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Background: Radiotheragnostics makes use of the same molecular targeting vectors, labeled either with a diagnostic or therapeutic radionuclide, ideally of the same chemical element. The matched pair of scandium radionuclides, Sc and Sc, satisfies the desired physical aspects for PET imaging and radionuclide therapy, respectively. While the production and application of Sc was extensively studied, Sc is still in its infancy. The aim of the present study was, therefore, to investigate and compare two different methods of Sc production, based on the neutron irradiation of enriched Ca and Ti targets, respectively. Methods: Sc was produced by thermal neutron irradiation of enriched Ca targets via the Ca(n,γ)Ca → Sc nuclear reaction and by fast neutron irradiation of Ti targets via the Ti(n,p)Sc nuclear reaction, respectively. The product was compared with regard to yield and radionuclidic purity. The chemical separation of Sc was optimized in order to obtain a product of sufficient quality determined by labeling experiments using DOTANOC. Finally, preclinical SPECT/CT experiments were performed in tumor-bearing mice and compared with the PET image of the Sc labeled counterpart. Results: Up to 2 GBq Sc was produced by thermal neutron irradiation of enriched Ca targets. The optimized chemical isolation of Sc from the target material allowed formulation of up to 1.5 GBq Sc with high radionuclidic purity (>99.99%) in a small volume (~700 μL) useful for labeling purposes. Three consecutive separations were possible by isolating the in-grown Sc from the Ca-containing fraction. Sc produced by fast neutron irradiated Ti targets resulted in a reduced radionuclidic purity (99.95-88.5%). The chemical purity of the separated Sc was determined by radiolabeling experiments using DOTANOC achievable at specific activities of 10 MBq/nmol. In vivo the Sc-DOTANOC performed equal to Sc-DOTANOC as determined by nuclear imaging. Conclusion: The production of Sc via the Ca(n,γ)Ca nuclear reaction demonstrated significant advantages over the Ti production route, as it provided higher quantities of a radionuclidically pure product. The subsequent decay of Ca enabled the repeated separation of the Sc daughter nuclide from the Ca parent nuclide. Based on the results obtained from this work, Sc shows potential to be produced in suitable quality for clinical application. [ABSTRACT FROM AUTHOR]

Background: Recently, 44 Sc (T1/2 =3.97h,Eβ+av = 632 keV, I = 94.3 %) has emerged as an attractive radiometal candidate for PET imaging using DOTA-functionalized biomolecules. The aim of this study was to investigate the potential of using NODAGA for the coordination of 44Sc. Two pairs of DOTA/NODAGA-derivatized peptides were investigated in vitro and in vivo and the results obtained with 44Sc compared with its 68Ga-labeled counterparts. DOTA-RGD and NODAGA-RGD, as well as DOTA-NOC and NODAGA-NOC, were labeled with 44Sc and 68Ga, respectively. The radiopeptides were investigated with regard to their stability in buffer solution and under metal challenge conditions using Fe3+ and Cu2+. Time-dependent biodistribution studies and PET/CT imaging were performed in U87MG and AR42J tumor-bearing mice. Results: Both RGD- and NOC-based peptides with a DOTA chelator were readily labeled with 44Sc and 68Ga, respectively, and remained stable over at least 4 half-lives of the corresponding radionuclide. In contrast, the labeling of NODAGA-functionalized peptides with 44Sc was more challenging and the resulting radiopeptides were clearly less stable than the DOTA-derivatized matches. 44Sc-NODAGA peptides were clearly more susceptible to metal challenge than 44Sc-DOTA peptides under the same conditions. Instability of 68Ga-labeled peptides was only observed if they were coordinated with a DOTA in the presence of excess Cu2+. Biodistribution data of the 44Sc-labeled peptides were largely comparable with the data obtained with the 68Ga-labeled counterparts. It was only in the liver tissue that the uptake of 68Ga-labeled DOTA compounds was markedly higher than for the 44 Sc-labeled version and this was also visible on PET/CT images. The 44Sc-labeled NODAGA-peptides showed a similar tissue distribution to those of the DOTA peptides without any obvious signs of in vivo instability. Conclusions: Although DOTA revealed to be the preferred chelator for stable coordination of 44Sc, the data presented in this work indicate the possibility of using NODAGA in combination with 44 Sc. In view of a clinical study, thorough investigations will be necessary regarding the labeling conditions and storage solutions in order to guarantee sufficient stability of 44 Sc-labeled NODAGA compounds. [ABSTRACT FROM AUTHOR]

Background: Terbium has attracted the attention of researchers and physicians due to the existence of four medically interesting radionuclides, potentially useful for SPECT and PET imaging, as well as for α- and β-radionuclide therapy. The aim of this study was to produce Tb ( T = 17.5 h, E = 1140 keV) and evaluate it in a preclinical setting in order to demonstrate its potential for PET imaging. For this purpose, DOTANOC was used for targeting the somatostatin receptor in AR42J tumor-bearing mice. Methods: Tb was produced by proton-induced spallation of tantalum targets, followed by an online isotope separation process at ISOLDE/CERN. After separation of Tb using cation exchange chromatography, it was directly employed for radiolabeling of DOTANOC. PET/CT scans were performed with AR42J tumor-bearing mice at different time points after injection of Tb-DOTANOC which was applied at variable molar peptide amounts. Lu-DOTANOC was prepared and used in biodistribution and SPECT/CT imaging studies for comparison with the PET results. Results: After purification, Tb was obtained at activities up to ~600 MBq. Radiolabeling of DOTANOC was achieved at a specific activity of 10 MBq/nmol with a radiochemical purity >98 %. The PET/CT scans of mice allowed visualization of AR42J tumor xenografts and the kidneys, in which the radiopeptide was accumulated. After injection of large peptide amounts, the tumor uptake was reduced as compared to the result after injection of small peptide amounts. PET images of mice, which received Tb-DOTANOC at small peptide amounts, revealed the best tumor-to-kidney ratios. The data obtained with Lu-DOTANOC in biodistribution and SPECT/CT imaging studies confirmed the Tb-based PET results. Conclusions: Production of 30-fold higher quantities of Tb as compared to the previously performed pilot study was feasible. This allowed, for the first time, labeling of a peptide at a reasonable specific activity and subsequent application for in vivo PET imaging. As a β-particle-emitting radiolanthanide, Tb would be of distinct value for clinical application, as it may allow exact prediction of the tissue distribution of therapeutic radiolanthanides. [ABSTRACT FROM AUTHOR]

Tb represents a powerful alternative to currently used α-emitters: the relatively short half-life (T = 4.1 h), low α-energy (3.97 MeV, I = 16.7 %), absence of α-emitting daughters and stable coordination via DOTA are favorable features for potential clinical application. In this letter, we wish to highlight the unique characteristics of Tb for PET imaging, based on its positron emission (E = 730 keV, I = 7.1 %) in addition to it's a therapeutic value. To this end, a preclinical study with a tumor-bearing mouse is presented. The perspective of alpha-PET makes Tb highly appealing for radiotheragnostic applications in future clinical trials. [ABSTRACT FROM AUTHOR]

The folate receptor (FR) is expressed in many tumor types, among those ovarian and lung cancer. Due to the high FR affinity of folic acid, it has been used for targeting of FR-positive tumors, allowing specific delivery of attached probes to the malignant tissue. Therefore, nuclear imaging of FR-positive cancer is of clinical interest for selecting patients who could benefit from innovative therapy concepts based on FR-targeting. Positron emission computed tomography (PET) has become an established technique in clinical routine because it provides an increased spatial resolution and higher sensitivity compared to single photon emission computed tomography (SPECT). Therefore, it is of critical importance to develop folate radiotracers suitable for PET imaging. This review article updates on the design, preparation and pre-clinical investigation of folate derivatives for radiolabeling with radioisotopes for PET. Among those the most relevant radionuclides so far are fluorine-18 (t½: 110 min, Eavβ+: 250 keV) and gallium-68 (t½: 68 min, Eav β+: 830 keV). Recent results obtained with new PET isotopes such as terbium-152 (t½: 17.5 h, Eβ+: 470 keV) or scandium-44 (t½: 3.97 h, Eav β+: 632 keV) are also presented and discussed. Current endeavors for clinical implementation of PET agents open new perspectives for identification of FR-positive malignancies in patients. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Use of folic acid radioconjugates for folate receptor (FR) targeting is a promising strategy for imaging purposes as well as for potential therapy of cancer and inflammatory diseases due to the frequent FR overexpression found on cancer cells and activated macrophages. Herein, we report on preclinical results using a novel DOTA-Bz-EDA-folate conjugate radiolabeled with [67Ga]-gallium. Methods: DOTA-Bz-EDA-folate was prepared by conjugation of ethylenediamine-(γ)-folate with 2-(p-isothiocyanobenzyl)-DOTA. Radiolabeling was carried out with 67GaCl3 according to standard procedures. Biodistribution studies of the tracer were performed in mice bearing FR-positive KB tumor xenografts. The effects on radiofolate biodistribution with coadministered renal uptake-blocking amino acids, diuretic agents, antifolates as well as different routes of administration were likewise investigated. Supportive imaging studies were performed using a small-animal single photon emission computed tomography (SPECT)/CT scanner. Results: 67Ga-DOTA-Bz-EDA-folate showed a high and specific accumulation in tumors (6.30%±0.75% ID/g, 1 h pi and 6.08%±0.89% ID/g, 4 h pi). Nonspecific radioactivity uptake in nontargeted tissues was negligible, but significant accumulation was found in FR-positive kidneys, which resulted in unfavorably low tumor-to-kidney ratios (<0.1). Coadministered amino acids or diuretics did not effectively reduce renal accumulation; in contrast, predosed pemetrexed did significantly reduce kidney uptake (<29% of control values). The SPECT/CT studies confirmed the excellent tumor-to-background contrast of 67Ga-radiofolate and the favorable reduction in kidney uptake (with improved imaging quality) resulting from pemetrexed administration. Conclusion: Conventional methods to reduce kidney uptake of radiofolates fail. However, the novel 67Ga-radiolabeled DOTA-Bz-EDA-folate can effectively be used to image FR-positive cancer and potentially inflammatory diseases. Due to its rapid blood clearance properties, this tracer is also a promising candidate for positron emission tomography imaging if radiolabeled with the short-lived [68Ga]-gallium radionuclide. [Copyright &y& Elsevier]

Prostate-specific antigen (PSA)-based screening for prostate cancer (PC) has dramatically increased early diagnosis. Current imaging techniques are not optimal to stage early PC adequately. A promising alternative to PC imaging is peptide-based scintigraphy using radiolabelled bombesin (BN) analogues that bind to gastrin-releasing peptide receptors (GRPR) being overexpressed in PC. When labelled to appropriate radionuclides BN targeting of GRPRs may also provide applications for peptide radionuclide receptor therapy (PRRT). Assessment studies under identical experimental conditions allowing a reliable comparison of the potential of such analogues are lacking. This study was performed to evaluate and directly compare five promising radiolabelled BN analogues for their targeting efficacy for PC under standardised conditions. The BN agonists [111In]DOTA-PESIN, [111In]AMBA, [111In]MP2346 and [111In]MP2653 and one antagonist [99mTc]Demobesin-1 were evaluated in GRPR-overexpressing human PC-3 tumour-bearing mice to determine peptide stability in vivo, biodistribution and GRPR targeting potential by animal SPECT/CT imaging and ex vivo autoradiography. HPLC analysis of blood showed intact Demobesin-1 at 5 and 15 min after injection (64.1 ± 1.6% and 41.0 ± 01%, respectively) being much less for the other compounds. AMBA, the second most stable analogue, showed 36.1 ± 2.7% and 9.8 ± 1.1% intact peptide after 5 and 15 min. PC-3 tumour uptake at 1 h was comparable for Demobesin-1, AMBA, PESIN and MP2346 (3.0 ± 0.4, 2.7 ± 0.5, 2.3 ± 0.5 and 2.1 ± 0.9%ID/g, respectively), but very low for MP2653 (0.9 ± 0.2%ID/g). In addition, MP2346 showed undesirably high uptake in the kidneys (7.9 ± 1.9%ID/g) being significantly less for the other analogues. AMBA, MP2346 and PESIN revealed favourable increases in tumour to blood ratios over time while changes in tumour to kidney and pancreas ratios for Demobesin-1 from 1 to 24 h after injection were significantly better than for the other analogues. All analogues visualised PC-3 tumours by SPECT/CT and autoradiography. In the present study the BN antagonist Demobesin-1 was the best performing analogue showing superior in vivo stability, highest tumour uptake and retention while pancreatic and renal clearance were rapid. PESIN and AMBA were the best GRP agonists with sufficient in vivo stabilities as well as high tumour uptake and retention. Based on these results all three analogues deserve further evaluation for clinical use in PC patients. [ABSTRACT FROM AUTHOR]

Proton therapy (PT) is a treatment with high dose conformality that delivers a highly-focused radiation dose to solid tumors. Targeted radionuclide therapy (TRT), on the other hand, is a systemic radiation therapy, which makes use of intravenously-applied radioconjugates. In this project, it was aimed to perform an initial dose-searching study for the combination of these treatment modalities in a preclinical setting. Therapy studies were performed with xenograft mouse models of folate receptor (FR)-positive KB and prostate-specific membrane antigen (PSMA)-positive PC-3 PIP tumors, respectively. PT and TRT using 177Lu-folate and 177Lu-PSMA-617, respectively, were applied either as single treatments or in combination. Monitoring of the mice over nine weeks revealed a similar tumor growth delay after PT and TRT, respectively, when equal tumor doses were delivered either by protons or by β¯-particles, respectively. Combining the methodologies to provide half-dose by either therapy approach resulted in equal (PC-3 PIP tumor model) or even slightly better therapy outcomes (KB tumor model). In separate experiments, preclinical positron emission tomography (PET) was performed to investigate tissue activation after proton irradiation of the tumor. The high-precision radiation delivery of PT was confirmed by the resulting PET images that accurately visualized the irradiated tumor tissue. In this study, the combination of PT and TRT resulted in an additive effect or a trend of synergistic effects, depending on the type of tumor xenograft. This study laid the foundation for future research regarding therapy options in the situation of metastasized solid tumors, where surgery or PT alone are not a solution but may profit from combination with systemic radiation therapy. [ABSTRACT FROM AUTHOR]

44Sc is a promising positron emission tomography (PET) radionuclide (T1/2 = 4.04 hours, Eβ+average = 632 keV) and can be made available, using a cyclotron production route, in substantial quantities as a highly pure product. Herein, the authors report on a first-in-human PET/CT study using 44Sc-DOTATOC prepared with cyclotron-produced 44Sc. The production of 44Sc was carried out through the 44Ca(p,n)44Sc nuclear reaction at Paul Scherrer Institut, Switzerland. After separation, 44Sc was shipped to Zentralklinik Bad Berka, Germany, where radiolabeling was performed, yielding radiochemically pure 44Sc-DOTATOC. Two patients, currently followed up after peptide receptor radionuclide therapy of metastatic neuroendocrine neoplasms, participated in this proof-of-concept study. Blood sampling was performed before and after application of 44Sc-DOTATOC. PET/CT acquisitions, performed at different time points after injection of 44Sc-DOTATOC, allowed detection of even very small lesions on delayed scans. No clinical adverse effects were observed and the laboratory hematological, renal, and hepatic profiles remained unchanged. In this study, cyclotron-produced 44Sc was used in the clinic for the first time. It is attractive for theranostic application with 177Lu, 90Y, or 47Sc as therapeutic counterparts. 44Sc-based radiopharmaceuticals will be of particular value for PET facilities without radiopharmacy, to which they can be shipped from a centralized production site. [ABSTRACT FROM AUTHOR]

Background: The favorable decay properties of Sc and Sc for PET make them promising candidates for future applications in nuclear medicine. An advantage Sc (T = 3.89 h, Eβ = 476 keV [88%]) exhibits over Sc, however, is the absence of co-emitted high energy γ-rays. While the production and application of Sc has been comprehensively discussed, research concerning Sc is still in its infancy. This study aimed at developing two different production routes for Sc, based on proton irradiation of enriched Ti and Ca target material. Results: Sc was produced via the Ti(p,α)Sc and Ca(p,n)Sc nuclear reactions, yielding activities of up to 225 MBq and 480 MBq, respectively. Sc was chemically separated from enriched metallic Ti (97.0%) and CaCO (57.9%) targets, using extraction chromatography. In both cases, ~90% of the final activity was eluted in a small volume of 700 μL, thereby, making it suitable for direct radiolabeling. The prepared products were of high radionuclidic purity, i.e. 98.2% Sc were achieved from the irradiation of Ti, whereas the product isolated from irradiated Ca consisted of 66.2% Sc and 33.3% Sc. A PET phantom study performed with Sc, via both nuclear reactions, revealed slightly improved resolution over Sc. In order to assess the chemical purity of the separated Sc, radiolabeling experiments were performed with DOTANOC, attaining specific activities of 5-8 MBq/nmol, respectively, with a radiochemical yield of >96%. Conclusions: It was determined that higher Sc activities were accessible via the Ca production route, with a comparatively less complex target preparation and separation procedure. The product isolated from irradiated Ti, however, revealed purer Sc with minor radionuclidic impurities. Based on the results obtained herein, the Ca route features some advantages (such as higher yields and direct usage of the purchased target material) over the Ti path when aiming at Sc production on a routine basis. [ABSTRACT FROM AUTHOR]

Background: The folate receptor alpha (FRα) is an interesting target for imaging and therapy of different cancers. We present the first in-human radiation dosimetry and radiation safety results acquired within a prospective, multicentric trial (NCT03242993) evaluating the 18F-AzaFol (3′-aza-2′-[18F]fluorofolic acid) as the first clinically assessed PET tracer targeting the FRα. Material and methods: Six eligible patients presented a histologically confirmed adenocarcinoma of the lung with measurable lesions (≥ 10 mm according to RECIST 1.1). TOF-PET images were acquired at 3, 11, 18, 30, 40, 50, and 60 min after the intravenous injection of 327 MBq (range 299–399 MBq) of 18F-AzaFol to establish dosimetry. Organ absorbed doses (AD), tumor AD, and patient effective doses (E) were assessed using the OLINDA/EXM v.2.0 software and compared with pre-clinical results. Results: No serious related adverse events were observed. The highest AD were in the liver, the kidneys, the urinary bladder, and the spleen (51.9, 45.8, 39.1, and 35.4 μGy/MBq, respectively). Estimated patient and gender-averaged E were 18.0 ± 2.6 and 19.7 ± 1.4 μSv/MBq, respectively. E in-human exceeded the value of 14.0 μSv/MBq extrapolated from pre-clinical data. Average tumor AD was 34.8 μGy/MBq (range 13.6–60.5 μGy/MBq). Conclusions: 18F-Azafol is a PET agent with favorable dosimetric properties and a reasonable radiation dose burden for patients which merits further evaluation to assess its performance. Trial registration: ClinicalTrial.gov, NCT03242993, posted on August 8, 2017 [ABSTRACT FROM AUTHOR]

In this study, it was aimed to investigate 149Tb-PSMA-617 for targeted α-therapy (TAT) using a mouse model of prostate-specific membrane antigen (PSMA)-expressing prostate cancer. 149Tb-PSMA-617 was prepared with >98% radiochemical purity (6 MBq/nmol) for the treatment of mice with PSMA-positive PC-3 PIP tumors. 149Tb-PSMA-617 was applied at 1 × 6 MBq (Day 0) or 2 × 3 MBq (Day 0 & Day 1 or Day 0 & Day 3) and the mice were monitored over time until they had reached a pre-defined endpoint which required euthanasia. The tumor growth was significantly delayed in mice of the treated groups as compared to untreated controls (p < 0.05). TAT was most effective in mice injected with 2 × 3 MBq (Day 0 & 1) resulting in a median lifetime of 36 days, whereas in untreated mice, the median lifetime was only 20 days. Due to the β+-emission of 149Tb, tumor localization was feasible using PET/CT after injection of 149Tb-PSMA-617 (5 MBq). The PET images confirmed the selective accumulation of 149Tb-PSMA-617 in PC-3 PIP tumor xenografts. The unique characteristics of 149Tb for TAT make this radionuclide of particular interest for future clinical translation, thereby, potentially enabling PET-based imaging to monitor the radioligand's tissue distribution. [ABSTRACT FROM AUTHOR]

Background: 64Cu (T1/2 = 12.7 h) is an important radionuclide for diagnostic purposes and used for positron emission tomography (PET). A previous method utilized at Paul Scherrer Institute (PSI) proved to be unreliable and, while a method using anion exchange chromatography is a popular choice worldwide, it was felt a different approach was required to obtain a robust chemical separation method. Methods: Enriched 64Ni targets were created by electroplating on gold foil. The targets were irradiated with protons degraded to approximately 11 MeV at PSI's Injector 2 72 MeV research cyclotron and subsequently dissolved in HCl. The resultant solution was loaded onto AG MP‐50 cation exchange resin and the 64Cu separated from its target material and radiocobalt impurities, produced as part of the irradiation process, using various specific mixtures of HCl/acetone solution. The eluted product was evaporated and picked up in dilute HCl (0.05 M). The chemical purity of 64Cu was determined by radiolabeling experiments at the highest possible molar activities. Results: Reproducible results were obtained, yielding 3.6 to 8.3 GBq 64Cu of high radionuclidic and radiochemical purity. The product was labeled to NODAGA‐RGD, achieved at up to 500 MBq/nmol, indicating the high chemical purity. In a proof‐of‐concept in vivo study, 64Cu‐NODAGA‐RGD was used for PET imaging of a tumor‐bearing mouse. Conclusion: The chemical separation devised to produce high‐quality 64Cu proved to be robust and reproducible. The concept can be used at medical cyclotrons utilizing a solid target station, such that 64Cu can be used at hospitals for PET imaging. [ABSTRACT FROM AUTHOR]

Introduction 44 Sc, a PET radionuclide, has promising decay characteristics (T 1/2 = 3.97 h, Eβ + av = 632 keV) for nuclear imaging and is an attractive alternative to the short-lived 68 Ga (T 1/2 = 68 min, Eβ + av = 830 keV). The aim of this study was the optimization of the 44 Sc production process at an accelerator, allowing its use for preclinical and clinical PET imaging. Methods 44 CaCO 3 targets were prepared and irradiated with protons (~ 11 MeV) at a beam current of 50 μA for 90 min. 44 Sc was separated from its target material using DGA extraction resin and concentrated using SCX cation exchange resin. Radiolabeling experiments at activities up to 500 MBq and stability tests were performed with DOTANOC by investigating different scavengers, including gentisic acid. Dynamic PET of an AR42J tumor-bearing mouse was performed after injection of 44 Sc-DOTANOC. Results The optimized chemical separation method yielded up to 2 GBq 44 Sc of high radionuclidic purity. In the presence of gentisic acid, radiolabeling of 44 Sc with DOTANOC was achieved with a radiochemical yield of ~ 99% at high specific activity (10 MBq/nmol) and quantities which would allow clinical application. The dynamic PET images visualized increasing uptake of 44 Sc-DOTANOC into AR42J tumors and excretion of radioactivity through the kidneys of the investigated mouse. Conclusions The concept “from-bench-to-bedside” was clearly demonstrated in this extended study using cyclotron-produced 44 Sc. Sufficiently high activities of 44 Sc of excellent radionuclidic purity are obtainable for clinical application, by irradiation of enriched calcium at a cyclotron. This work demonstrates a promising basis for introducing 44 Sc to clinical routine of nuclear imaging using PET. [ABSTRACT FROM AUTHOR]

Purpose: The folate receptor (FR) is a promising target for nuclear imaging due to its overexpression in many different cancer types. A drawback of using folate radioconjugates is the high accumulation of radioactivity in the kidneys. Therefore, the aim of this study was to develop a 18 F-labeled folate conjugate with an albumin-binding entity to enhance the blood circulation time and hence improve the tumor-to-kidney ratio. Procedures: The novel 18 F-folate was prepared by conjugation of a 18 F-labeled glucose azide to an alkyne-functionalized folate precursor containing an albumin-binding entity via Cu(I)-catalyzed 1,3-dipolar cycloaddition. The radioconjugate was tested in vitro on FR-positive KB tumor cells and by biodistribution and positron emission tomography (PET) imaging studies using KB tumor-bearing mice. Results: The radiosynthesis of the albumin-binding [ 18 F]fluorodeoxyglucose–folate ([ 18 F]3) resulted in a radiochemical yield of 1–2 % decay corrected (d.c.) and a radiochemical purity of ≥95 %. The specific activity of [ 18 F]3 ranged from 20 to 50 GBq/μmol. In vitro experiments revealed FR-specific binding of [ 18 F]3 to KB tumor cells. In vivo we found an increasing uptake of [ 18 F]3 into tumor xenografts over time reaching a value of ∼ 15 % injected dose (ID)/g at 4 h post-injection (p.i.). Uptake in the kidneys (∼ 13 % ID/g; 1 h p.i.) was approximately fourfold reduced compared to previously published 18 F-labeled folic acid derivatives. An excellent visualization of tumor xenografts with an unprecedentedly high tumor-to-kidney ratio (∼ 1) was obtained by PET imaging. Conclusions: [ 18 F]3 showed a favorable accumulation in tumor xenografts compared to the same folate conjugate without albumin-binding properties. Moreover, the increased tumor-to-kidney ratios improved the PET imaging quality significantly, in spite of a somewhat higher background radioactivity which was a consequence of the slower blood clearance of [ 18 F]3. [ABSTRACT FROM AUTHOR]

Radiolabeled folate derivatives have the potential to target folate receptor-positive tumor cells for noninvasive diagnosis via positron emission tomography (PET) and single photon emission computed tomography (SPECT). We report the regiospecific synthesis of N2-(N,N-dimethylaminomethylene)-2¢-nitrofolic acid di-tert-butyl ester (13) and N2-(N,N-dimethylaminomethylene)-N10- formyl-2¢-nitrofolic acid dimethyl ester (25), which are precursors for the radiolabeling of folic acid with the PET isotope 18F. A modular synthetic strategy was applied: Fmoc- and Boc-protected 4-amino- 2-nitrobenzoic acid were linked via amide bonds to di-tert-butyl L-glutamate and dimethyl L-glutamate, respectively, to form building blocks 10 and 19. After Fmoc and Boc removal, both compounds were coupled to 6-(bromomethyl)pterin hydrobromide to give crude 2¢-nitrofolic acid di-tert-butyl ester and 2¢-nitrofolic acid dimethyl ester. After formylation of 2¢-nitrofolic acid dimethyl ester at N10 and the introduction of an N,N-dimethylaminomethylene group at N2, precursor 25 was obtained in an overall yield of 3%. The analogous 2¢-fluoroderivative 28 was obtained in 7% overall yield from 4-amino-2-fluorobenzoic acid. Precursor 13 was obtained from 2¢-nitrofolic acid di-tert-butyl ester in 6% yield after N2-protection. The synthesis of the reference materials 2¢-nitro- and 2¢-fluorofolic acid was achieved by the reaction of N-(4-amino-2- nitrobenzoyl)- and N-(4-amino-2-fluorobenzoyl)-L-glutamic acid with 6-(bromomethyl)pterin hydrobromide, giving 7% and 14% overall yield, respectively. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: Radiolabeled bombesin (BN) conjugates are promising radiotracers for imaging and therapy of breast and prostate tumors in which BN2/gastrin-releasing peptide (GRP) receptors are overexpressed. However, the low in vivo stability of BN conjugates may limit their clinical application. In an attempt to improve their pharmacokinetics and counteract their rapid enzymatic degradation, we prepared a series of polyethylene glycol (PEG)-ylated BN(7-14) analogues for radiolabeling with 99mTc(CO)3 and evaluated them in vitro and in vivo. Methods: Derivatization of a stabilized (NαHis)Ac-BN(7-14)[Cha13,Nle14] analogue with linear PEG molecules of various sizes [5 kDa (PEG5), 10 kDa (PEG10) and 20 kDa (PEG20)] was performed by PEGylation of the ɛ-amino group of a β3hLys-βAla-βAla spacer between the stabilized BN sequence and the (NαHis)Ac chelator. The analogues were then radiolabeled by employing the 99mTc-tricarbonyl technique. Binding affinity and internalization/externalization studies were performed in vitro in human prostate carcinoma PC-3 cells. Stability was investigated in vitro in human plasma and in vivo in Balb/c mice. Finally, single photon emission computed tomography (SPECT)/X-ray computed tomography studies were performed in nude mice bearing PC-3 tumor xenografts. Results: PEGylation did not affect the binding affinity of BN analogues, as the binding affinity for BN2/GRP receptors remained high (K d<0.9 nM). However, in vitro binding kinetics of the PEGylated analogues were slower. Steady-state condition was reached after 4 h, and the total cell binding was 10 times lower than that for the non-PEGylated counterpart. Besides, PEGylation improved the stability of BN conjugates in vitro and in vivo. The BN derivative conjugated with a PEG5 molecule showed the best pharmacokinetics in vivo, i.e., faster blood clearance and preferential renal excretion. The tumor uptake of the 99mTc-PEG5-Lys-BN conjugate was slightly higher compared to that of the non-PEGylated analogue (3.91%±0.44% vs. 2.80%±0.28% injected dose per gram 1 h postinjection, p.i.). Tumor retention was also increased, resulting in a threefold higher amount of radioactivity in the tumor at 24 h p.i. Furthermore, decreased hepatobiliary excretion and increased tumor-to-nontarget ratios (tumor-to-blood: 17.1 vs. 2.1; tumor-to-kidney: 1.1 vs. 0.4; tumor-to-liver: 5.8 vs. 1.0, 24 h p.i.) were observed and further confirmed via small-animal SPECT images 1 h p.i. Conclusion: PEGylation proved to be an effective strategy to enhance the tumor-targeting potential of 99mTc-labeled BN-based radiopharmaceuticals and probably other radiolabeled peptides. [Copyright &y& Elsevier]

Scandium-44 has been proposed as a valuable radionuclide for Positron Emission Tomography (PET). Recently, scandium-43 was introduced as a more favorable option, as it does not emit high-energy γ-radiation; however, its currently employed production method results in a mixture of scandium-43 and scandium-44. The interest in new radionuclides for diagnostic nuclear medicine critically depends on the option for image-based quantification. We aimed to evaluate and compare the quantitative capabilities of scandium-43/scandium-44 in a commercial PET/CT device with respect to more conventional clinical radionuclides (fluorine-18 and gallium-68). With this purpose, we characterized and compared quantitative PET data from a mixture of scandium-43/scandium-44 (~68% scandium-43), scandium-44, fluorine-18 and gallium-68, respectively. A NEMA image-quality phantom was filled with the different radionuclides using clinical-relevant lesion-to-background activity concentration ratios; images were acquired in a Siemens Biograph Vision PET/CT. Quantitative accuracy with scandium-43/scandium-44 in the phantom's background was within 9%, which is in agreement with fluorine-18-based PET standards. Coefficient of variance (COV) was 6.32% and signal recovery in the lesions provided RCmax (recovery coefficient) values of 0.66, 0.90, 1.03, 1.04, 1.12 and 1.11 for lesions of 10-, 13-, 17-, 22-, 28- and 37-mm diameter, respectively. These results are in agreement with EARL reference values for fluorine-18 PET. The results in this work showed that accurate quantitative scandium-43/44 PET/CT is achievable in commercial devices. This may promote the future introduction of scandium-43/44-labelled radiopharmaceuticals into clinical use. [ABSTRACT FROM AUTHOR]

44Sc has favorable properties for cancer diagnosis using Positron Emission Tomography (PET) making it a promising candidate for application in nuclear medicine. The implementation of its production with existing compact medical cyclotrons would mean the next essential milestone in the development of this radionuclide. While the production and application of 44Sc has been comprehensively investigated, the development of specific targetry and irradiation methods is of paramount importance. As a result, the target was optimized for the 44Ca(p,n)44Sc nuclear reaction using CaO instead of CaCO3, ensuring decrease in target radioactive degassing during irradiation and increased radionuclidic yield. Irradiations were performed at the research cyclotron at the Paul Scherrer Institute (~11 MeV, 50 µA, 90 min) and the medical cyclotron at the University of Bern (~13 MeV, 10 µA, 240 min), with yields varying from 200 MBq to 16 GBq. The development of targetry, chemical separation as well as the practical issues and implications of irradiations, are analyzed and discussed. As a proof-of-concept study, the 44Sc produced at the medical cyclotron was used for a preclinical study using a previously developed albumin-binding prostate-specific membrane antigen (PSMA) ligand. This work demonstrates the feasibility to produce 44Sc with high yields and radionuclidic purity using a medical cyclotron, equipped with a commercial solid target station. [ABSTRACT FROM AUTHOR]

Overexpression of folate receptors (FRs) on different tumor types (e.g., ovarian, lung) make FRs attractive in vivo targets for directed diagnostic/therapeutic agents. Currently, no diagnostic agent suitable for positron emission tomography (PET) has been adopted for clinical FR imaging. In this work, two 55Co-labeled albumin-binding folate derivatives-[55Co]Co-cm10 and [55Co]Co-rf42-with characteristics suitable for PET imaging have been developed and evaluated. High radiochemical yields (≥95%) and in vitro stabilities (≥93%) were achieved for both compounds, and cell assays demonstrated FR-mediated uptake. Both 55Co-labeled folate conjugates demonstrated high tumor uptake of 17% injected activity per gram of tissue (IA/g) at 4 h in biodistribution studies performed in KB tumor-bearing mice. Renal uptake was similar to other albumin-binding folate derivatives, and liver uptake was lower than that of previously reported [64Cu]Cu-rf42. Small animal PET/CT images confirmed the biodistribution results and showed the clear delineation of FR-expressing tumors. [ABSTRACT FROM AUTHOR]