(89)Zr, a radiometal nuclide with high potential for molecular imaging with PET: chemistry, applications and remaining challenges.

Molecular imaging-and especially Positron Emission Tomography (PET)-is of increasing importance for the diagnosis of various diseases and thus is experiencing increasing dissemination. Consequently, there is a growing demand for appropriate PET tracers which allow for a specific accumulation in the target structure as well as its visualization and exhibit decay characteristics matching their in vivo pharmacokinetics. To meet this demand, the development of new targeting vectors as well as the use of uncommon radionuclides becomes increasingly important. Uncommon nuclides in this regard enable the utilization of various selectively accumulating bioactive molecules such as peptides, antibodies, their fragments, other proteins and artificial structures for PET imaging in personalized medicine. Among these radionuclides, 89Zr (t1/2 = 3.27 days and mean Eβ+ = 0.389 MeV) has attracted increasing attention within the last years due to its favorably long half-life, which enables imaging at late time-points, being especially favorable in case of slowly-accumulating targeting vectors. This review outlines the recent developments in the field of 89Zr-labeled bioactive molecules, their potential and application in PET imaging and beyond, as well as remaining challenges

Silicon-[18F]Fluorine Radiochemistry: Basics, Applications and Challenges

Silicon-[18F]Fluorine (Si-18F) radiochemistry has recently emerged alongside other unconventional approaches such as aluminum-F-18 and boron-F-18 based labeling strategies, reshaping the landscape of modern F-18-radiochemistry. All these novel methodologies are driven by the demand for more convenient F-18-labeling procedures to further disseminate one of the most sophisticated imaging technologies, Positron Emission Tomography (PET). The PET methodology requires special radionuclides such as F-18 (one of the most prominent examples) to be introduced into bioactive molecules. Si-F-18 radiochemistry contributed greatly towards the development of new radiopharmaceuticals for PET imaging. Herein, we describe the radiochemical basics of Si-F-18 bond formation, the application of Si-F-18 tracers for PET imaging, and additionally, the inherent chemical intricacies of this methodology

τBu₂SiF-Derivatized D₂-Receptor Ligands: The First SiFA-Containing Small Molecule Radiotracers for Target-Specific PET-Imaging

The synthesis, radiolabeling and in vitro evaluation of new silicon-fluoride acceptor (SiFA) derivatized D-2-receptor ligands is reported. The SiFA-technology simplifies the introduction of fluorine-18 into target specific biomolecules for Positron-Emission-Tomography (PET). However, one of the remaining challenges, especially for small molecules such as receptor-ligands, is the bulkiness of the SiFA-moiety. We therefore synthesized four Fallypride SiFA-conjugates derivatized either directly at the benzoic acid ring system (SiFA-DMFP, SiFA-FP, SiFA-DDMFP) or at the butyl-side chain (SiFA-M-FP) and tested their receptor affinities. We found D2-receptor affinities for all compounds in the nanomolar range (Ki(SiFA-DMFP) = 13.6 nM, Ki(SiFA-FP) = 33.0 nM, Ki(SiFA-DDMFP) = 62.7 nM and Ki(SiFA-M-FP) = 4.21 nM). The radiofluorination showed highest yields when 10 nmol of the precursors were reacted with F-18]fluoride/TBAHCO(3) in acetonitrile. After a reversed phased cartridge purification the desired products could be isolated as an injectable solution after only 10 min synthesis time with radiochemical yields (RCY) of more than 40% in the case of SiFA-DMFP resulting in specific activities >41 GBq/mu mol (>1,100 Ci/mmol). Furthermore, the radiolabeled products were shown to be stable in the injectable solutions, as well as in human plasma, for at least 90 min

Microfluidics: A Groundbreaking Technology for PET Tracer Production?

Application of microfluidics to Positron Emission Tomography ( PET) tracer synthesis has attracted increasing interest within the last decade. The technical advantages of microfluidics, in particular the high surface to volume ratio and resulting fast thermal heating and cooling rates of reagents can lead to reduced reaction times, increased synthesis yields and reduced by-products. In addition automated reaction optimization, reduced consumption of expensive reagents and a path towards a reduced system footprint have been successfully demonstrated. The processing of radioactivity levels required for routine production, use of microfluidic-produced PET tracer doses in preclinical and clinical imaging as well as feasibility studies on autoradiolytic decomposition have all given promising results. However, the number of microfluidic synthesizers utilized for commercial routine production of PET tracers is very limited. This study reviews the state of the art in microfluidic PET tracer synthesis, highlighting critical design aspects, strengths, weaknesses and presenting several characteristics of the diverse PET market space which are thought to have a significant impact on research, development and engineering of microfluidic devices in this field. Furthermore, the topics of batch- and single-dose production, cyclotron to quality control integration as well as centralized versus de-centralized market distribution models are addressed

Comparison between 68Ga-bombesin (68Ga-BZH3) and the cRGD tetramer 68Ga-RGD4 studies in an experimental nude rat model with a neuroendocrine pancreatic tumor cell line

BACKGROUND: Serotonergic neurons in the rodent hypothalamus are implicated in key neuroendocrine and metabolic functions, including circadian rhythmicity. However, the assessment of the serotonergic system in the human hypothalamus in vivo is difficult as delineation of the hypothalamus is cumbersome with conventional region-of-interest analysis. In the present study, we aimed to develop a method to visualize serotonin transporters (SERT) in the hypothalamus. Additionally, we tested the hypothesis that hypothalamic SERT binding ratios are different between patients with hypothalamic impairment (HI), pituitary insufficiency (PI), and control subjects (C). METHODS: SERT availability was determined in 17 subjects (6 HI, 5 PI, and 6 healthy controls), 2 h after injection of 123I-N-ω-fluoropropyl-2β-carboxymethoxy-3β-(4-iodophenyl) nortropane ([123I]FP-CIT), using single-photon emission computed tomography (performed on a brain-dedicated system) fused with individual magnetic resonance imaging (MRI) scans of the brain. The hypothalamus (representing specific SERT binding) and cerebellum (representing nonspecific binding) were manually delineated on each MRI to assess [123I]FP-CIT binding and specific-to-nonspecific binding ratios. RESULTS: In each healthy subject, [123I]FP-CIT binding was higher in the hypothalamus than in the cerebellum, and the mean hypothalamic binding ratio of SERT was 0.29 ± 0.23. We found no difference in hypothalamic binding ratios between HI, PI, and control subjects (HI 0.16 ± 0.24, PI 0.45 ± 0.39, C 0.29 ± 0.23, p value 0.281). CONCLUSIONS: We were able to demonstrate SERT binding in the human hypothalamus in vivo. However, we did not find altered hypothalamic SERT binding in patients with hypothalamic impairment. TRIAL REGISTRATION: Netherlands Trial Register: NTR2520

Silicon-[18F]Fluorine Radiochemistry: Basics, Applications and Challenges

Silicon-[18F]Fluorine (Si-18F) radiochemistry has recently emerged alongside other unconventional approaches such as aluminum-F-18 and boron-F-18 based labeling strategies, reshaping the landscape of modern F-18-radiochemistry. All these novel methodologies are driven by the demand for more convenient F-18-labeling procedures to further disseminate one of the most sophisticated imaging technologies, Positron Emission Tomography (PET). The PET methodology requires special radionuclides such as F-18 (one of the most prominent examples) to be introduced into bioactive molecules. Si-F-18 radiochemistry contributed greatly towards the development of new radiopharmaceuticals for PET imaging. Herein, we describe the radiochemical basics of Si-F-18 bond formation, the application of Si-F-18 tracers for PET imaging, and additionally, the inherent chemical intricacies of this methodology

Dosimetry and optimal scan time of 18FSiTATE-PET/CT in patients with neuroendocrine tumours

PURPOSE Radiolabelled somatostatin analogues targeting somatostatin receptors (SSR) are well established for combined positron emission tomography/computer tomography (PET/CT) imaging of neuroendocrine tumours (NET). 18FSiTATE has recently been introduced showing high image quality, promising clinical performance and improved logistics compared to the clinical reference standard 68Ga-DOTA-TOC. Here we present the first dosimetry and optimal scan time analysis. METHODS Eight NET patients received a 18FSiTATE-PET/CT (250 ± 66~MBq) with repeated emission scans (10, 30, 60, 120, 180~min after injection). Biodistribution in normal organs and SSR-positive tumour uptake were assessed. Dosimetry estimates for risk organs were determined using a combined linear-monoexponential model, and by applying 18F S-values and reference target masses for the ICRP89 adult male or female (OLINDA 2.0). Tumour-to-background ratios were compared quantitatively and visually between different scan times. RESULTS After 1 h, normal organs showed similar tracer uptake with only negligible changes until 3 h post-injection. In contrast, tracer uptake by tumours increased progressively for almost all types of metastases, thus increasing tumour-to-background ratios over time. Dosimetry resulted in a total effective dose of 0.015 ± 0.004~mSv/MBq. Visual evaluation revealed no clinically relevant discrepancies between later scan times, but image quality was rated highest in 60 and 120~min images. CONCLUSION 18FSiTATE-PET/CT in NET shows overall high tumour-to-background ratios from 60 to 180~min after injection and an effective dose comparable to 68Ga-labelled alternatives. For clinical use of 18FSiTATE, the best compromise between image quality and tumour-to-background contrast is reached at 120~min, followed by 60~min after injection

(89)Zr, a radiometal nuclide with high potential for molecular imaging with PET: chemistry, applications and remaining challenges.

Molecular imaging-and especially Positron Emission Tomography (PET)-is of increasing importance for the diagnosis of various diseases and thus is experiencing increasing dissemination. Consequently, there is a growing demand for appropriate PET tracers which allow for a specific accumulation in the target structure as well as its visualization and exhibit decay characteristics matching their in vivo pharmacokinetics. To meet this demand, the development of new targeting vectors as well as the use of uncommon radionuclides becomes increasingly important. Uncommon nuclides in this regard enable the utilization of various selectively accumulating bioactive molecules such as peptides, antibodies, their fragments, other proteins and artificial structures for PET imaging in personalized medicine. Among these radionuclides, 89Zr (t1/2 = 3.27 days and mean Eβ+ = 0.389 MeV) has attracted increasing attention within the last years due to its favorably long half-life, which enables imaging at late time-points, being especially favorable in case of slowly-accumulating targeting vectors. This review outlines the recent developments in the field of 89Zr-labeled bioactive molecules, their potential and application in PET imaging and beyond, as well as remaining challenges

Towards Radiolabeled EGFR-Specific Peptides: Alternatives to GE11

The human epidermal growth factor receptor (EGFR) is closely related to several cancer-promoting processes and overexpressed on a variety of tumor types, rendering it an important target structure for the imaging and therapy of several malignancies. To date, approaches to develop peptidic radioligands able to specifically address and visualize EGFR-positive tumors have been of limited success. Most of the attempts were based on the lead GE11, as this peptide was previously described to be a highly potent EGFR-specific agent. However, since it has recently been shown that GE11 exhibits an insufficient affinity to the EGFR in monomeric form to be suitable as a basis for the development of tracers based on it, in the present work we investigated which other peptides might be suitable as lead structures for the development of EGFR-specific peptidic radiotracers. For this purpose, we developed 68Ga-labeled radioligands based on the peptides D4, P1, P2, CPP, QRH, EGBP and Pep11, having been described before as EGFR-specific. In addition, we also tested three truncated versions of the endogenous EGFR ligand hEGF (human epidermal growth factor) with respect to their ability to specifically target the EGFR with high affinity. Therefore, chelator-modified labeling precursors of the mentioned peptides were synthesized, radiolabeled with 68Ga and the obtained radioligands were evaluated for their hydrophilicity/lipophilicity, stability against degradation by human serum peptidases, in vitro tumor cell uptake, and receptor affinity in competitive displacement experiments on EGFR-positive A431 cells. Although all NODA-GA-modified (NODA-GA: (1,4,7-triazacyclononane-4,7-diyl)diacetic acid-1-glutaric acid) labeling precursors could be obtained more or less efficient in yields between 5 and 74%, the 68Ga-radiolabeling proved to be unsuccessful for two of the three truncated versions of hEGF ([68Ga]Ga-8 and [68Ga]Ga-9), producing several side-products. For the other agents [68Ga]Ga-1–[68Ga]Ga-7, [68Ga]Ga-10 and [68Ga]Ga-11, high radiochemical yields and purities of ≥98% and molar activities of up to 114 GBq/µmol were obtained. In the assay investigating the radiopeptide susceptibilities against serum peptidase degradation, the EGBP-based agent demonstrated a limited stability with a half-life of only 66.4 ± 3.0 min, whereas the other tracers showed considerably higher stabilities of up to an 8000 min half-life. Finally, all radiotracer candidates were evaluated in terms of tumor cell internalization and receptor binding potential on EGFR-positive A431 cell. In these experiments, all developed agents failed to show an EGFR-specific tumor cell uptake or a relevant EGFR-affinity. By contrast, the positive controls tested under identical conditions, [125I]I-hEGF and hEGF demonstrated the expected high EGFR-specific tumor cell uptake (33.6% after 1 h, being reduced to 1.9% under blocking conditions) and affinity (IC50 value of 15.2 ± 3.3 nM). Thus, these results indicate that none of the previously described peptidic agents developed for EGFR targeting appears to be a reasonable choice as a lead structure for the development of radiopeptides for targeting of EGFR-positive tumors. Likewise, the tested truncated variants of the endogenous hEGF do not seem to be promising alternatives for this purpose

Microfluidics: A Groundbreaking Technology for PET Tracer Production?

Application of microfluidics to Positron Emission Tomography ( PET) tracer synthesis has attracted increasing interest within the last decade. The technical advantages of microfluidics, in particular the high surface to volume ratio and resulting fast thermal heating and cooling rates of reagents can lead to reduced reaction times, increased synthesis yields and reduced by-products. In addition automated reaction optimization, reduced consumption of expensive reagents and a path towards a reduced system footprint have been successfully demonstrated. The processing of radioactivity levels required for routine production, use of microfluidic-produced PET tracer doses in preclinical and clinical imaging as well as feasibility studies on autoradiolytic decomposition have all given promising results. However, the number of microfluidic synthesizers utilized for commercial routine production of PET tracers is very limited. This study reviews the state of the art in microfluidic PET tracer synthesis, highlighting critical design aspects, strengths, weaknesses and presenting several characteristics of the diverse PET market space which are thought to have a significant impact on research, development and engineering of microfluidic devices in this field. Furthermore, the topics of batch- and single-dose production, cyclotron to quality control integration as well as centralized versus de-centralized market distribution models are addressed