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The butyric acid scaffold is the base structure of several human metabolites that serve diverse and prominent biochemical roles including as oxidative sources of cellular energy and as substrates for biosynthesis. Derivatization of metabolites through incorporation of fluorine often alters bioactivity and can facilitate detection and analysis by nuclear magnetic resonance or positron emission tomography depending upon the fluorine isotope employed. We describe the synthesis of two new fluorinated butyric acids (and three related esters) that are derivatives of the metabolites acetoacetic acid and 3-hydroxybutyric acid. 4-Fluoro-3-hydroxybutyric acid is prepared from epoxy ester precursors via ring opening by triethylamine trihydrofluoride. 2-Fluoroacetoacetic acid is prepared by electrophilic fluorination of an acid-labile β-keto ester. The gradual pH-dependent decarboxylation of 2-fluoroacetoacetic acid is investigated by19 F NMR spectroscopy. [ABSTRACT FROM AUTHOR]

Radiolabeled peptides have been the subject of intense research efforts for targeted diagnostic imaging and radiotherapy over the last 20 years. Peptides offer several advantages for receptor imaging and targeted radiotherapy. The low molecular weight of peptides allows for rapid clearance from the blood and non-target tissue, which results in favorable target-to-non-target ratios. Moreover, peptides usually display good tissue penetration and they are generally non-immunogenic. A major drawback is their potential low metabolic stability. The majority of currently used radiolabeled peptides for targeted molecular imaging and therapy of cancer is labeled with various radiometals like 99mTc, 68Ga, and 177Lu. However, over the last decade an increasing number of 18F-labeled peptides have been reported. Despite of obvious advantages of 18F like its ease of production in large quantities at high specific activity, the low β+ energy (0.64 MeV) and the favorable half-life (109.8 min), 18F-labeling of peptides remains a special challenge. The first part of this review will provide a brief overview on chemical strategies for peptide labeling with 18F. A second part will discuss recent technological advances for 18F-labeling of peptides with special focus on microfluidic technology, automation, and kit-like preparation of 18F-labeled peptides. [ABSTRACT FROM AUTHOR]

4-[18F]Fluoroiodobenzene ([18F]FIB) is a versatile building block in 18F radiochemistry used in various transition metal-mediated C-C and C-N cross-coupling reactions and [18F]fluoroarylation reactions. Various synthesis routes have been described for the preparation of [18F]FIB. However, to date, no automated synthesis of [18F]FIB has been reported to allow access to larger amounts of [18F]FIB in high radiochemical and chemical purity. Herein, we describe an automated synthesis of no-carrier-added [18F]FIB on a GE TRACERlab™ FX automated synthesis unit starting from commercially available (4-iodophenyl)diphenylsulfonium triflate as the labelling precursor. [18F]FIB was prepared in high radiochemical yields of 89 ± 10% (decay-corrected, n = 7) within 60 min, including HPLC purification. The radiochemical purity exceeded 95%, and specific activity was greater than 40 GBq/µmol. Typically, from an experiment, 6.4 GBq of [18F]FIB could be obtained starting from 10.4 GBq of [18F]fluoride. Copyright © 2013 John Wiley & Sons, Ltd. [ABSTRACT FROM AUTHOR]

Radiolabeling of peptides with the short-lived positron emitter fluorine-18 is usually a challenging endeavour. Conventional radiolabeling reactions mostly require fairly large amounts of peptides as labeling precursors, and extensive synthesis times. Intrinsic advantages of microfluidic technology permit to overcome these hurdles. Herein, we describe how microfluidic technology combined with [18F]FDG as readily available PET radiotracer allows for fast and high yielding radiolabeling reactions of peptides with fluorine-18. [ABSTRACT FROM AUTHOR]

Positron emission tomography (PET) is a preclinical and clinical imaging technique extensively used to study and visualize biological and physiological processes in vivo. Fluorine-18 (18F) is the most frequently used positron emitter for PET imaging due to its convenient 109.8 min half-life, high yield production on small biomedical cyclotrons, and well-established radiofluorination chemistry. The presence of fluorine atoms in many drugs opens new possibilities for developing radioligands labelled with fluorine-18. The trifluoromethyl group (CF3) represents a versatile structural motif in medicinal and pharmaceutical chemistry to design and synthesize drug molecules with favourable pharmacological properties. This fact also makes CF3 groups an exciting synthesis target from a PET tracer discovery perspective. Early attempts to synthesize [18F]CF3-containing radiotracers were mainly hampered by low radiochemical yields and additional challenges such as low radiochemical purity and molar activity. However, recent innovations in [18F]trifluoromethylation chemistry have significantly expanded the chemical toolbox to synthesize fluorine-18-labelled radiotracers. This review presents the development of significant [18F]trifluoromethylation chemistry strategies to apply [18F]CF3-containing radiotracers in preclinical and clinical PET imaging studies. The continuous growth of PET as a crucial functional imaging technique in biomedical and clinical research and the increasing number of CF3-containing drugs will be the primary drivers for developing novel [18F]trifluoromethylation chemistry strategies in the future. [ABSTRACT FROM AUTHOR]

Abstract: Introduction: 4-[18F]Fluorobenzylamine ([18F]FBA) is an important building block for the synthesis of 18F-labeled compounds. Synthesis of [18F]FBA usually involves application of strong reducing agents like LiAlH4 which is challenging to handle in automated synthesis units (ASUs). Therefore, alternative methods for the preparation of [18F]FBA compatible with remotely-controlled syntheses in ASUs are needed. Methods: 18F]FBA was prepared in a remotely-controlled synthesis unit (GE TRACERlab™ FX) based on Ni(II)-mediated borohydride exchange resin (BER) reduction of 4-[18F]fluorobenzonitrile ([18F]FBN). [18F]FBA was used for the synthesis of novel thiol-reactive prosthetic group 4-[18F]fluorobenzyl)maleimide [18F]FBM and Hsp90 inhibitor 17-(4-[18F]fluorobenzylamino)-17-demethoxy-geldanamycin [18F] GA. Results: [18F]FBA could be prepared in high radiochemical yield greater than 80% (decay-corrected) within 60min. In a typical experiment, 7.4GBq of [18F]FBA could be obtained in high radiochemical purity of greater than 95% starting from 10GBq of cyclotron-produced n.c.a. [18F]fluoride. [18F]FBA was used for the preparation of 4-[18F]fluorobenzyl)maleimide as a novel prosthetic group for labeling of thiol groups as demonstrated with tripeptide glutathione. [18F]FBA was also used as building block for the syntheses of small molecules as exemplified by the preparation of Hsp90 inhibitor 17-(4-[18F]fluorobenzylamino)-17-demethoxy-geldanamycin. Conclusion: The described remotely-controlled synthesis of [18F]FBA will significantly improve the availability of [18F]FBA as an important and versatile building block for the development of novel 18F-labeled compounds containing a fluorobenzylamine moiety. [Copyright &y& Elsevier]

Localized hypoxia, the physiological hallmark of many clinical pathologies, is the consequence of acute or chronic ischemia in the affected region or tissue. The versatility, sensitivity, quantitative nature, and increasing availability of positron emission tomography (PET) make it the preclinical and clinical method of choice for functional imaging of tissue hypoxia at the molecular level. The progress and current status of radiotracers for hypoxia-specific PET imaging are reviewed in this article including references mainly focused on radiochemistry and also relevant to molecular imaging of hypoxia in preclinical and clinical studies. [ABSTRACT FROM AUTHOR]

Abstract: The development of rapid radiolabeling techniques under mild reaction conditions involving the short-lived positron emitter fluorine-18 remains a special challenge in organic PET chemistry. This work describes a novel and facile application of the traceless Staudinger ligation as a mild and versatile labeling method for preparation of various radiotracers labeled with fluorine-18. [Copyright &y& Elsevier]

Abstract: The radiosynthesis of [N-methyl-11C]Org 34850 as a potential brain glucocorticoid receptor (GR)-binding radiotracer is described. The radiosynthesis was accomplished via N-methylation of the corresponding desmethyl precursor with [11C]methyl triflate in a remotely controlled synthesis module to give the desired compound in a radiochemical yield of 23±5% (decay-corrected, based upon [11C]CO2) at a specific activity of 47±12GBq/μmol (n=15) at the end-of-synthesis (EOS). The radiochemical purity after semi-preparative HPLC purification exceeded 95%. The total synthesis time was 35–40min after end-of-bombardment (EOB). The radiotracer is rapidly metabolized in rat plasma leading to the formation of two more hydrophilic metabolites as the major metabolites. Radiopharmacological evaluation involving biodistribution and small animal PET imaging in normal Wistar rats showed that the compound [N-methyl-11C]Org 34850 is not able to sufficiently penetrate the blood–brain barrier. Therefore, compound [N-methyl-11C]Org 34850 seems not to be a suitable PET radiotracer for imaging rat brain GRs. However, involvement of Pgp or species differences requires further clarification to establish whether the radiotracer [N-methyl-11C]Org 34850 may still represent a suitable candidate for imaging GRs in humans. [Copyright &y& Elsevier]

Abstract: A series of 1,4- and 1,5-diaryl substituted 1,2,3-triazoles was synthesized by either Cu(I)-catalyzed or Ru(II)-catalyzed 1,3-dipolar cycloaddition reactions between 1-azido-4-methane-sulfonylbenzene 9 and a panel of various para-substituted phenyl acetylenes (4-H, 4-Me, 4-OMe, 4-NMe2, 4-Cl, 4-F). All compounds were used in in vitro cyclooxygenase (COX) assays to determine the combined electronic and steric effects upon COX-1 and COX-2 inhibitory potency and selectivity. Structure-activity relationship studies showed that compounds having a vicinal diaryl substitution pattern showed more potent COX-2 inhibition (IC50 =0.03–0.36μM) compared to their corresponding 1,3-diaryl-substituted counterparts (IC50 =0.15 to >10.0μM). In both series, compounds possessing an electron-withdrawing group (Cl and F) at the para-position of one of the aryl rings displayed higher COX-2 inhibition potency and selectivity as determined for compounds containing electron-donating groups (Me, OMe, NMe2). The obtained data show, that the central carbocyclic or heterocyclic ring system as found in many COX-2 inhibitors can be replaced by a central 1,2,3-triazole unit without losing COX-2 inhibition potency and selectivity. The high COX-2 inhibition potency of some 1,2,3-triazoles having a vicinal diaryl substitution pattern along with their ease in synthesis through versatile Ru(II)-catalyzed click chemistry make this class of compounds interesting candidates for further design and synthesis of highly selective and potent COX-2 inhibitors. [Copyright &y& Elsevier]

Abstract: The radiosynthesis and radiopharmacological evaluation of 1-[11C]methoxy-4-(2-(4-(methanesulfonyl)phenyl)cyclopent-1-enyl)-benzene [ 11 C]5 as novel PET radiotracer for imaging of COX-2 expression is described. The radiotracer was prepared via O-methylation reaction with [11C]methyl iodide in 19% decay-corrected radiochemical yield at a specific activity of 20–25GBq/μmol at the end-of-synthesis within 35min. The radiotracer [ 11 C]5 was evaluated in vitro using various pro-inflammatory and tumor cell lines showing high functional expression of COX-2 at baseline or after induction. In vivo biodistribution of compound [ 11 C]5 was characterized in male Wistar rats. Compound [ 11 C]5 was rapidly metabolized in rat plasma, and more pronounced, in mouse plasma. In vivo kinetics and tumor uptake were demonstrated by dynamic small animal PET studies in a mouse tumor xenograft model. Tumor uptake of radioactivity was clearly visible overtime. However, radioactivity uptake in the tumor could not be blocked by the pre-injection of nonradioactive compound 5. Therefore, it can be concluded that radioactivity uptake in the tumor was not COX-2 mediated. [Copyright &y& Elsevier]

Abstract: In our effort to develop imaging agents for brain glucocorticoid receptors, we have prepared several novel glucocorticoids possessing a 2-methylsulfanyl-acetyl side chain. The synthesis was accomplished via a Mitsunobu reaction with thiobenzoic acid starting from cortisol, prednisolone, dexamethasone and triamcinolone acetonide to give the corresponding S-thiobenzoates in 75–82% yield. Subsequent saponification and reaction with methyl iodide afforded C-21 methylthioethers in 68–82% yield. All compounds were tested in an in vitro glucocorticoid receptor-binding assay. Triamcinolone acetonide-based compound 12 showed promising binding affinity of 144% relative to dexamethasone (100%). Compound 12 was selected for radiolabeling with the short-lived positron emitter carbon-11. The radiolabeling was carried out starting from S-thiobenzoate 8 and in situ formation of the corresponding sodium thiolate, which was further reacted with [11C]methyl iodide. The obtained radiochemical yield was 20–30%. The specific activity was determined to be 20–40GBq/μmol at the end-of-synthesis, and the radiochemical purity exceeded 98%. [Copyright &y& Elsevier]

Abstract: The radiosynthesis and the radiopharmacological characterization of [ 11 C]AL-438 as a nonsteroidal ligand for the glucocorticoid receptor (GR) is described. Radiolabeling of the corresponding desmethyl precursor 10 with [11C]MeI gave [ 11 C]AL-438 in decay-corrected radiochemical yields of 30±4% (based upon [11C]CO2) within 35min at a specific radioactivity of 10–15GBq/μmol at the end-of-synthesis. The radiopharmacological evaluation of [ 11 C]AL-438 involved biodistribution and small animal PET imaging in rats, and autoradiography studies using rat brain sections. Biodistribution studies were performed in male Wistar rats and demonstrated high radioactivity uptake in pituitary and brain. However, the inability of high dose corticosterone to block binding would suggest that the radioactivity accumulation in the brain was not receptor-mediated. [Copyright &y& Elsevier]

Background: The radiometal gallium-68 (68Ga) is increasingly used in diagnostic positron emission tomography (PET), with 68Ga-labeled radiopharmaceuticals developed as potential higher-resolution imaging alternatives to traditional 99mTc agents. In precision medicine, PET applications of 68Ga are widespread, with 68Ga radiolabeled to a variety of radiotracers that evaluate perfusion and organ function, and target specific biomarkers found on tumor lesions such as prostate-specific membrane antigen, somatostatin, fibroblast activation protein, bombesin, and melanocortin. Main body: These 68Ga radiopharmaceuticals include agents such as [68Ga]Ga-macroaggregated albumin for myocardial perfusion evaluation, [68Ga]Ga-PLED for assessing renal function, [68Ga]Ga-t-butyl-HBED for assessing liver function, and [68Ga]Ga-PSMA for tumor imaging. The short half-life, favourable nuclear decay properties, ease of radiolabeling, and convenient availability through germanium-68 (68Ge) generators and cyclotron production routes strongly positions 68Ga for continued growth in clinical deployment. This progress motivates the development of a set of common guidelines and standards for the 68Ga radiopharmaceutical community, and recommendations for centers interested in establishing 68Ga radiopharmaceutical production. Conclusion: This review outlines important aspects of 68Ga radiopharmacy, including 68Ga production routes using a 68Ge/68Ga generator or medical cyclotron, standardized 68Ga radiolabeling methods, quality control procedures for clinical 68Ga radiopharmaceuticals, and suggested best practices for centers with established or upcoming 68Ga radiopharmaceutical production. Finally, an outlook on 68Ga radiopharmaceuticals is presented to highlight potential challenges and opportunities facing the community. [ABSTRACT FROM AUTHOR]

Lanthanum radiometals are well positioned to serve as theranostic PET radiometals for targeted radionuclide therapy. The positron emitters 132La and 133La show promise to serve as unique PET imaging agents for 225Ac targeted alpha-particle therapy, the 134Ce/134La pair has PET imaging potential with both 225Ac and 227Th, and 135La has potential in targeted Auger-Meitner electron therapy. With easily accessible cyclotron production routes, effective and efficient chemical separations, and robust chelation chemistry, these radionuclides are well poised for additional preclinical and clinical PET and targeted radionuclide therapy studies. This review summarizes recent advances in radiolanthanum production and preclinical applications that demonstrate the strong potential of these radionuclides in PET and targeted radionuclide therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

Molecular imaging probes enable the early and accurate detection of disease-specific biomarkers and facilitate personalized treatment of many chronic diseases, including cancer. Among current clinically used functional imaging modalities, positron emission tomography (PET) plays a significant role in cancer detection and in monitoring the response to therapeutic interventions. Several preclinical and clinical studies have demonstrated the crucial involvement of cyclooxygenase-2 (COX-2) isozyme in cancer development and progression, making COX-2 a promising cancer biomarker. A variety of COX-2-targeting PET radioligands has been developed based on anti-inflammatory drugs and selective COX-2 inhibitors. However, many of those suffer from non-specific binding and insufficient metabolic stability. This article highlights examples of COX-2-targeting PET radioligands labelled with the short-lived positron emitter 18F, including radiosynthesis and PET imaging studies published in the last decade (2012–2021). [ABSTRACT FROM AUTHOR]

Simple Summary: Being able to detect and image tumors is extremely important for proper diagnosis and treatment. The most sensitive technique, positron emission tomography (PET), is widely applied for such a purpose. Additionally, fluorescence imaging can be used to visually see the margins between healthy and cancerous tissue during surgery. These two techniques can be combined to optimize patient outcomes by ensuring maximum tumor removal. This review will discuss the work that has been done recently to combine these two imaging capabilities into one imaging agent. Dual probes that possess positron emission tomography (PET) and fluorescence imaging (FI) capabilities are precision medicine tools that can be used to improve patient care and outcomes. Detecting tumor lesions using PET, an extremely sensitive technique, coupled with fluorescence-guided surgical resection of said tumor lesions can maximize the removal of cancerous tissue. The development of novel molecular probes is important for targeting different biomarkers as every individual case of cancer has different characteristics. This short review will discuss some aspects of dual PET/FI probes and explore the recently reported examples. [ABSTRACT FROM AUTHOR]

Abstract: The study describes the use of [18F]FDG as 18F building block for the direct labelling of various aminooxy-functionalised peptides via chemoselective oxime formation. [Copyright &y& Elsevier]

Live‐cell imaging with fluorescent probes is an essential tool in chemical biology to visualize the dynamics of biological processes in real‐time. Intracellular disease biomarker imaging remains a formidable challenge due to the intrinsic limitations of conventional fluorescent probes and the complex nature of cells. This work reports the in cellulo assembly of a fluorescent probe to image cyclooxygenase‐2 (COX‐2). We developed celecoxib‐azide derivative 14, possessing favorable biophysical properties and excellent COX‐2 selectivity profile. In cellulo strain‐promoted fluorogenic click chemistry of COX‐2‐engaged compound 14 with non/weakly‐fluorescent compounds 11 and 17 formed fluorescent probes 15 and 18 for the detection of COX‐2 in living cells. Competitive binding studies, biophysical, and comprehensive computational analyses were used to describe protein‐ligand interactions. The reported new chemical toolbox enables precise visualization and tracking of COX‐2 in live cells with superior sensitivity in the visible range. [ABSTRACT FROM AUTHOR]

• Gasdermin D (GSDMD) activation occurs in oligodendrocytes and CNS macrophages. • GDSMD and Ninjurin 1 are induced in neuroinflammatory demyelination. • GSDMD genetic deletion reduces neuroinflammatory demyelination and axonal injury. • GSDMD activation represents a potential therapeutic target for progressive MS. Neuroinflammation coupled with demyelination and neuro-axonal damage in the central nervous system (CNS) contribute to disease advancement in progressive multiple sclerosis (P-MS). Inflammasome activation accompanied by proteolytic cleavage of gasdermin D (GSDMD) results in cellular hyperactivation and lytic death. Using multiple experimental platforms, we investigated the actions of GSDMD within the CNS and its contributions to P-MS. Brain tissues from persons with P-MS showed significantly increased expression of GSDMD, NINJ1, IL-1β, and −18 within chronic active demyelinating lesions compared to MS normal appearing white matter and nonMS (control) white matter. Conditioned media (CM) from stimulated GSDMD+/+ human macrophages caused significantly greater cytotoxicity of oligodendroglial and neuronal cells, compared to CM from GSDMD-/- macrophages. Oligodendrocytes and CNS macrophages displayed increased Gsdmd immunoreactivity in the central corpus callosum (CCC) of cuprizone (CPZ)-exposed Gsdmd+/+ mice, associated with greater demyelination and reduced oligodendrocyte precursor cell proliferation, compared to CPZ-exposed Gsdmd-/- animals. CPZ-exposed Gsdmd+/+ mice exhibited significantly increased G-ratios and reduced axonal densities in the CCC compared to CPZ-exposed Gsdmd-/- mice. Proteomic analyses revealed increased brain complement C1q proteins and hexokinases in CPZ-exposed Gsdmd-/- animals. [18F]FDG PET imaging showed increased glucose metabolism in the hippocampus and whole brain with intact neurobehavioral performance in Gsdmd-/- animals after CPZ exposure. GSDMD activation in CNS macrophages and oligodendrocytes contributes to inflammatory demyelination and neuroaxonal injury, offering mechanistic and potential therapeutic insights into P-MS pathogenesis. [ABSTRACT FROM AUTHOR]

This article highlights recent developments of SPECT and PET diagnostic imaging surrogates for targeted alpha particle therapy (TAT) radiopharmaceuticals. It outlines the rationale for using imaging surrogates to improve diagnostic-scan accuracy and facilitate research, and the properties an imaging-surrogate candidate should possess. It evaluates the strengths and limitations of each potential imaging surrogate. Thirteen surrogates for TAT are explored: 133La, 132La, 134Ce/134La, and 226Ac for 225Ac TAT; 203Pb for 212Pb TAT; 131Ba for 223Ra and 224Ra TAT; 123I, 124I, 131I and 209At for 211At TAT; 134Ce/134La for 227Th TAT; and 155Tb and 152Tb for 149Tb TAT. [ABSTRACT FROM AUTHOR]

Simple Summary: Metastatic melanoma is a deadly disease that claims thousands of lives each year despite the introduction of several new drugs into the clinic over the past decade, inspiring the need for novel therapeutics. We investigate targeting melanin pigment, which causes melanoma, with protein molecules called antibodies, which carry a radioactive payload to visualize or treat melanoma tumors. In this study, we imaged and treated melanoma in mice using a c8C3 antibody to melanin and two radioisotopes of lead—Lead-203 for imaging and Lead-212 for therapy. Imaging with Lead-203-bound antibodies allowed for visualization of the tumors in mice, while treatment with Lead-212-bound antibodies slowed down the growth of these aggressive tumors. The treatment was not toxic to mice. We concluded that the melanin-targeting Lead-203/Lead-212-bound c8C3 antibody is a promising agent for imaging and therapy of metastatic melanoma (so-called theranostic), which warrants further investigation. Metastatic melanoma is a deadly disease that claims thousands of lives each year despite the introduction of several immunotherapeutic agents into the clinic over the past decade, inspiring the development of novel therapeutics and the exploration of combination therapies. Our investigations target melanin pigment with melanin-specific radiolabeled antibodies as a strategy to treat metastatic melanoma. In this study, a theranostic approach was applied by first labeling a chimeric antibody targeting melanin, c8C3, with the SPECT radionuclide 203Pb for microSPECT/CT imaging of C57Bl6 mice bearing B16-F10 melanoma tumors. Imaging was followed by radioimmunotherapy (RIT), whereby the c8C3 antibody is radiolabeled with a 212Pb/212Bi "in vivo generator", which emits cytotoxic alpha particles. Using microSPECT/CT, we collected sequential images of B16-F10 murine tumors to investigate antibody biodistribution. Treatment with the 212Pb/212Bi-labeled c8C3 antibody demonstrated a dose-response in tumor growth rate in the 5–10 µCi dose range when compared to the untreated and radiolabeled control antibody and a significant prolongation in survival. No hematologic or systemic toxicity of the treatment was observed. However, administration of higher doses resulted in a biphasic tumor dose response, with the efficacy of treatment decreasing when the administered doses exceeded 10 µCi. These results underline the need for more pre-clinical investigation of targeting melanin with 212Pb-labeled antibodies before the clinical utility of such an approach can be assessed. [ABSTRACT FROM AUTHOR]

The first application of sulfo-click chemistry with 18F-labeled thio acids is described. The simple one-pot/three-component reaction proceeded rapidly within 30 min using mild reaction conditions to give various 18F-labeled small molecule N-acylsulfonamides in radiochemical conversions of 38–99%, and radiolabeled peptides in 20–25% isolated and decay-corrected radiochemical yields. [ABSTRACT FROM AUTHOR]

Fluorine-18 labeled 6-fluoro-6-deoxy-D-fructose (6-[18F]FDF) targets the fructose-preferred facilitative hexose transporter GLUT5, which is expressed predominantly in brain microglia and activated in response to inflammatory stimuli. We hypothesize that 6-[18F]FDF will specifically image microglia following neuroinflammatory insult. 6-[18F]FDF and, for comparison, [18F]FDG were evaluated in unilateral intra-striatal lipopolysaccharide (LPS)-injected male and female rats (50 µg/animal) by longitudinal dynamic PET imaging in vivo. In LPS-injected rats, increased accumulation of 6-[18F]FDF was observed at 48 h post-LPS injection, with plateaued uptake (60–120 min) that was significantly higher in the ipsilateral vs. contralateral striatum (0.985 ± 0.047 and 0.819 ± 0.033 SUV, respectively; p = 0.002, n = 4M/3F). The ipsilateral–contralateral difference in striatal 6-[18F]FDF uptake expressed as binding potential (BPSRTM) peaked at 48 h (0.19 ± 0.11) and was significantly decreased at one and two weeks. In contrast, increased [18F]FDG uptake in the ipsilateral striatum was highest at one week post-LPS injection (BPSRTM = 0.25 ± 0.06, n = 4M). Iba-1 and GFAP immunohistochemistry confirmed LPS-induced activation of microglia and astrocytes, respectively, in ipsilateral striatum. This proof-of-concept study revealed an early response of 6-[18F]FDF to neuroinflammatory stimuli in rat brain. 6-[18F]FDF represents a potential PET radiotracer for imaging microglial GLUT5 density in brain with applications in neuroinflammatory and neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a progressive and inflammatory demyelinating disease of the CNS. Peroxisomes perform critical functions that contribute to CNS homeostasis. We investigated peroxisome injury and mitigating effects of peroxisome-restorative therapy on inflammatory demyelination in models of MS. Human autopsied CNS tissues (male and female), human cell cultures, and cuprizonemediated demyelination mice (female) were examined by RT-PCR, Western blotting, and immunolabeling. The therapeutic peroxisome proliferator, 4-phenylbutyrate (4-PBA) was investigated in vitro and in vivo. White matter from MS patients showed reduced peroxisomal transcript and protein levels, including PMP70, compared with non-MS controls. Cultured human neural cells revealed that human microglia contained abundant peroxisomal proteins. TNF-a-exposed microglia displayed reduced immunolabeling of peroxisomal proteins, PMP70 and PEX11β, which was prevented with 4-PBA. In human myeloid cells exposed to TNF-a or nigericin, suppression of PEX11β and catalase protein levels were observed to be dependent on NLRP3 expression. Hindbrains from cuprizoneexposed mice showed reduced Abcd1, Cat, and Pex5l transcript levels, with concurrent increased Nlrp3 and Il1b transcript levels, which was abrogated by 4-PBA. In the central corpus callosum, Iba-1 in CNS-associated macrophages and peroxisomal thiolase immunostaining after cuprizone exposure was increased by 4-PBA. 4-PBA prevented decreased myelin basic protein and neurofilament heavy chain immunoreactivity caused by cuprizone exposure. Cuprizone-induced neurobehavioral deficits were improved by 4-PBA treatment. Peroxisome injury in CNS-associated macrophages contributed to neuroinflammation and demyelination that was prevented by 4-PBA treatment. A peroxisome-targeted therapy might be valuable for treating inflammatory demyelination and neurodegeneration in MS. [ABSTRACT FROM AUTHOR]

Parathyroid hormone (PTH) is an 84 amino acid peptide hormone that plays a key role in bone and mineral metabolism. The biological actions of PTH are mediated via the N-terminal PTH(1-34) fragment, serving as the PTH receptor-binding sequence, and which is therefore used clinically to treat conditions of low bone mass such as osteoporosis. In this study, PTH(1-34) was conjugated with non-radioactive (stable F isotope) N-succinimidyl 4-fluorobenzoate (SFB) leading to three isomeric mono-fluorobenzoated (FBz) PTH followed by Liquid chromatography-Tandem mass spectrometry (LC-MS/MS) assisted structural identification. Corresponding [18F]SFB-labeled PTH derivatives were prepared respectively and the Lys13 site-specific labeled [18F]FBz PTH was isolated by HPLC with radiochemical purity >99% and specific activity of 2.78 GBq/µmol, suitable for future application with in vivo pharmacokinetic/pharmacodynamic studies of PTH, using preclinical Positron Emission Tomography Computed Tomography (PET/CT) imaging. [ABSTRACT FROM AUTHOR]

• Nine novel pyridinyl amide derivatives. • Amide location and spacer role critical for activity. • Compound 3 demonstrated good antiproliferative activity against K562 and HepG2 cells. • Molecular docking reveals targeted mechanism of action with bcr/abl tyrosine, EGFR, HER2. • Notable cancer cell selectivity over normal cells and low cytotoxicity towards HDFa. A novel series of secondary pyridinyl amides, reinforced with the methylsulfonyl pharmacophore unit, was designed and synthesized. Further, we determined the antiproliferative activities of these compounds through experimental assays and analyzed their interactions with Breakpoint Cluster Region/Abelson (bcr/abl), Epidermal Growth Factor Receptor (EGFR), and Human Epidermal Growth Factor Receptor 2 (HER2) tyrosine kinases using molecular autodocking techniques. We grouped these amides into three categories, classified by the type of spacer that binds the pyridine ring to the amide nitrogen atom. Additionally, within each group, we strategically positioned the amide moiety at the ortho, meta , or para position on the pyridyl ring. Among the studied amides, compound 3 exhibited the best overall antiproliferative activity against human immortalized myelogenous leukemia (K562) (IC 50 = 26 µM), human leukemia monocytic cell line (THP-1) (IC 50 = 81 µM), and human hepatocellular carcinoma (HepG2) (IC 50 = 210 µM). Molecular docking studies revealed that compound 3 binds effectively to bcr/abl, EGFR, and HER2 tyrosine kinases, demonstrating strong interactions with crucial active site amino acids, indicative of its targeted antiproliferative mechanism. All investigated compounds showed either very minor or no cytotoxicity against human dermal fibroblast adult cells. [Display omitted] [ABSTRACT FROM AUTHOR]

Background: Tissue hypoxia is a pathological condition characterized by reducing oxygen supply. Hypoxia is a hallmark of tumor environment and is commonly observed in many solid tumors. Non-invasive imaging techniques like positron emission tomography (PET) are at the forefront of detecting and monitoring tissue hypoxia changes in vivo. Results: We have developed a novel 18F-labeled radiotracer for hypoxia PET imaging based on cytotoxic agent benznidazole. Radiotracer N-(4-[18F]fluorobenzyl)-2-(2-nitro-1H-imidazol-1-yl)acetamide ([18F]FBNA) was synthesized through acylation chemistry with readily available 4-[18F]fluorobenzyl amine. Radiotracer [18F]FBNA was obtained in good radiochemical yields (47.4 ± 5.3%) and high radiochemical purity (> 95%). The total synthesis time was 100 min, including HPLC purification and the molar activity was greater than 40 GBq/µmol. Radiotracer [18F]FBNA was stable in saline and mouse serum for 6 h. [18F]FBNA partition coefficient (logP = 1.05) was found to be more lipophilic than [18F]EF-5 (logP = 0.75), [18F]FMISO (logP = 0.4) and [18F]FAZA (logP = − 0.4). In vitro studies showed that [18F]FBNA accumulates in gastric cancer cell lines AGS and MKN45 under hypoxic conditions. Conclusions: Hence, [18F]FBNA represents a novel and easy-to-prepare PET radioligand for imaging hypoxia. [ABSTRACT FROM AUTHOR]

The study describes the Sonogashira cross-coupling reaction with 4-[18F]fluoroiodobenzene ([18F]FIB) as novel and efficient method for rapid labelling of peptides with the short-lived positron emitter fluorine-18. [ABSTRACT FROM AUTHOR]

Production of antibody fragments in heterologous hosts such as E scherichia coli provides a unique and cost-effective method to develop engineered vectors for tumor targeting. A single-chain Fragment variable (scFv) of the murine monoclonal antibody MAb-B43.13 targeting CA125 in epithelial ovarian cancer was previously developed, expressed, purified and proposed as a functional targeting entity for biomedical applications. However, the yields from its soluble expression in heterologous systems were very low for any practical use in preclinical translational research; leave alone the defeated objective of convenient and cost-effective production. In the present work, the anti-CA125 scFv gene was re-organized and sub-cloned into pET-22b(+) vector to be in frame with the pelB leader peptide for periplasmic localization and C-terminal hexa-histidine tag to facilitate downstream purification. Six variants of the scFv were constructed to investigate the impact of variable domain orientations, inter-domain peptide linker sequences and codon optimization on the soluble expression of the scFv using Rosetta 2(DE3) as the E. coli host supplemented with tRNAs for rare codons. Expression in shake flask cultures under the control of an inducible T7 promoter and subsequent purification by cobalt based immobilized metal affinity chromatography yielded differential amounts of high purity scFv for all constructs. Here, we report up to 14-fold increase in the soluble expression of the scFv primarily as a result of codon optimization with minor effects from inter-domain peptide linkers and variable domain orientation in the anti-CA125 scFv molecule. All the scFv constructs expressed and purified were found to be immunoreactive for in vitro targeting of CA125 antigen. [ABSTRACT FROM AUTHOR]

Deregulation and changes in energy metabolism are emergent and important biomarkers of cancer cells. The uptake of hexoses in cancer cells is mediated by a family of facilitative hexose membrane-transporter proteins known as Glucose Transporters (GLUTs). In the clinic, numerous breast cancers do not show elevated glucose metabolism (which is mediated mainly through the GLUT1 transporter) and may use fructose as an alternative energy source. The principal fructose transporter in most cancer cells is GLUT5, and its mRNA was shown to be elevated in human breast cancer. This offers an alternative strategy for early detection using fructose analogs. In order to selectively scout GLUT5 binding-pocket requirements, we designed, synthesized and screened a new class of fructose mimics based upon the 2,5-anhydromannitol scaffold. Several of these compounds display low millimolar IC50 values against the known high-affinity 18F-labeled fructose-based probe 6-deoxy-6-fluoro-D-fructose (6-FDF) in murine EMT6 breast cancer cells. In addition, this work used molecular docking and molecular dynamics simulations (MD) with previously reported GLUT5 structures to gain better insight into hexose–GLUT interactions with selected ligands governing their preference for GLUT5 compared to other GLUTs. The improved inhibition of these compounds, and the refined model for their binding, set the stage for the development of high-affinity molecular imaging probes targeting cancers that express the GLUT5 biomarker. [ABSTRACT FROM AUTHOR]

Cu(I)-mediated [3+2]cycloaddition between azides and alkynes has evolved into a valuable bioconjugation tool in radiopharmaceutical chemistry. We have developed a simple, convenient and reliable radiosynthesis of 4-[F]fluoro- N-methyl- N-(propyl-2-yn-1-yl)benzenesulfonamide ( [ F]F-SA) as a novel aromatic sulfonamide-based click chemistry building block. [ F]F-SA could be prepared in a remotely controlled synthesis unit in 32 ± 5 % decay-corrected radiochemical yield in a total synthesis time of 80 min. The determined lipophilicity of [ F]F-SA (log P = 1.7) allows handling of the radiotracer in aqueous solutions. The versatility of [ F]F-SA as click chemistry building block was demonstrated by the labeling of a model peptide (phosphopeptide), protein (HSA), and oligonucleotide (L-RNA). The obtained radiochemical yields were 77 % (phosphopeptide), 55-60 % (HSA), and 25 % (L-RNA), respectively. Despite the recent emergence of a multitude of highly innovative novel bioconjugation methods for F labeling of biopolymers, Cu(I)-mediated click chemistry with [ F]F-SA represents a reliable, robust and efficient radiolabeling technique for peptides, proteins, and oligonucleotides with the short-lived positron emitter F. [ABSTRACT FROM AUTHOR]

Abstract: The widely used 18F-prosthetic group N-succinimidyl-4-[18F]fluorobenzoate ([18F]SFB) and the recently developed N-[6-(4-[18F]fluorobenzylidene)aminooxyhexyl]maleimide ([18F]FBAM) were investigated for radiolabeling of two representative phosphatidylserine-binding peptides. The prosthetic groups were compared with respect to required reactions conditions for optimum labeling, radiolabeling yield and chemoselectivity. The N-terminus labeled product produced by reaction of [18F]SFB with binding peptide LIKKPF was produced in 18% radiochemical yield while no N-terminus labeled product could be isolated following [18F]SFB reaction with PDGLSR. When the peptides were modified by addition of a cysteine residue at the N-terminus they provided almost quantitative radiochemical yields with [18F]FBAM. Results indicate that for the peptides in this study, [18F]FBAM is a more useful prosthetic group compared to [18F]SFB due to its excellent chemoselectivity and high radiochemical yield. [Copyright &y& Elsevier]

The synthesis of novel nitro-substituted derivatives of the tyrosine kinase inhibitor Semaxinib (SU5416) is described. The reaction of various substituted oxindoles with 3,5-dimethylpyrrol-2-carbaldehyde derivatives under Knoevenagel conditions gave an array of nitro-substituted derivatives of Semaxinib (SU5416) in high yields of 72-87%. [ABSTRACT FROM AUTHOR]

Abstract: The results of [11C]CH3I synthesis through hydrogen gas reduction of [11C]CO2 on different nickel catalysts (HARSHAW-nickel, SHIMALITE-nickel, nickel on silica/alumina, nickel nanosize 99.99%) followed by gas phase iodination using a TRACERlab FXC synthesis unit are reported. Further reaction parameters such as furnace temperatures, flow rate of hydrogen gas and reduction time were optimized. It was found that reduction of [11C]CO2 proceeded in 28–83% yield depending on the nickel catalyst and temperature. The gas phase iodination (methane conversion) gave 31–62% of [11C]CH3I depending on temperature and amount of iodine in the iodine furnace. [11C]CH3I was used for heteroatom methylation reactions exemplified by a piperazine and a phenol ( 1 and 3 ). The specific activity of the 11C-labelled products 2 and 4 was determined after HPLC purification and solid-phase extraction. Compounds 2 and 4 were obtained in 8–14% radiochemical yield (decay-corrected, based upon trapped [11C]CH4) within 30min. The specific activity was determined to be in the range of 20–30GBq/μmol at the end-of-synthesis. Nickel catalyst nanosize was found to be superior compared with other Ni catalysts tested. The relatively low specific activity may be mainly due to carbon contaminations originating from the long copper tubing (500m) between the cyclotron and the radiochemistry facility. [Copyright &y& Elsevier]

Abstract: The novel thiol-group-selective bifunctional 18F-labeling agent N-[6-(4-[18F]fluoro-benzylidene)aminooxyhexyl]maleimide ([18F]FBAM) has been developed. The bifunctional labeling precursor N-(6-aminoxyhexyl)maleimide containing a thiol-reactive maleimide group and a carbonyl-group-reactive aminooxy group was prepared in only three steps in a total chemical yield of 59%. Subsequent radiolabeling with 4-[18F]fluorobenzaldehyde gave the bifunctional 18F-labeling agent [18F]FBAM in a radiochemical yield of 29%. In a typical experiment, 3.88 GBq of [18F]fluoride could be converted into 723 MBq of [18F]FBAM within 69 min. Conjugation of [18F]FBAM with thiol groups was exemplified with the cystein-containing tripeptide glutathione and with various apolipoproteins of human low-density lipoprotein (LDL) subfractions. The latter was evaluated with respect to the uptake of [18F]FBAM-LDL subfractions in human hepatoma cells (HepG2) in vitro. In vivo biodistribution studies in rats revealed high stability for [18F]FBAM-LDL subfractions. Moreover, the metabolic fate of [18F]FBAM-LDL subfractions in vivo was delineated by dynamic positron emission tomography studies using a dedicated small animal tomograph. Data were compared to former studies that used the NH2-reactive 18F-labeling agent N-succinimidyl-4-[18F]fluorobenzoate. The compound [18F]FBAM can be considered as an excellent prosthetic group for the selective and mild 18F labeling of thiol-group-containing biomolecules suitable for subsequent investigations in vitro and in vivo. [Copyright &y& Elsevier]

Cover Feature: In Cellulo Generation of Fluorescent Probes for Live-Cell Imaging of Cylooxygenase-2 (Chem. Eur. J. 10/2021) Keywords: cancer; drug design; fluorescence; fluorogenic click chemistry; imaging agents; live cell imaging EN cancer drug design fluorescence fluorogenic click chemistry imaging agents live cell imaging 3189 3189 1 02/17/21 20210215 NES 210215 B In cellulo generation of fluorescent probes b is an essential tool in chemical biology to visualize the dynamics of biological processes in real-time. Cancer, drug design, fluorescence, fluorogenic click chemistry, imaging agents, live cell imaging. [Extracted from the article]

Copper-64 (64Cu, t 1/2 = 12.7 h) is a positron emitter well suited for theranostic applications with beta-emitting 67Cu for targeted molecular imaging and radionuclide therapy. The present work aims to evaluate the radionuclidic purity and radiochemistry of 64Cu produced via the 68Zn(p,nα)64Cu nuclear reaction. Macrocyclic chelators DOTA, NOTA, TETA, and prostate-specific membrane antigen ligand PSMA I&T were radiolabeled with purified 64Cu and tested for in vitro stability. [64Cu]Cu-PSMA I&T was used to demonstrate in vivo PET imaging using 64Cu synthesized via the 68Zn(p,nα)64Cu production route and its suitability as a theranostic imaging partner alongside 67Cu therapy. 64Cu was produced on a 24 MeV TR-24 cyclotron at a beam energy of 23.5 MeV and currents up to 70 μA using 200 mg 68Zn encapsulated within an aluminum‑indium-graphite sealed solid target assembly. 64Cu semi-automated purification was performed using a NEPTIS Mosaic-LC synthesis unit employing CU, TBP, and TK201 (TrisKem) resins. Radionuclidic purity was measured by HPGe gamma spectroscopy, while ICP-OES assessed elemental purity. Radiolabeling was performed with NOTA at room temperature and DOTA, TETA, and PSMA I&T at 95 °C. 64Cu incorporation was studied by radio-TLC. 64Cu in vitro stability of [64Cu]Cu-NOTA, [64Cu]Cu-DOTA, [64Cu]Cu-TETA, and [64Cu]Cu-PSMA I&T was assessed at 37 °C from 0 to 72 h in human blood serum. Preclinical PET imaging was performed at 1, 24, and 48 h post-injection with [64Cu]Cu-PSMA I&T in LNCaP tumor-bearing mice and compared with [68Ga]Ga-PSMA I&T. Maximum purified activity of 4.9 GBq [64Cu]CuCl 2 was obtained in 5 mL of pH 2–3 solution, with 2.9 GBq 64Cu concentrated in 0.5 mL. HPGe gamma spectroscopy of purified 64Cu detected <0.3 % co-produced 67Cu at EOB with no other radionuclidic impurities. ICP-OES elemental analysis determined <1 ppm Al, Zn, In, Fe, and Cu in the [64Cu]CuCl 2 product. NOTA, DOTA, TETA, and PSMA I&T were radiolabeled with 64Cu, resulting in maximum molar activities of 164 ± 6 GBq/μmol, 155 ± 31 GBq/μmol, 266 ± 34 GBq/μmol, and 117 ± 2 GBq/μmol, respectively. PET imaging in PSMA-expressing LNCaP xenografts resulted in high tumor uptake (SUV mean = 1.65 ± 0.1) using [64Cu]Cu-PSMA I&T, while [68Ga]Ga-PSMA I&T yielded an SUV mean of 0.76 ± 0.14 after 60 min post-injection. 64Cu was purified in a small volume amenable for radiolabeling, with yields suitable for preclinical and clinical application. The 64Cu production and purification process and the favourable PET imaging properties confirm the 68Zn(p,nα)64Cu nuclear reaction as a viable 64Cu production route for facilities with access to a higher energy proton cyclotron, compared to using expensive 64Ni target material and the 64Ni(p,n)64Cu nuclear reaction. Our 64Cu production technique provides an alternative production route with the potential to improve 64Cu availability for preclinical and clinical studies alongside 67Cu therapy. [Display omitted] [ABSTRACT FROM AUTHOR]

This review outlines the accomplishments and potential developments of targeted alpha (α) particle therapy (TAT). It discusses the therapeutic advantages of the short and highly ionizing path of α-particle emissions; the ability of TAT to complement and provide superior efficacy over existing forms of radiotherapy; the physical decay properties and radiochemistry of common α-emitters, including 225Ac, 213Bi, 224Ra, 212Pb, 227Th, 223Ra, 211At, and 149Tb; the production techniques and proper handling of α-emitters in a radiopharmacy; recent preclinical developments; ongoing and completed clinical trials; and an outlook on the future of TAT. [ABSTRACT FROM AUTHOR]

This study reports the high-yield production of a novel 133/135La theranostic pair at a 22 MeV proton beam energy as an attractive alternative to the recently introduced 132/135La pair, demonstrating over an order of magnitude production increase of 133/135La (231 ± 8 MBq 133La and 166 ± 5 MBq 135La at End of Bombardment (EOB)) compared to 11.9 MeV production of 132/135La (0.82 ± 0.06 MBq 132La and 19.0 ± 1.2 MBq 135La) for 500 µA·min irradiations. A new sealed solid cyclotron target is introduced, which is fast to assemble, easy to handle, storable, and contains reusable components. Radiolabeling with macrocyclic chelators DOTA and macropa achieved full incorporation, with respective apparent 133La molar activites of 33 ± 5 GBq/µmol and 30 ± 4 GBq/µmol. PET centers with access to a 22 MeV capable cyclotron could produce clinically-relevant doses of 133/135La, via natBa irradiation, as a standalone theranostic agent for PET imaging and Auger electron therapy. With lower positron energies and less energetic and abundant gamma rays than 68Ga, 44Sc and 132La, 133La appears to be an attractive radiometal candidate for PET applications requiring a higher scanning resolution, a relatively long isotopic half-life, ease of handling, and a low patient dose. [ABSTRACT FROM AUTHOR]

Purpose: The present study describes the analysis of amino acid transporters ASCT1, ASCT2, LAT1, and xc− in breast cancer under normoxic and hypoxic conditions. [18F]FDOPA-PET and [18F]FSPG-PET were used as imaging biomarkers to probe l-type amino acid transporter (LAT1) and cystine-glutamate antiporter (xc−) in breast cancer models. Procedures: LAT1 and xc− transporters were studied under normoxic and hypoxic conditions with radiotracers [18F]FDOPA and [18F]FSPG in estrogen receptor–positive (ER+) MCF7 and triple-negative MDA-MB231 cells and in human mammary epithelial MCF10A control cells. Protein expression was analyzed using Western blot and immunohistochemistry. Results: ASCT1 protein expression levels were comparable in all three cell lines, while noticeable ASCT2 expression levels were only found in MCF10A control cells. Higher LAT1 protein expression was detected in ER+ MCF7 cells. High xc− protein expression levels were detected in MDA-MB231 cells. Uptake of [18F]FDOPA through LAT1 was significantly higher in MCF7 versus MDA-MB231 cells, while the uptake of [18F]FSPG through xc− resulted in the opposite confirming expression and functional differences for both amino acid transporters in different breast cancer models. Hypoxia significantly increased [18F]FDOPA uptake in MCF7 cells and [18F]FSPG uptake in MDA-MB231 cells. In vivo PET imaging revealed substantially higher tumor uptake of [18F]FDOPA in MCF7 tumors as well as [18F]FSPG uptake in MDA-MB231 tumors confirming differences detected in vitro. Conclusions: ER+ breast cancer cells express higher levels of amino acid transporter LAT1, whereas triple-negative breast cancer cells express more xc−. Cellular uptake and PET imaging experiments with [18F]FDOPA and [18F]FSPG confirmed functional LAT1 and xc− expression profiles. There was initial evidence that hypoxia regulates the function of both amino acid transporters in breast cancer. The results further indicated that [18F]FDOPA and [18F]FSPG are suitable radiotracer to distinguish between ER+ and triple-negative breast cancer types. [ABSTRACT FROM AUTHOR]

Radiolabeled peptides play a central role in nuclear medicine as radiotheranostics for targeted imaging and therapy of cancer. We have recently proposed the use of metabolically stabilized GRPR antagonist BBN2 for radiolabeling with 18F and 68Ga and subsequent PET imaging of GRPRs in prostate cancer. The present work studied the impact of 44gSc- and 68Ga-labeled DOTA complexes attached to GRPR antagonist BBN2 on the in vitro GRPR binding affinity, and their biodistribution and tumor uptake profiles in MCF7 breast and PC3 prostate cancer models. DOTA-Ava-BBN2 was radiolabeled with radiometals 68Ga and 44gSc. Gastrin-releasing peptide receptor (GRPR) affinities of peptides were assessed in PC3 prostate cancer cells. GRPR expression profiles were studied in human breast cancer tissue samples and MCF7 breast cancer cells. PET imaging of 68Ga- and 44gSc-labeled peptides was performed in MCF7 and PC3 xenografts as breast and prostate cancer models. Radiopeptides [68Ga]Ga-DOTA-Ava-BBN2 and [44gSc]Sc-DOTA-Ava BBN2 were prepared in radiochemical yields of 70–80% (decay-corrected), respectively. High binding affinities were found for both peptides (IC 50 = 15 nM (natGa) and 5 nM (natSc)). Gene expression microarray analysis revealed high GRPR mRNA expression levels in estrogen receptor (ER)-positive breast cancer, which was further confirmed with Western blot and immunohistochemistry. However, PET imaging showed only low tumor uptake of both radiotracers in MCF7 xenografts ([68Ga]Ga-DOTA-BBN2 (SUV 60min 0.27 ± 0.06); [44gSc]Sc-DOTA-BBN2 (SUV 60min 0.20 ± 0.03)). In contrast, high tumor uptake and retention were found for both radiopeptides in PC3 tumors ([68Ga]Ga-DOTA-BBN2 (SUV 60min 0.46 ± 0.07); [44gSc]Sc-DOTA-BBN2 (SUV 60min 0.51 ± 0.11)). Comparison of 68Ga- and 44gSc-labeled DOTA-Ava-BBN2 peptides revealed slight but noticeable differences of the radiometal with an impact on the in vitro GRPR receptor binding properties in PC3 cells. No differences were found in their in vivo biodistribution profiles in MCF7 and PC3 xenografts. Radiopeptides [68Ga]Ga-DOTA-Ava-BBN2 and [44gSc]Sc-DOTA-Ava-BBN2 displayed comparable tumor uptake and retention profiles with rapid blood and renal clearance profiles in both tumor models. The favorable PET imaging performance of [44gSc]Sc-DOTA-Ava-BBN2 in prostate cancer should warrant the development of an [43Sc]Sc-DOTA-Ava-BBN2 analog for clinical translation which comes with a main γ-line of much lower energy and intensity compared to 44gSc. [ABSTRACT FROM AUTHOR]