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The high affinity and specificity of peptides towards biological targets, in addition to their favorable pharmacological properties, has encouraged the development of many peptide-based pharmaceuticals, including peptide-based positron emission tomography (PET) radiopharmaceuticals. However, the poor in vivo stability of unmodified peptides against proteolysis is a major challenge that must be overcome, as it can result in an impractically short in vivo biological half-life and a subsequently poor bioavailability when used in imaging and therapeutic applications. Consequently, many biologically and pharmacologically interesting peptide-based drugs may never see application. A potential way to overcome this is using peptide analogues designed to mimic the pharmacophore of a native peptide while also containing unnatural modifications that act to maintain or improve the pharmacological properties. This review explores strategies that have been developed to increase the metabolic stability of peptide-based pharmaceuticals. It includes modifications of the C- and/or N-termini, introduction of d- or other unnatural amino acids, backbone modification, PEGylation and alkyl chain incorporation, cyclization and peptide bond substitution, and where those strategies have been, or could be, applied to PET peptide-based radiopharmaceuticals.

The one-pot reaction of 2,6-bis(diphenylmethyl)-4-methoxyaniline with tert-butylnitrite, BTEAC and DABSO in the presence of CuCl2 provided an unexpected 3H-indazole product 8. The structure of the compound was determined by HRMS, IR, NMR and further confirmed by single crystal X-ray crystallography. The compound crystallises in the triclinic P-1 space group, with unit cell parameters a = 9.2107 (4), b = 10.0413 (5), c = 14.4363 (6) Å, α = 78.183 (2), β = 87.625 (2), γ = 71.975 (2)°. The formation of 8 proceeded through a facile intramolecular [2 + 3] cycloaddition of the diazo intermediate 9. The molecules of 8 are organised by edge–face Ar–H···π, face–face π···π, and bifurcated OCH2–H···N interactions. In addition to these, there are Ar–H···H–Ar close contacts, (edge–edge and surrounding inversion centres) arranged as infinite tapes along the a direction.

The oxytocin/oxytocin receptor (OT/OTR) signalling system is involved in socioemotional behaviours, garnering interest as a therapeutic target across multiple clinical conditions. Despite its potential, our limited understanding of how to optimally target it and the scarcity of molecular tools for in vivo studies hinder therapeutic development. Molecular imaging techniques, such as Positron Emission Tomography (PET), can bridge this gap by furnishing direct insights into ligand biodistribution, receptor visualisation and ligand-receptor engagement. Here, we report the design, synthesis and biochemical and pharmacological characterisation of five OT-like peptides as novel PET tracers for investigating the OT/OTR signalling system. dOTK 8 [SFB] emerged as the most promising OT-like lead. The radioactive version [ 18 F]dOTK 8 [SFB] was produced using a microfluidic reaction approach and validated by preclinical PET imaging of healthy rats after intravenous ligand administration. [ 18 F]dOTK 8 [SFB] exhibited specific accumulation in OTR-rich tissues, affirming OTR-specificity and suitability as a new OT-like PET radiotracer for investigating OT/OTR biodistribution in humans. The oxytocin/oxytocin receptor (OT/OTR) signalling system is a promising therapeutic target for socioemotional disorders, yet its clinical potential is limited by a lack of in vivo molecular tools. Here, the authors develop and validate [ 18 F]dOTK 8 [SFB] as a PET radiotracer, demonstrating its specificity and potential for in vivo mapping OT/OTR biodistribution.

The importance of the sulfur-fluorine bond is starting to increase in modern medicinal chemistry literature. This is due to a better understanding of the stability and reactivity of this moiety depending on the various oxidation states of sulfur. Furthermore, several commercial reagents used for mild and selective fluorination of organic molecules are based on the known reactivity of S-F groups. In this review, we will show how these examples are translating into the 18 F field, both for use as stable tags in finished radiopharmaceuticals and as mildly reactive fluoride-relay intermediates. Finally, we also discuss current opportunities where examples of non-radioactive S-F applications/chemistry may be translated into future 18 F radiochemistry applications.

The one-pot reaction of 2,6-bis(diphenylmethyl)-4-methoxyaniline with tert -butylnitrite, BTEAC and DABSO in the presence of CuCl 2 provided an unexpected 3 H -indazole product 8 . The structure of the compound was determined by HRMS, IR, NMR and further confirmed by single crystal X-ray crystallography. The compound crystallises in the triclinic P -1 space group, with unit cell parameters a = 9.2107 (4), b = 10.0413 (5), c = 14.4363 (6) Å, α = 78.183 (2), β = 87.625 (2), γ = 71.975 (2)°. The formation of 8 proceeded through a facile intramolecular [2 + 3] cycloaddition of the diazo intermediate 9 . The molecules of 8 are organised by edge–face Ar–H···π, face–face π···π, and bifurcated OCH 2 –H···N interactions. In addition to these, there are Ar–H···H–Ar close contacts, (edge–edge and surrounding inversion centres) arranged as infinite tapes along the a direction.

The one-pot reaction of 2,6-bis(diphenylmethyl)-4-methoxyaniline with tert-butylnitrite, BTEAC and DABSO in the presence of CuCl2 provided an unexpected 3H-indazole product 8. The structure of the compound was determined by HRMS, IR, NMR and further confirmed by single crystal X-ray crystallography. The compound crystallises in the triclinic P-1 space group, with unit cell parameters a = 9.2107 (4), b = 10.0413 (5), c = 14.4363 (6) Å, α = 78.183 (2), β = 87.625 (2), γ = 71.975 (2)°. The formation of 8 proceeded through a facile intramolecular [2 + 3] cycloaddition of the diazo intermediate 9. The molecules of 8 are organised by edge-face Ar-H···π, face-face π···π, and bifurcated OCH2-H···N interactions. In addition to these, there are Ar-H···H-Ar close contacts, (edge-edge and surrounding inversion centres) arranged as infinite tapes along the a direction.The one-pot reaction of 2,6-bis(diphenylmethyl)-4-methoxyaniline with tert-butylnitrite, BTEAC and DABSO in the presence of CuCl2 provided an unexpected 3H-indazole product 8. The structure of the compound was determined by HRMS, IR, NMR and further confirmed by single crystal X-ray crystallography. The compound crystallises in the triclinic P-1 space group, with unit cell parameters a = 9.2107 (4), b = 10.0413 (5), c = 14.4363 (6) Å, α = 78.183 (2), β = 87.625 (2), γ = 71.975 (2)°. The formation of 8 proceeded through a facile intramolecular [2 + 3] cycloaddition of the diazo intermediate 9. The molecules of 8 are organised by edge-face Ar-H···π, face-face π···π, and bifurcated OCH2-H···N interactions. In addition to these, there are Ar-H···H-Ar close contacts, (edge-edge and surrounding inversion centres) arranged as infinite tapes along the a direction.

Microfluidic techniques are increasingly being used to synthesize positron-emitting radiopharmaceuticals. Several reports demonstrate higher incorporation yields, with shorter reaction times and reduced amounts of reagents compared with traditional vessel-based techniques. Microfluidic techniques, therefore, have tremendous potential for allowing rapid and cost- effective optimization of new radiotracers. This protocol describes the implementation of a suitable microfluidic process to optimize classical [sup.18]F radiofluorination reactions by rationalizing the time and reagents used. Reaction optimization varies depending on the systems used, and it typically involves 5-10 experimental days of up to 4 h of sample collection and analysis. In particular, the protocol allows optimization of the key fluidic parameters in the first tier of experiments: reaction temperature, residence time and reagent ratio. Other parameters, such as solvent, activating agent and precursor concentration need to be stated before the experimental runs. Once the optimal set of parameters is found, repeatability and scalability are also tested in the second tier of experiments. This protocol allows the standardization of a microfluidic methodology that could be applied in any radiochemistry laboratory, in order to enable rapid and efficient radiosynthesis of new and existing [[sup.18]F]-radiotracers. Here we show how this method can be applied to the radiofluorination optimization of [[sup.18]F]-MEL050, a melanoma tumor imaging agent. This approach, if integrated into a good manufacturing practice (GMP) framework, could result in the reduction of materials and the time required to bring new radiotracers toward preclinical and clinical applications.

A quick route towards new radiofluorinated tracers is important for the development of PET imaging. An efficient, reliable method for optimizing radiofluorination conditions using a microfluidic chemistry approach is described in this protocol. Microfluidic techniques are increasingly being used to synthesize positron-emitting radiopharmaceuticals. Several reports demonstrate higher incorporation yields, with shorter reaction times and reduced amounts of reagents compared with traditional vessel-based techniques. Microfluidic techniques, therefore, have tremendous potential for allowing rapid and cost-effective optimization of new radiotracers. This protocol describes the implementation of a suitable microfluidic process to optimize classical 18 F radiofluorination reactions by rationalizing the time and reagents used. Reaction optimization varies depending on the systems used, and it typically involves 5–10 experimental days of up to 4 h of sample collection and analysis. In particular, the protocol allows optimization of the key fluidic parameters in the first tier of experiments: reaction temperature, residence time and reagent ratio. Other parameters, such as solvent, activating agent and precursor concentration need to be stated before the experimental runs. Once the optimal set of parameters is found, repeatability and scalability are also tested in the second tier of experiments. This protocol allows the standardization of a microfluidic methodology that could be applied in any radiochemistry laboratory, in order to enable rapid and efficient radiosynthesis of new and existing [ 18 F]-radiotracers. Here we show how this method can be applied to the radiofluorination optimization of [ 18 F]-MEL050, a melanoma tumor imaging agent. This approach, if integrated into a good manufacturing practice (GMP) framework, could result in the reduction of materials and the time required to bring new radiotracers toward preclinical and clinical applications.

Purpose The first biological evaluation of two potent fluorine-18 radiolabelled inhibitors of caspase-3/7 was achieved in a cerebral stroke rat model to visualize apoptosis. Procedures In vivo characteristics of isatins [ 18 F]- 2 and [ 18 F]- 3 were studied and compared by μPET to previously described 1-[4-(2-[ 18 F]fluoroethyl)benzyl]-5-(2-methoxymethylpyrrolidin-1-ylsulfonyl)isatin ([ 18 F]- 1 ) and to 2-(5-[ 18 F]fluoropentyl)-2-methyl-malonic acid ([ 18 F]ML-10) used as a reference radiotracer in a rat stroke model. Results [ 18 F]- 2 and [ 18 F]- 3 were radiolabelled with high radiochemical purity and high specific radioactivity. Radioactivity uptakes in ischemic and contralateral brain regions were weak for the three radiolabelled isatins and lower for [ 18 F]ML-10. In μPET, time activity curves showed significant uptake differences between both regions of interest for [ 18 F]- 1 after 45 min. No differences were observed for [ 18 F]ML-10. Conclusions Radiolabelled isatins are more promising radiotracers to image apoptosis than [ 18 F]ML-10 in this stroke animal model without craniectomy. In particular, [ 18 F]- 1 presented significant uptake in apoptotic area 45 min after administration

The first biological evaluation of two potent fluorine-18 radiolabelled inhibitors of caspase-3/7 was achieved in a cerebral stroke rat model to visualize apoptosis.PURPOSEThe first biological evaluation of two potent fluorine-18 radiolabelled inhibitors of caspase-3/7 was achieved in a cerebral stroke rat model to visualize apoptosis.In vivo characteristics of isatins [(18)F]-2 and [(18)F]-3 were studied and compared by μPET to previously described 1-[4-(2-[(18)F]fluoroethyl)benzyl]-5-(2-methoxymethylpyrrolidin-1-ylsulfonyl)isatin ([(18)F]-1) and to 2-(5-[(18)F]fluoropentyl)-2-methyl-malonic acid ([(18)F]ML-10) used as a reference radiotracer in a rat stroke model.PROCEDURESIn vivo characteristics of isatins [(18)F]-2 and [(18)F]-3 were studied and compared by μPET to previously described 1-[4-(2-[(18)F]fluoroethyl)benzyl]-5-(2-methoxymethylpyrrolidin-1-ylsulfonyl)isatin ([(18)F]-1) and to 2-(5-[(18)F]fluoropentyl)-2-methyl-malonic acid ([(18)F]ML-10) used as a reference radiotracer in a rat stroke model.[(18)F]-2 and [(18)F]-3 were radiolabelled with high radiochemical purity and high specific radioactivity. Radioactivity uptakes in ischemic and contralateral brain regions were weak for the three radiolabelled isatins and lower for [(18)F]ML-10. In μPET, time activity curves showed significant uptake differences between both regions of interest for [(18)F]-1 after 45 min. No differences were observed for [(18)F]ML-10.RESULTS[(18)F]-2 and [(18)F]-3 were radiolabelled with high radiochemical purity and high specific radioactivity. Radioactivity uptakes in ischemic and contralateral brain regions were weak for the three radiolabelled isatins and lower for [(18)F]ML-10. In μPET, time activity curves showed significant uptake differences between both regions of interest for [(18)F]-1 after 45 min. No differences were observed for [(18)F]ML-10.Radiolabelled isatins are more promising radiotracers to image apoptosis than [(18)F]ML-10 in this stroke animal model without craniectomy. In particular, [(18)F]-1 presented significant uptake in apoptotic area 45 min after administration.CONCLUSIONSRadiolabelled isatins are more promising radiotracers to image apoptosis than [(18)F]ML-10 in this stroke animal model without craniectomy. In particular, [(18)F]-1 presented significant uptake in apoptotic area 45 min after administration.