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Special Issue "Preparation of Radiopharmaceuticals and Their Use in Drug Development"

A special issue of Molecules (ISSN 1420-3049). This special issue belongs to the section "Medicinal Chemistry".

Deadline for manuscript submissions: closed (30 May 2015)

Special Issue Editor

Guest Editor
Dr. Svend Borup Jensen

Nuklearmedicinsk Afdeling - Hobrovej 18-22, Postboks 365, 9100 Aalborg, Denmark
Website | E-Mail
Phone: 004597665495
Interests: PET-radiochemistry, gallium-68, drug degradation profiles; medicinal gum; infection imaging, analytical methods; medicinal chemistry

Special Issue Information

Dear Colleagues,

The journals Molecules and Pharmaceuticals will jointly be publishing a Special Issue covering the topic "Preparation of Radiopharmaceuticals and Their Use in Drug Development". I would like to invite you to make submissions addressing topics regarding Preparation of Radiopharmaceuticals with the aim at exploring their potential use in Drug Discovery.

The use of radiopharmaceuticals in drug development has many different applications.

Labeling a potential drug with a radionuclide for imaging and inject radiopharmaceuticals into animals or human can immediately give information about the in vivo destiny of the compound by applying PET- or SPECT scanners Does a radioactive drug accumulation in the site where the drug is supposed to have its effect or does it not reach the target organ or tumor at all? If radionuclides are employed throughout the whole process of developing new drugs, especially if the results are negative and the potential drug can be discarded early on in the process, a lot of effort and money can be saved. An alternative way of obtaining information about the in vivo destiny/effect of a potential drug is to imagine, for example, a target organ or a tumor with radiopharmaceuticals before and after treatment with a drug. This technique will most likely be widespread when it comes to personalized medicine, when a scan with a radiopharmaceutical can determine if a certain drug has its desired effect or if the physician has to try something else.

Determining how a drug is metabolized is an integrated part of drug development. Labeling a drug with radionuclide giving it a radioactive tag can help to find it subsequently and to quantify metabolites. If the metabolites can be extracted, the solutions can be examined by common analytical measurements. If the metabolites are incorporated into tissue and for that reason more difficult to find, a quick radioactive measurement can determine which tissue samples contain metabolites and/or radioactive labeled drug.

Using ionizing radiation in the treatment of tumor is also an application for radiopharmaceuticals which is expected to expand greatly in the years to come. By labeling a specific compounds with a radionuclide used for diagnostics we can see if it accumulates in the tumor. The same compound is thereafter combined with a radionuclide for treatment.

The purpose of this Special Issue is to host research and review papers on the Preparation of Radiopharmaceuticals and their potential use in Drug Discovery

Dr. Svend Borup Jensen
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All papers will be peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Molecules is an international peer-reviewed open access monthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. The Article Processing Charge (APC) for publication in this open access journal is 1800 CHF (Swiss Francs). Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.


Keywords

  • radioactive isotopes
  • PET and SPEC molecules
  • radiopharmaceuticals
  • quality control
  • Purification techniques
  • ionizing radiation

Published Papers (10 papers)

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Research

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Open AccessArticle A Promising PET Tracer for Imaging of α7 Nicotinic Acetylcholine Receptors in the Brain: Design, Synthesis, and in Vivo Evaluation of a Dibenzothiophene-Based Radioligand
Molecules 2015, 20(10), 18387-18421; doi:10.3390/molecules201018387
Received: 15 July 2015 / Revised: 25 September 2015 / Accepted: 28 September 2015 / Published: 9 October 2015
Cited by 4 | PDF Full-text (1677 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Changes in the expression of α7 nicotinic acetylcholine receptors (α7 nAChRs) in the human brain are widely assumed to be associated with neurological and neurooncological processes. Investigation of these receptors in vivo depends on the availability of imaging agents such as
[...] Read more.
Changes in the expression of α7 nicotinic acetylcholine receptors (α7 nAChRs) in the human brain are widely assumed to be associated with neurological and neurooncological processes. Investigation of these receptors in vivo depends on the availability of imaging agents such as radioactively labelled ligands applicable in positron emission tomography (PET). We report on a series of new ligands for α7 nAChRs designed by the combination of dibenzothiophene dioxide as a novel hydrogen bond acceptor functionality with diazabicyclononane as an established cationic center. To assess the structure-activity relationship (SAR) of this new basic structure, we further modified the cationic center systematically by introduction of three different piperazine-based scaffolds. Based on in vitro binding affinity and selectivity, assessed by radioligand displacement studies at different rat and human nAChR subtypes and at the structurally related human 5-HT3 receptor, we selected the compound 7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-fluorodibenzo-[b,d]thiophene 5,5-dioxide (10a) for radiolabeling and further evaluation in vivo. Radiosynthesis of [18F]10a was optimized and transferred to an automated module. Dynamic PET imaging studies with [18F]10a in piglets and a monkey demonstrated high uptake of radioactivity in the brain, followed by washout and target-region specific accumulation under baseline conditions. Kinetic analysis of [18F]10a in pig was performed using a two-tissue compartment model with arterial-derived input function. Our initial evaluation revealed that the dibenzothiophene-based PET radioligand [18F]10a ([18F]DBT-10) has high potential to provide clinically relevant information about the expression and availability of α7 nAChR in the brain. Full article
(This article belongs to the Special Issue Preparation of Radiopharmaceuticals and Their Use in Drug Development)
Open AccessArticle Development of a Single Vial Kit Solution for Radiolabeling of 68Ga-DKFZ-PSMA-11 and Its Performance in Prostate Cancer Patients
Molecules 2015, 20(8), 14860-14878; doi:10.3390/molecules200814860
Received: 31 May 2015 / Revised: 31 July 2015 / Accepted: 3 August 2015 / Published: 14 August 2015
Cited by 15 | PDF Full-text (1391 KB) | HTML Full-text | XML Full-text
Abstract
Prostate-specific membrane antigen (PSMA), a type II glycoprotein, is highly expressed in almost all prostate cancers. By playing such a universal role in the disease, PSMA provides a target for diagnostic imaging of prostate cancer using positron emission tomography/computed tomography (PET/CT). The PSMA-targeting
[...] Read more.
Prostate-specific membrane antigen (PSMA), a type II glycoprotein, is highly expressed in almost all prostate cancers. By playing such a universal role in the disease, PSMA provides a target for diagnostic imaging of prostate cancer using positron emission tomography/computed tomography (PET/CT). The PSMA-targeting ligand Glu-NH-CO-NH-Lys-(Ahx)-HBED-CC (DKFZ-PSMA-11) has superior imaging properties and allows for highly-specific complexation of the generator-based radioisotope Gallium-68 (68Ga). However, only module-based radiolabeling procedures are currently available. This study intended to develop a single vial kit solution to radiolabel buffered DKFZ-PSMA-11 with 68Ga. A 68Ge/68Ga-generator was utilized to yield 68GaCl3 and major aspects of the kit development were assessed, such as radiolabeling performance, quality assurance, and stability. The final product was injected into patients with prostate cancer for PET/CT imaging and the kit performance was evaluated on the basis of the expected biodistribution, lesion detection, and dose optimization. Kits containing 5 nmol DKFZ-PSMA-11 showed rapid, quantitative 68Ga-complexation and all quality measurements met the release criteria for human application. The increased precursor content did not compromise the ability of 68Ga-DKFZ-PSMA-11 PET/CT to detect primary prostate cancer and its advanced lymphatic- and metastatic lesions. The 68Ga-DKFZ-PSMA-11 kit is a robust, ready-to-use diagnostic agent in prostate cancer with high diagnostic performance. Full article
(This article belongs to the Special Issue Preparation of Radiopharmaceuticals and Their Use in Drug Development)
Figures

Open AccessArticle The Influence of the Combination of Carboxylate and Phosphinate Pendant Arms in 1,4,7-Triazacyclononane-Based Chelators on Their 68Ga Labelling Properties
Molecules 2015, 20(7), 13112-13126; doi:10.3390/molecules200713112
Received: 10 May 2015 / Revised: 10 July 2015 / Accepted: 13 July 2015 / Published: 21 July 2015
Cited by 5 | PDF Full-text (883 KB) | HTML Full-text | XML Full-text
Abstract
In order to compare the coordination properties of 1,4,7-triazacyclononane (tacn) derivatives bearing varying numbers of phosphinic/carboxylic acid pendant groups towards 68Ga, 1,4,7-triazacyclononane-7-acetic-1,4-bis(methylenephosphinic) acid (NOPA) and 1,4,7- triazacyclononane-4,7-diacetic-1-[methylene(2-carboxyethyl)phosphinic] acid (NO2AP) were synthesized using Mannich reactions with trivalent or pentavalent forms of H-phosphinic
[...] Read more.
In order to compare the coordination properties of 1,4,7-triazacyclononane (tacn) derivatives bearing varying numbers of phosphinic/carboxylic acid pendant groups towards 68Ga, 1,4,7-triazacyclononane-7-acetic-1,4-bis(methylenephosphinic) acid (NOPA) and 1,4,7- triazacyclononane-4,7-diacetic-1-[methylene(2-carboxyethyl)phosphinic] acid (NO2AP) were synthesized using Mannich reactions with trivalent or pentavalent forms of H-phosphinic acids as phosphorus components. Stepwise protonation constants logK1–3 12.06, 3.90 and 1.95, and stability constants with GaIII and CuII, logKGaL 24.01 and logKCuL 16.66, were potentiometrically determined for NOPA. Both ligands were labelled with 68Ga and compared with NOTA (tacn-N,N′,N-triacetic acid) and NOPO, a TRAP-type [tacn-N,N′,N- tris(methylenephosphinic acid)] chelator. At pH 3, NOPO and NOPA showed higher labelling efficiency (binding with lower ligand excess) at both room temperature and 95 °C, compared to NO2AP and NOTA. Labelling efficiency at pH = 0–3 correlated with a number of phosphinic acid pendants: NOPO >> NOPA > NO2AP >> NOTA; however, it was more apparent at 95 °C than at room temperature. By contrast, NOTA was found to be labelled more efficiently at pH > 4 compared to the ligands with phosphinic acids. Overall, replacement of a single phosphinate donor with a carboxylate does not challenge 68Ga labelling of TRAP-type chelators. However, the presence of carboxylates facilitates labelling at neutral or weakly acidic pH. Full article
(This article belongs to the Special Issue Preparation of Radiopharmaceuticals and Their Use in Drug Development)
Open AccessArticle Dual Radiolabeling as a Technique to Track Nanocarriers: The Case of Gold Nanoparticles
Molecules 2015, 20(7), 12863-12879; doi:10.3390/molecules200712863
Received: 23 May 2015 / Revised: 22 June 2015 / Accepted: 10 July 2015 / Published: 16 July 2015
Cited by 3 | PDF Full-text (1872 KB) | HTML Full-text | XML Full-text
Abstract
Gold nanoparticles (AuNPs) have shown great potential for use in nanomedicine and nanotechnologies due to their ease of synthesis and functionalization. However, their apparent biocompatibility and biodistribution is still a matter of intense debate due to the lack of clear safety data. To
[...] Read more.
Gold nanoparticles (AuNPs) have shown great potential for use in nanomedicine and nanotechnologies due to their ease of synthesis and functionalization. However, their apparent biocompatibility and biodistribution is still a matter of intense debate due to the lack of clear safety data. To investigate the biodistribution of AuNPs, monodisperse 14-nm dual-radiolabeled [14C]citrate-coated [198Au]AuNPs were synthesized and their physico-chemical characteristics compared to those of non-radiolabeled AuNPs synthesized by the same method. The dual-radiolabeled AuNPs were administered to rats by oral or intravenous routes. After 24 h, the amounts of Au core and citrate surface coating were quantified using gamma spectroscopy for 198Au and liquid scintillation for the 14C. The Au core and citrate surface coating had different biodistribution profiles in the organs/tissues analyzed, and no oral absorption was observed. We conclude that the different components of the AuNPs system, in this case the Au core and citrate surface coating, did not remain intact, resulting in the different distribution profiles observed. A better understanding of the biodistribution profiles of other surface attachments or cargo of AuNPs in relation to the Au core is required to successfully use AuNPs as drug delivery vehicles. Full article
(This article belongs to the Special Issue Preparation of Radiopharmaceuticals and Their Use in Drug Development)
Figures

Open AccessCommunication Practical Radiosynthesis and Preclinical Neuroimaging of [11C]isradipine, a Calcium Channel Antagonist
Molecules 2015, 20(6), 9550-9559; doi:10.3390/molecules20069550
Received: 28 April 2015 / Revised: 19 May 2015 / Accepted: 20 May 2015 / Published: 26 May 2015
Cited by 1 | PDF Full-text (1179 KB) | HTML Full-text | XML Full-text
Abstract
In the interest of developing in vivo positron emission tomography (PET) probes for neuroimaging of calcium channels, we have prepared a carbon-11 isotopologue of a dihydropyridine Ca2+-channel antagonist, isradipine. Desmethyl isradipine (4-(benzo[c][1,2,5]oxadiazol-4-yl)-5-(isopropoxycarbonyl)-2,6-dimethyl-1,4-dihydropyridine -3-carboxylic acid) was reacted with [11
[...] Read more.
In the interest of developing in vivo positron emission tomography (PET) probes for neuroimaging of calcium channels, we have prepared a carbon-11 isotopologue of a dihydropyridine Ca2+-channel antagonist, isradipine. Desmethyl isradipine (4-(benzo[c][1,2,5]oxadiazol-4-yl)-5-(isopropoxycarbonyl)-2,6-dimethyl-1,4-dihydropyridine -3-carboxylic acid) was reacted with [11C]CH3I in the presence of tetrabutylammonium hydroxide in DMF in an HPLC injector loop to produce the radiotracer in a good yield (6 ± 3% uncorrected radiochemical yield) and high specific activity (143 ± 90 GBq·µmol−1 at end-of-synthesis). PET imaging of normal rats revealed rapid brain uptake at baseline (0.37 ± 0.08% ID/cc (percent of injected dose per cubic centimeter) at peak, 15–60 s), which was followed by fast washout. After pretreatment with isradipine (2 mg·kg−1, i.p.), whole brain radioactivity uptake was diminished by 25%–40%. This preliminary study confirms that [11C]isradipine can be synthesized routinely for research studies and is brain penetrating. Further work on Ca2+-channel radiotracer development is planned. Full article
(This article belongs to the Special Issue Preparation of Radiopharmaceuticals and Their Use in Drug Development)
Open AccessArticle Synthesis, 18F-Radiolabelling and Biological Characterization of Novel Fluoroalkylated Triazine Derivatives for in Vivo Imaging of Phosphodiesterase 2A in Brain via Positron Emission Tomography
Molecules 2015, 20(6), 9591-9615; doi:10.3390/molecules20069591
Received: 17 April 2015 / Revised: 4 May 2015 / Accepted: 18 May 2015 / Published: 26 May 2015
Cited by 7 | PDF Full-text (2462 KB) | HTML Full-text | XML Full-text
Abstract
Phosphodiesterase 2A (PDE2A) is highly and specifically expressed in particular brain regions that are affected by neurological disorders and in certain tumors. Development of a specific PDE2A radioligand would enable molecular imaging of the PDE2A protein via positron emission tomography (PET). Herein we
[...] Read more.
Phosphodiesterase 2A (PDE2A) is highly and specifically expressed in particular brain regions that are affected by neurological disorders and in certain tumors. Development of a specific PDE2A radioligand would enable molecular imaging of the PDE2A protein via positron emission tomography (PET). Herein we report on the syntheses of three novel fluoroalkylated triazine derivatives (TA24) and on the evaluation of their effect on the enzymatic activity of human PDE2A. The most potent PDE2A inhibitors were 18F-radiolabelled ([18F]TA3 and [18F]TA4) and investigated regarding their potential as PET radioligands for imaging of PDE2A in mouse brain. In vitro autoradiography on rat brain displayed region-specific distribution of [18F]TA3 and [18F]TA4, which is consistent with the expression pattern of PDE2A protein. Metabolism studies of both [18F]TA3 and [18F]TA4 in mice showed a significant accumulation of two major radiometabolites of each radioligand in brain as investigated by micellar radio-chromatography. Small-animal PET/MR studies in mice using [18F]TA3 revealed a constantly increasing uptake of activity in the non-target region cerebellum, which may be caused by the accumulation of brain penetrating radiometabolites. Hence, [18F]TA3 and [18F]TA4 are exclusively suitable for in vitro investigation of PDE2A. Nevertheless, further structural modification of these promising radioligands might result in metabolically stable derivatives. Full article
(This article belongs to the Special Issue Preparation of Radiopharmaceuticals and Their Use in Drug Development)
Open AccessArticle Preliminary Biological Evaluation of 18F-FBEM-Cys-Annexin V a Novel Apoptosis Imaging Agent
Molecules 2015, 20(3), 4902-4914; doi:10.3390/molecules20034902
Received: 22 December 2014 / Revised: 24 February 2015 / Accepted: 6 March 2015 / Published: 17 March 2015
Cited by 7 | PDF Full-text (1737 KB) | HTML Full-text | XML Full-text
Abstract
A novel annexin V derivative (Cys-Annexin V) with a single cysteine residue at its C-terminal has been developed and successfully labeled site-specifically with 18F-FBEM. 18F-FBEM was synthesized by coupling 18F-fluorobenzoic acid (18F-FBA) with N-(2-aminoethyl)maleimide using optimized reaction conditions.
[...] Read more.
A novel annexin V derivative (Cys-Annexin V) with a single cysteine residue at its C-terminal has been developed and successfully labeled site-specifically with 18F-FBEM. 18F-FBEM was synthesized by coupling 18F-fluorobenzoic acid (18F-FBA) with N-(2-aminoethyl)maleimide using optimized reaction conditions. The yield of 18F-FBEM-Cys-Annexin V was 71.5% ± 2.0% (n = 4, based on the starting 18F-FBEM, non-decay corrected). The radiochemical purity of 18F-FBEM-Cys-Annexin V was >95%. The specific radioactivities of 18F-FBEM and 18F-FBEM-Cys-Annexin V were >150 and 3.17 GBq/µmol, respectively. Like the 1st generation 18F-SFB-Annexin V, the novel 18F-FBEM-Cys-Annexin V mainly shows renal and to a lesser extent, hepatobiliary excretion in normal mice. In rat hepatic apoptosis models a 3.88 ± 0.05 (n = 4, 1 h) and 10.35 ± 0.08 (n = 4, 2 h) increase in hepatic uptake of 18F-FBEM-Cys-Annexin V compared to normal rats was observed after injection via the tail vein. The liver uptake ratio (treated/control) at 2 h p.i. as measured via microPET correlated with the ratio of apoptotic nuclei in liver observed using TUNEL histochemistry, indicating that the novel 18F-FBEM-Cys-Annexin V is a potential apoptosis imaging agent. Full article
(This article belongs to the Special Issue Preparation of Radiopharmaceuticals and Their Use in Drug Development)
Open AccessArticle Synthesis and in Silico Evaluation of Novel Compounds for PET-Based Investigations of the Norepinephrine Transporter
Molecules 2015, 20(1), 1712-1730; doi:10.3390/molecules20011712
Received: 20 November 2014 / Revised: 7 January 2015 / Accepted: 14 January 2015 / Published: 20 January 2015
Cited by 4 | PDF Full-text (1308 KB) | HTML Full-text | XML Full-text
Abstract
Since the norepinephrine transporter (NET) is involved in a variety of diseases, the investigation of underlying dysregulation-mechanisms of the norepinephrine (NE) system is of major interest. Based on the previously described highly potent and selective NET ligand 1-(3-(methylamino)-1-phenylpropyl)-3-phenyl-1,3-dihydro-2H-benzimidaz- ol-2-one (Me@APPI), this
[...] Read more.
Since the norepinephrine transporter (NET) is involved in a variety of diseases, the investigation of underlying dysregulation-mechanisms of the norepinephrine (NE) system is of major interest. Based on the previously described highly potent and selective NET ligand 1-(3-(methylamino)-1-phenylpropyl)-3-phenyl-1,3-dihydro-2H-benzimidaz- ol-2-one (Me@APPI), this paper aims at the development of several fluorinated methylamine-based analogs of this compound. The newly synthesized compounds were computationally evaluated for their interactions with the monoamine transporters and represent reference compounds for PET-based investigation of the NET. Full article
(This article belongs to the Special Issue Preparation of Radiopharmaceuticals and Their Use in Drug Development)

Review

Jump to: Research

Open AccessReview Methods to Increase the Metabolic Stability of 18F-Radiotracers
Molecules 2015, 20(9), 16186-16220; doi:10.3390/molecules200916186
Received: 16 June 2015 / Revised: 20 August 2015 / Accepted: 26 August 2015 / Published: 3 September 2015
Cited by 8 | PDF Full-text (1526 KB) | HTML Full-text | XML Full-text
Abstract
The majority of pharmaceuticals and other organic compounds incorporating radiotracers that are considered foreign to the body undergo metabolic changes in vivo. Metabolic degradation of these drugs is commonly caused by a system of enzymes of low substrate specificity requirement, which is
[...] Read more.
The majority of pharmaceuticals and other organic compounds incorporating radiotracers that are considered foreign to the body undergo metabolic changes in vivo. Metabolic degradation of these drugs is commonly caused by a system of enzymes of low substrate specificity requirement, which is present mainly in the liver, but drug metabolism may also take place in the kidneys or other organs. Thus, radiotracers and all other pharmaceuticals are faced with enormous challenges to maintain their stability in vivo highlighting the importance of their structure. Often in practice, such biologically active molecules exhibit these properties in vitro, but fail during in vivo studies due to obtaining an increased metabolism within minutes. Many pharmacologically and biologically interesting compounds never see application due to their lack of stability. One of the most important issues of radiotracers development based on fluorine-18 is the stability in vitro and in vivo. Sometimes, the metabolism of 18F-radiotracers goes along with the cleavage of the C-F bond and with the rejection of [18F]fluoride mostly combined with high background and accumulation in the skeleton. This review deals with the impact of radiodefluorination and with approaches to stabilize the C-F bond to avoid the cleavage between fluorine and carbon. Full article
(This article belongs to the Special Issue Preparation of Radiopharmaceuticals and Their Use in Drug Development)
Open AccessReview 68Ga-Based Radiopharmaceuticals: Production and Application Relationship
Molecules 2015, 20(7), 12913-12943; doi:10.3390/molecules200712913
Received: 7 June 2015 / Revised: 25 June 2015 / Accepted: 6 July 2015 / Published: 16 July 2015
Cited by 24 | PDF Full-text (5371 KB) | HTML Full-text | XML Full-text
Abstract
The contribution of 68Ga to the promotion and expansion of clinical research and routine positron emission tomography (PET) for earlier better diagnostics and individualized medicine is considerable. The potential applications of 68Ga-comprising imaging agents include targeted, pre-targeted and non-targeted imaging. This
[...] Read more.
The contribution of 68Ga to the promotion and expansion of clinical research and routine positron emission tomography (PET) for earlier better diagnostics and individualized medicine is considerable. The potential applications of 68Ga-comprising imaging agents include targeted, pre-targeted and non-targeted imaging. This review discusses the key aspects of the production of 68Ga and 68Ga-based radiopharmaceuticals in the light of the impact of regulatory requirements and endpoint pre-clinical and clinical applications. Full article
(This article belongs to the Special Issue Preparation of Radiopharmaceuticals and Their Use in Drug Development)
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