMA-617 the ratios were higher and no statistically significant differences were observed. Total and % activity were highest in liver followed by kidneys, spleen, small intestine and salivary glands. Rapid wash out was seen in liver and spleen and gradually over time in kidneys. Kidneys received the highest radiation absorbed dose of 0.354 (0.180-0.488) mSv/MBq. No adverse pharmacological effects were observed.

Conclusion: In conclusion [Sc]Sc-PSMA-617 PET is suitable for PET imaging of prostate cancer tissue. [Sc]Sc-PSMA-617 shows promise to enable pre-therapeutic dosimetry in clinical settings. However, the clinical advantages for individual dosimetry or other applications like intraoperative applications have to be investigated in further studies.
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http://dx.doi.org/10.7150/thno.20586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5695136PMC
March 2018

The Beginning and Development of the Theranostic Approach in Nuclear Medicine, as Exemplified by the Radionuclide Pair Y and Y.

Pharmaceuticals (Basel) 2017 Jun 20;10(2). Epub 2017 Jun 20.

Institute of Neuroscience and Medicine (INM), INM-5 (nuclear Chemistry), Research Center Jülich, Jülich D-52425, Germany.

In the context of radiopharmacy and molecular imaging, the concept of theranostics entails a therapy-accompanying diagnosis with the aim of a patient-specific treatment. Using the adequate diagnostic radiopharmaceutical, the disease and the state of the disease are verified for an individual patient. The other way around, it verifies that the radiopharmaceutical in hand represents a target-specific and selective molecule: the "best one" for that individual patient. Transforming diagnostic imaging into quantitative dosimetric information, the optimum radioactivity (expressed in maximum radiation dose to the target tissue and tolerable dose to healthy organs) of the adequate radiotherapeutical is applied to that individual patient. This theranostic approach in nuclear medicine is traced back to the first use of the radionuclide pair Y/Y, which allowed a combination of PET and internal radiotherapy. Whereas the β-emitting therapeutic radionuclide Y (t½ = 2.7 d) had been available for a long time via the Sr/Y generator system, the β⁺ emitter Y (t½ = 14.7 h) had to be developed for medical application. A brief outline of the various aspects of radiochemical and nuclear development work (nuclear data, cyclotron irradiation, chemical processing, quality control, etc.) is given. In parallel, the paper discusses the methodology introduced to quantify molecular imaging of Y-labelled compounds in terms of multiple and long-term PET recordings. It highlights the ultimate goal of radiotheranostics, namely to extract the radiation dose of the analogue Y-labelled compound in terms of mGy or mSv per MBq Y injected. Finally, the current and possible future development of theranostic approaches based on different PET and therapy nuclides is discussed.
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http://dx.doi.org/10.3390/ph10020056DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5490413PMC
June 2017