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Purpose: Due to their long circulation time in the blood, monoclonal antibodies (mAbs) such as trastuzumab, are usually radiolabeled with long-lived positron emitters for the development of agents for Positron Emission Tomography (PET) imaging. Manganese-52 (52Mn, t1/2 = 5.6 d, β+ = 29.6%, E(βave) = 242 keV) is suitable for imaging at longer time points providing a complementary technique to Zirconium-89 (89Zr, t1/2 = 3.3 d, β+ = 22.7%, E(βave) = 396 keV)) because of its long half-life and low positron energy. To exploit these properties, we aimed to investigate suitable bifunctional chelators that could be readily conjugated to antibodies and labeled with 52Mn under mild conditions using trastuzumab as a proof-of-concept. Procedures: Trastuzumab was incubated with S-2-(4-isothiocyanatobenzyl)-1,4,7,10-tetraazacyclododecane tetraacetic acid (p-SCN-Bn-DOTA), 1-Oxa-4,7,10-tetraazacyclododecane-5-S-(4-isothiocyantobenzyl)-4,7,10-triacetic acid (p-SCN-Bn-Oxo-DO3A), and 3,6,9,15-tetraazabicyclo[9.3.1] pentadeca-1(15),11,13-triene-4-S-(4-isothiocyanatobenzyl)-3,6,9-triacetic acid (p-SCN-Bn-PCTA) at a tenfold molar excess. The immunoconjugates were purified, combined with [52Mn]MnCl2 at different ratios, and the labeling efficiency was assessed by iTLC. The immunoreactive fraction of the radiocomplex was determined through a Lindmo assay. Cell studies were conducted in HER2 + (BT474) and HER2- (MDA-MB-468) cell lines followed by in vivo studies. Results: Trastuzumab-Oxo-DO3A was labeled within 30 min at 37 °C with a radiochemical yield (RCY) of 90 ± 1.5% and with the highest specific activity of the chelators investigated of 16.64 MBq/nmol. The labeled compound was purified with a resulting radiochemical purity of > 98% and retained a 67 ± 1.2% immunoreactivity. DOTA and PCTA immunoconjugates resulted in < 50 ± 2.5% (RCY) with similar specific activity. Mouse serum stability studies of [52Mn]Mn-Oxo-DO3A-trastuzumab showed 95% intact complex for over 5 days. Cell uptake studies showed higher uptake in HER2 + (12.51 ± 0.83% /mg) cells compared to HER2- (0.85 ± 0.10%/mg) cells. PET images of mice bearing BT474 tumors showed high tumor uptake that was consistent with the biodistribution (42.02 ± 2.16%ID/g, 14 d) compared to MDA-MB-468 tumors (2.20 ± 0.80%ID/g, 14 d). Additionally, both models exhibited low bone uptake of < 1% ID/g. Conclusion: The bifunctional chelator p-SCN-Bn-Oxo-DO3A is promising for the development of 52Mn radiopharmaceuticals as it was easily conjugated, radiolabeled at mild conditions, and illustrated stability for a prolonged duration both in vitro and in vivo. High-quality PET/CT images of [52Mn]Mn-Oxo-DO3A-trastuzumab were obtained 14 d post-injection. This study illustrates the potential of [52Mn]Mn-Oxo-DO3A for the evaluation of antibodies using PET imaging. [ABSTRACT FROM AUTHOR]

• Nanobodies are ideal candidates for molecular imaging. • A key variable determining the in vivo performance of a nanobody-derived molecular imaging tracer is the engineering strategy. • Modular site-specific conjugation and antibody engineering strategies are recommended to develop next-generation molecular imaging tracers. In recent years, nanobodies have emerged as ideal imaging agents for molecular imaging. Molecular nanobody imaging combines the specificity of nanobodies with the sensitivity of state-of-the-art molecular imaging modalities, such as positron emission tomography (PET). Given that modifications of nanobodies alter their pharmacokinetics (PK), the engineering strategies that combine nanobodies with radionuclides determine the effectiveness, reliability, and safety of the molecular imaging probes. In this review, we introduce conjugation strategies that have been applied to engineer nanobodies, including random conjugation, 99mTc tricarbonyl chemistry, sortase A-mediated site-specific conjugation, maleimide-cysteine chemistry, and click chemistries. We also summarize the latest advances in nanobody molecular imaging tracers, emphasizing their preclinical and clinical use. In addition, we elaborate on nanobody-based near-infrared fluorescence (NIRF) imaging and image-guided surgery. [ABSTRACT FROM AUTHOR]

Radioimmunoconjugates consists of a monoclonal antibody (mAb) linked to a radionuclide. Monoclonal antibodies (mAbs) are immunoglobulins able to recognize unique epitopes on a single antigen. MAbs therapy has emerged as a significant therapeutic choice for different types of cancer. When they contain a radioactive isotope for diagnostic or therapeutic purposes they belong to the group of radiopharmaceuticals. Radioisotopes are atoms that emit radiation and are used based on the type of radiation that is emitted. There are three types of radiation, alpha, beta, and gamma radiation. Alpha and beta radiation has a short range and are primarily used for radiotherapy purposes. Gamma radiation, on the other hand, has a wider range, is used for diagnostics, and can be detected using specialized detection systems. To formulate a stable radiopharmaceutical, it is important to provide a stable link between the isotope and the carrier molecules (proteins, monoclonal antibodies, peptides, nanoparticles). The bifunctional chelators (BFC) contain a metal chelating group on one side and covalently binding to the biological molecules on the other side. Radioimmunoconjugates are the majority applied radiopharmaceuticals worldwide for diagnostic and therapeutic purposes and are composed of radioactive elements attached to the immune molecules, like monoclonal antibodies. Diagnostic radioimmunoconjugates can be used for body imaging and mostly for the identification of positive lesions and metastasis, while radiotherapeutics has shown efficacy in the treatment of solid tumors and hematologic malignancies. [ABSTRACT FROM AUTHOR]

Synthetic ways to introduce functional groups (CO2 Me, CO2 H, OCH2 CO2 H, OCH2 C≡CH, CH2 OH, CH2 Cl, CH2 N3) into the pyridine ring of pyridine-containing azacrown compounds are described. These groups were introduced at position-4 of the pyridine ring, while keeping the macrocyclic carboxylate groups available for metal chelation. The derivatives were obtained by macrocyclization reaction of 4-substituted, trimethyl pyridine-2,4,6-tricarboxylate or by modification of methyl ester group in pyridine fragment of macrocycles. Obtained derivatives can be applied for preparing radiotherapeutic agents by conjugation to different vector biomolecules for targeted drug delivery to cancer cells without damaging healthy tissue. [ABSTRACT FROM AUTHOR]

Bifunctional chelators as parts of modular metal‐based radiopharmaceuticals are responsible for stable complexation of the radiometal ion and for covalent linkage between the complex and the targeting vector. To avoid loss of complex stability, the bioconjugation strategy should not interfere with the radiometal chelation by occupying coordinating groups. The C9 position of the very stable CuII chelator 3,7‐diazabicyclo[3.3.1]nonane (bispidine) is virtually predestined to introduce functional groups for facile bioconjugation as this functionalisation does not disturb the metal binding centre. We describe the preparation and characterisation of a set of novel bispidine derivatives equipped with suitable functional groups for diverse bioconjugation reactions, including common amine coupling strategies (bispidine‐isothiocyanate) and the Cu‐free strain‐promoted alkyne–azide cycloaddition. We demonstrate their functionality and versatility in an exemplary way by conjugation to an antibody‐based biomolecule and validate the obtained conjugate in vitro and in vivo. [ABSTRACT FROM AUTHOR]

The field of targeted radionuclide therapy is rapidly growing, highlighting the need for wider radionuclide availability. Soft Lewis acid ions, such as radioisotopes of platinum, rhodium and palladium, are particularly underdeveloped. This is due in part to a lack of compatible bifunctional chelators. These allow for the practical bioconjugation to targeting vectors, in turn enabling radiolabeling. The [16]andS4 macrocycle has been reported to chelate a number of relevant soft metal ions. In this work, we present a procedure for synthesizing [16]andS4 in 45% yield (five steps, 12% overall yield), together with a selection of strategies for preparing bifunctional derivatives. An ester-linked N-hydroxysuccimide ester (NHS, seven steps, 4% overall yield), an ether-linked isothiocyanate (NCS, eight steps, 5% overall yield) and an azide derivative were prepared. In addition, a new route to a carbon-carbon linked carboxylic acid functionalized derivative is presented. Finally, a general method for conjugating the NHS and NCS derivatives to a polar peptide (octreotide) is presented, by dissolution in water:acetonitrile (1:1), buffered to pH 9.4 using borate. The reported compounds will be readily applicable in radiopharmaceutical chemistry, by facilitating the labeling of a range of molecules, including peptides, with relevant soft radiometal ions.

Radiometals are an exciting class of radionuclides because of the large number of metallic elements available that have medically useful isotopes. To properly harness radiometals, they must be securely bound by chelators, which must be carefully matched to the radiometal ion to maximize radiolabeling performance and the stability of the resulting complex. This chapter focuses on practical aspects of radiometallation chemistry including chelator selection, radiolabeling procedures and conditions, radiolysis prevention, purification, quality control, requisite equipment and reagents, and useful tips., (© 2024. The Author(s), under exclusive license to Springer Science+Business Media, LLC, part of Springer Nature.)

PCTA[12] is a 12‐membered tetraaza‐macrocyclic ligand that incorporates a pyridine unit within the macrocyclic ring and three acetate pendant arms. Unlike DOTA and NOTA chelators, PCTA is a recent entry to the field of macrocyclic polyaminocarboxylate ligands available to complex a variety of M2+/M3+ ions for biomedical applications such as diagnostic and radiotherapeutic. Despite the promising properties of its chelates, only a few of bifunctional chelating agents (BFCAs) derived from PCTA have been described so far. Based on our very recent methodology for the preparation of PCTA[12] itself, we report here the efficient synthesis of several BFCAs derived from PCTA bearing a free reactive function group, mainly devoted to conjugation purposes: ester, carboxylic acid, alcohol, aliphatic amine, aromatic amine, maleimide, bromo or azide functions. These functions were introduced either on the 4‐position of the pyridine ring or on the methylene carbon atom of the central acetate chelating arm, while keeping the three carboxylate groups available for metal chelation. Moreover, two of these BFCAs‐PCTA were used for conjugation with a tetrapeptide (cholecystokinin analogue), a bioactive molecule (biotin), or a solid support (silica gel). [ABSTRACT FROM AUTHOR]

Infrared and Raman spectroscopy are effective techniques that allow collecting information about secondary structure of proteins, including antibodies. Trastuzumab, antibody used in our study was in a freeze-dried form, conjugated with different bifunctional chelators and linked with the stable isotopes of lutetium and yttrium. The characterization of the final immunoconjugates showed no significant changes in the structure demonstrated by the presence of the amide bands characteristic for a α-helices and β-sheets structures. These methods could be applied during the production of the antibody freeze-dried kit formulations for the labeling with the radioactive isotopes. [ABSTRACT FROM AUTHOR]

Abstract: Monoclonal conjugates using radionuclides are widely used in the diagnosis or therapy of cancer. A number of ligand molecules per protein molecule (L/P ratio) are a crucial factor affecting the monoclonal conjugate efficacy and safety. For proper and accurate dosing of monoclonal conjugates, it is necessary to establish the L/P ratio before they are applied. The aim of this work was the development of a simple, efficient, non-radioactive, and low-cost spectrophotometric method for L/P ratio measurement. The method is based on transchelation reaction between the monoclonal conjugate and yttrium(III)-methylthymol blue complex followed at wavelength of 590 nm. The method operates in the L/P ratio range of 0.32-8.00 and the results are satisfactorily comparable to the conventional mass spectrometric method.Graphical abstract: [ABSTRACT FROM AUTHOR]

Purpose: The present paper reports a systematic study on the effect of bifunctional chelators (BFC) namely, NOTA, DOTA, and DTPA, on the radiochemical formulation, in vitro stability, and in vivo biological properties of 68Ga-labeled RGD peptide derivatives.Methods: The three RGD conjugates namely, NOTA-Bn-E-[c(RGDfk)]2, DOTA-Bn-E-[c(RGDfk)]2, and DTPA-Bn-E-[c(RGDfk)]2 were radiolabeled with 68Ga and the radiolabeling was optimized with respect to the ligand amount, radiolabeling time, and temperature. Further, the 68Ga complexes were assessed for their in vitro and in vivo stabilities. The biodistribution studies of the three radiolabeled conjugates were carried out in C57BL/6 mice bearing melanoma tumor at 30 min and 1 h post-adimistration.Results: NOTA-Bn-E-[c(RGDfk)]2 could be radiolabeled with 68Ga at room temperature while DOTA-Bn-E-[c(RGDfk)]2 and DTPA-Bn-E-[c(RGDfk)]2 were radiolabeled at high temperature. 68Ga-NOTA-Bn-E-[c(RGDfk)]2 was found to be the most kinetically rigid in in vitro stability assay. The uptake of the three radiolabeled peptide conjugates in melanoma tumor was comparable at 1 h post-administration (NOTA; DOTA; DTPA (% I.D./g):: 2.78 ± 0.38; 3.08 ± 1.1; 3.36 ± 0.49). However, the tumor/background ratio of 68Ga-NOTA-Bn-E-[c(RGDfk)]2 was the best amongst the three radiotracers. 68Ga-complexes of NOTA-Bn-E-[c(RGDfk)]2 and DOTA-Bn-E-[c(RGDfk)]2 showed excellent in vivo stability while 68Ga-DTPA-Bn-E-[c(RGDfk)]2 showed significant metabolic degradation.Conclusion: These studies show that 68Ga-NOTA-Bn-E-[c(RGDfk)]2 would be the most appropriate 68Ga-labeled radiotracer and the most amenable for kit formulation. [ABSTRACT FROM AUTHOR]

Technetium-99m (99mTc) is a widely used radionuclide, and the development of 99mTc imaging agents continues to be in demand. This overview discusses basic principles of 99mTc radiopharmaceutical preparation and design and focuses on the 99mTc radiochemistry relevant to its pharmaceutical applications. The 99mTc complexes are described based on the most typical examples in each category, keeping up with the state-of-the-art in the field. In addition, the main current strategies to develop targeted 99mTc radiopharmaceuticals are summarized. [ABSTRACT FROM AUTHOR]

PET based blood pool imaging tracers have tremendous potential for detection of vascular abnormalities. We synthesized Ga-1,4,7-triazacyclononane-1,4,7-triacetic acid-human serum albumin (Ga-NOTA-HSA) ( 1a) towards use in blood pool imaging and compared it with Ga-1,4,7,10-tetraazacyclo-dodecane-1,4,7,10-tetraacetic acid-HSA (Ga-DOTA-HSA) ( 2a). Both 1a and 2a had similar biodistribution profiles with ≥70% ID/g activity in blood at 2 min p.i. About 50% of initial radioactivity was retained in blood at 2 h p.i. However, the plasma stability of 1a was superior to that of 2a. Results of our study indicate that Ga-NOTA-HSA can be further investigated for clinical blood pool imaging applications. [ABSTRACT FROM AUTHOR]

Two compact and symmetrical bifunctional tetrahydroxamate chelators, 1 and 2 , were synthesized and evaluated for labeling antibodies with 89 Zr for imaging with positron emission tomography. Using 2,2′-iminodiacetamide as the backbone, four hydroxamate-containing moieties coupled to the diacetamide nitrogen were used for 89 Zr labeling, while a pendant connected to the amino group provided an isothiocyanate group for coupling to the antibody. Both 1 - and 2 -conjugated Trastuzumab were labeled with 89 Zr efficiently (>90% radiolabeling yield), and their 89 Zr-labeled products maintained comparable immunoreactivity to Trastuzumab. Compared to 89 Zr-labeled deferoxamine-conjugated Trastuzumab, 89 Zr- 1 - and 89 Zr- 2 -Trastuzumab showed faster demetalation in mouse plasma, and also displayed higher bone uptake in mice. Despite suboptimal stability of 89 Zr complexes of 1 and 2 , our design strategy led to tetrahydroxamate chelators for efficient 89 Zr labeling, and could be potentially modified to provide novel chelators with improved stability. [ABSTRACT FROM AUTHOR]

Derivatives of 3,4-hydroxypyridinones have been extensively studied for in vivo Fe3+ sequestration. Deferiprone, a 1,2-dimethyl-3,4-hydroxypyridinone, is now routinely used for clinical treatment of iron overload disease. Hexadentate tris(3,4-hydroxypyridinone) ligands (THP) complex Fe3+ at very low iron concentrations, and their high affinities for oxophilic trivalent metal ions have led to their development for new applications as bifunctional chelators for the positron emitting radiometal, 68Ga3+, which is clinically used for molecular imaging in positron emission tomography (PET). THP-peptide bioconjugates rapidly and quantitatively complex 68Ga3+ at ambient temperature, neutral pH and micromolar concentrations of ligand, making them amenable to kit-based radiosynthesis of 68Ga PET radiopharmaceuticals. 68Ga-labelled THP-peptides accumulate at target tissue in vivo, and are excreted largely via a renal pathway, providing high quality PET images. [ABSTRACT FROM AUTHOR]

Herein, we report a mild and efficient synthesis of a NODASA-functionalized peptide, which was initiated with a Michael addition reaction between monomethyl fumarate and 1,4,7-triazacyclononane. [ABSTRACT FROM AUTHOR]

The cyclotron-based production of positron-emitting Cu using the (p,α) reaction at 11.7 MeV was investigated starting from natural-zinc (Zn) and enriched Zn-foil targets, as well as its subsequent purification. For Zn, a combination of three resins were assessed to separate Cu from contaminating Ga and Zn. The specific activity of the purified Cu determined using ICP-MS analysis ranged from 143.3 ± 14.3(SD) to 506.2 ± 50.6 MBq/µg while the titration method using p-SCN-Bn-DOTA, p-SCN-Bn-NOTA and diamsar gave variable results (4.7 ± 0.2-412.5 ± 15.3 MBq/µg), with diamsar lying closest to the ICP-MS values. Results suggest that the p-SCN-Bn-DOTA and p-SCN-Bn-NOTA titration methods are significantly affected by the presence of trace-metal contaminants. [ABSTRACT FROM AUTHOR]

The positron-emitting radionuclide copper-64 is of interest in the development of new molecular imaging agents for use with positron emission tomography. This account highlights the development and application of macrocyclic chelators that have been designed to form complexes of copper-64 that are exceptionally stable in vivo and can be readily conjugated to biologically active molecules and nanoparticles. "Click chemistry" is discussed as a conjugation technique that is bioorthogonal with both pre- and postlabeling capabilities. Enzyme-mediated site-specific strategies are introduced as new conjugation techniques with the potential to improve homogeneity, reproducibility, and the likelihood for retention of full biological function of targeted tracers for noninvasive diagnostic imaging. [ABSTRACT FROM AUTHOR]

While the 90Sr/90Y generator is the exclusive source of obtaining `no carrier added' 90Y for targeted therapy, the presence of trace metals in the radiolabeling solutions poses a serious challenge owing to their ability to diminish the 90Y complexation yields with bifunctional chelators (BFCs). p-SCN-Bn-PCTA is a novel ligand having faster complexation kinetics with a number of radiometals. In this work, a systematic investigation was performed to evaluate the chelating ability of p-SCN-Bn-PCTA for 90Y and the influence of trace metal ions on it's complexation with 90Y in comparison to p-SCN-Bn-DTPA and p-SCN-Bn-DOTA using 90YCl3 obtained from an electrochemical generator. Results from our study indicate that while p-SCN-Bn-PCTA gave very good radiolabeling yields with 90Y when the reaction was carried out by heating for few minutes, it was most sensitive to the presence of trace metals, especially Fe(III). An independent and useful observation is that p-SCN-Bn-PCTA could be considered as the ligand of choice for assessing the chemical purity of generator derived 90Y. [ABSTRACT FROM AUTHOR]

Abstract: Measurement of the rate of loss of 64Cu from the chelators used in the preparation of 64Cu-labeled proteins is critical to the development of effective 64Cu-labeled radiopharmaceuticals. Typically, however, this assessment has been made indirectly, by comparison of the relative uptake of the labeled proteins in the liver, or under non-physiological conditions such as hot 5M HCl. In the present study, we measured the rate of loss of 64Cu from a series of chelators (DOTA, TETA, and NOTA) that are commonly used to label proteins as a function of [Cu2+] (1, 2, and 5μM) and pH (7.5, 6.0. and 5.0). We found that 64Cu-NOTA is somewhat more kinetically stable than 64Cu-TETA and that both 64Cu-NOTA and 64Cu-TETA are much more kinetically stable than 64Cu-DOTA. Furthermore, the rate of loss of 64Cu from Cu-DOTA increased with higher [Cu2+] and pH while the rate of loss of 64Cu from Cu-TETA and Cu-NOTA was minimally dependent on [Cu2+] and pH. These results suggest that NOTA is preferable to TETA and DOTA for the preparation of 64Cu-labeled proteins. [Copyright &y& Elsevier]

Abstract: Introduction: The development of novel bifunctional chelates for attaching copper-64 to biomolecules has been an active area of research for several years. However, many of these 64Cu-chelates have poor in vivo stability or harsh radiolabeling conditions. Methods: In this study, two triazacyclononane analogs; C-NE3TA (4-carboxymethyl-7-[2-(carboxymethyl-amino)-3-(4-nitro-phenyl)-propyl]-[1,4,7]triazo-nan-1-yl-acetic acid) and N-NE3TA (4-carboxymethyl-7-[2-[carboxymethyl-(4-nitro-benzyl)-amino]-ethyl]-[1,4,7]triazonan-1-yl-acetic acid) were evaluated for their labeling efficiency with 64Cu at room temperature and evaluated in vitro and in vivo. In vitro studies included complexation kinetics with Cu(II) using a spectrophotometric method and rat serum stability, while the in vivo biodistribution was evaluated using SCID mice. Results: C-NE3TA and N-NE3TA were labeled at >95% efficiency up to ~3.4Ci/μmol. Both C-NE3TA and N-NE3TA formed complexes with Cu(II) almost immediately, with the Cu(II) complexation by C-NE3TA being faster than the formation of Cu(II)-N-NE3TA. Both 64Cu-N-NE3TA and 64Cu-C-NE3TA were 96.1% and 90.5% intact after 48h incubation in rat serum, respectively. This is compared to 64Cu complexes of the control chelators, p-NH2-Bn-DOTA and p-NH2-Bn-NOTA, with 93.9% and 97.9% retention of 64Cu in the complex, respectively. In vivo evaluation of 64Cu-N-NE3TA and 64Cu-C-NE3TA demonstrates good clearance from normal tissues except for the liver, where 59% and 51% of the radioactivity is retained at 24h compared to 1h for 64Cu-N-NE3TA and 64Cu-C-NE3TA, respectively. This compares to 78% and 3% retention for 64Cu-p-NH2-Bn-DOTA and 64Cu-p-NH2-Bn-NOTA. Conclusions: These studies demonstrate that while N-NE3TA and C-NE3TA appear to be superior chelators for 64Cu than p-NH2-Bn-DOTA, they are not better than p-NH2-Bn-NOTA. Nevertheless, it may still be interesting to evaluate these chelators after conjugation to biomolecules. [Copyright &y& Elsevier]

Abstract: We report a straightforward and efficient synthetic strategy for the synthesis of three model glycine-arginine-glycine-aspartic acid-glycine (GRGDG) conjugates based on derivatives of NOTA and of their Ga(III) complexes targeted to the integrin ανβ3 receptor. 71Ga NMR spectroscopy showed that the Ga(III)-labeled conjugates are highly stable in aqueous solution. The 67Ga-labeled conjugates proved to have high kinetic stability and showed a weak but specific binding to the receptors in a U87MG-glioblastoma cell line. [ABSTRACT FROM AUTHOR]

Abstract: Endoradiotherapy represents an alternative therapeutic method in cancer treatment with advantageous features compared to chemotherapy and radiation therapy. Intelligent dose delivery concepts using small drugs, peptides or antibodies as radionuclide carriers enable the verification of a selective accumulation in the tumour lesion and to reduce radiation toxicity for the peripheral organs. The development of endoradiotherapeutic agents, especially chelator-conjugated biomolecules, for example ibritumomab tiuxetan or DOTATOC, gains importance due to the stable complexation of versatile radiometals, such as 90Y or 177Lu. The rational design of novel target binding sides and their grafting into a drug scaffold is a highly promising strategy, which may promote further implication in endoradiotherapy. This review highlights the basic concepts of endoradiotherapy and discusses the potential of targeted therapy and the properties of energy-rich particles emitted by radionuclides for tumour therapy. [Copyright &y& Elsevier]

Abstract: This report concerns synthesis, 68Ga-radiolabelling and stability data of 1,4,7-triazacyclononane-1,4-diacetic acid-7-p-isothio-cyanatophenyl-acetic acid (NODAPA-NCS), 1,4,7-triazacyclononane-1-acetic acid-4,7-di-p-isothiocyanatophenyl-acetic acid (NODAPA-(NCS)2) and 1,4,7-triazacyclononane-1,4-diacetic acid-7-p-hydroxyphenyl-acetic acid (NODAPA-OH), versatile bifunctional chelators with potential for molecular imaging. Protein binding and exemplified conjugation are also reported. [Copyright &y& Elsevier]

Abstract: We describe a convenient scalable synthesis of 4-carbomethoxy-6,6′-dimethyl-2,2′-bipyridine based on the application of modified Negishi cross-coupling conditions. The use of this building block in the preparation of a number of dissymmetrically 6,6′-trisubstituted-2,2′-bipyridines and of bifunctional lanthanide chelators is also reported. [Copyright &y& Elsevier]

Abstract: The novel pyrazolyl containing ligands 4-(HOOC)pz(CH2)2NH(CH2)2NH2 (L1) and 4-(HOOCCH2)-3,5-Me2pz(CH2)2NH(CH2)2NH2 (L2), and 3,5-Me2pz(CH2)2S(CH2)2SCH2CH3 (L3), 3,5-Me2pz(CH2)2S(CH2)2SCH2COOEt (L4) and 3,5-Me2pz(CH2)2S(CH2)2SCH2COOH (L5) were synthesized, and their ability to stabilise complexes with the fac-[M(CO)3]+ (M=Re,99mTc) moiety was evaluated. Reactions of L1–L5 with the Re(I) tricarbonyl starting materials (NEt4)2[Re(CO)3Br3] and/or [Re(CO)5Br] afforded complexes fac-[Re(CO)3(κ3-L)] (L=L1–L5 (1–5)), which contain the pyrazolyl ancillary ligands coordinated in a tridentate fashion. Complexes 1–5 were characterized by the common analytical techniques, which included single crystal X-ray diffraction analysis in the case of 4. The structural analysis of 4 confirmed the tridentate coordination mode of the pyrazole-dithioether ligand, which is facially coordinated to the Re(I) centre through the nitrogen from the pyrazole ring and the two thioether sulphur atoms, without involvement of the terminal ester functional group. The distorted octahedral coordination environment around the metal is completed by the three facial carbonyl ligands. The radioactive congeners of complexes 1, 3 and 4, fac-[99mTc(CO)3(κ3-L)]+ (L=L1 (1a), L3 (3a), L4 (4a)), have been prepared by reacting the precursor fac-[99mTc(CO)3(H2O)3]+ with the corresponding ligands, and their identity confirmed by HPLC comparison with the rhenium surrogates. Complexes 1a and 3a have been challenged in the presence of a large excess of histidine or cysteine, in order to evaluate their in vitro stability. Only a negligible displacement was observed, indicating that pyrazole-diamine and pyrazole-dithioether chelators provide a high kinetic inertness and/or stability to organometallic complexes with the fac-[99mTc(CO)3]+ moiety. [Copyright &y& Elsevier]

Hydroxypyridinones (HOPOs) have been used in the chelation therapy of iron and actinide metals. Their application in metal-based radiopharmaceuticals has also been increasing in recent years. This review article focuses on how multidentate HOPOs can be used in targeted radiometal-based diagnostic and therapeutic radiopharmaceuticals. The general structure of radiometal-based targeted radiopharmaceuticals, a brief description of siderophores, the basic structure and properties of bidentate HOPO, some representative HOPO multidentate chelating agents, radiopharmaceuticals based on HOPO multidentate bifunctional chelators for gallium-68, thorium-227 and zirconium-89, as well as the future prospects of HOPO multidentate bifunctional chelators in other metal-based radiopharmaceuticals are described and discussed in turn. The HOPO metal-based radiopharmaceuticals that have shown good prospects in clinical and preclinical studies are gallium-68, thorium-227 and zirconium-89 radiopharmaceuticals. We expect HOPO multidentate bifunctional chelators to be a very promising platform for building novel targeted radiometal-based diagnostic and therapeutic radiopharmaceuticals. [ABSTRACT FROM AUTHOR]

One of the most rapidly growing options in the management of cancer therapy is Targeted Alpha Therapy (TAT) through which lethal α-emitting radionuclides conjugated to tumor-targeting vectors selectively deliver high amount of radiation to cancer cells. 225 Ac, 212 Bi, 211 At, 213 Bi, and 223Ra have been investigated by plenty of clinical trials and preclinical researches for the treatment of smaller tumor burdens, micro-metastatic disease, and post-surgery residual disease. In order to send maximum radiation to tumor cells while minimizing toxicity in normal cells, a high affinity of targeting vectors to cancer tissue is essential. Besides that, the stable and specific complex between chelating agent and α-emitters was found as a crucial parameter. The present review was planned to highlight recent achievements about TAT-based targeting vectors and chelating agents and provide further insight for future researches., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

The field of targeted radionuclide therapy is rapidly growing, highlighting the need for wider radionuclide availability. Soft Lewis acid ions, such as radioisotopes of platinum, rhodium and palladium, are particularly underdeveloped. This is due in part to a lack of compatible bifunctional chelators. These allow for the practical bioconjugation to targeting vectors, in turn enabling radiolabeling. The [16]andS4 macrocycle has been reported to chelate a number of relevant soft metal ions. In this work, we present a procedure for synthesizing [16]andS4 in 45% yield (five steps, 12% overall yield), together with a selection of strategies for preparing bifunctional derivatives. An ester-linked N-hydroxysuccimide ester (NHS, seven steps, 4% overall yield), an ether-linked isothiocyanate (NCS, eight steps, 5% overall yield) and an azide derivative were prepared. In addition, a new route to a carbon-carbon linked carboxylic acid functionalized derivative is presented. Finally, a general method for conjugating the NHS and NCS derivatives to a polar peptide (octreotide) is presented, by dissolution in water:acetonitrile (1:1), buffered to pH 9.4 using borate. The reported compounds will be readily applicable in radiopharmaceutical chemistry, by facilitating the labeling of a range of molecules, including peptides, with relevant soft radiometal ions. [ABSTRACT FROM AUTHOR]

Pretargeting is widely explored in immunoPET as a strategy to reduce radiation exposure of non-target organs and allow the use of short-lived radionuclides that would not otherwise be compatible with the slow pharmacokinetic profiles of antibodies. Here we investigate a pretargeting strategy based on gallium-68 and the chelator THPMe as a high-affinity pair capable of combining in vivo. After confirming the ability of THPMe to bind 68Ga in vivo at low concentrations, the bifunctional THPMe-NCS was conjugated to a humanised huA33 antibody targeting the A33 glycoprotein. Imaging experiments performed in nude mice bearing A33-positive SW1222 colorectal cancer xenografts compared pretargeting (100 μg of THPMe-NCS-huA33, followed after 24 h by 8–10 MBq of 68Ga3+) with both a directly labelled radioimmunoconjugate (89Zr-DFO-NCS-huA33, 88 μg, 7 MBq) and a 68Ga-only negative control (8–10 MBq of 68Ga3+). Imaging was performed 25 h after antibody administration (1 h after 68Ga3+ administration for negative control). No difference between pretargeting and the negative control was observed, suggesting that pretargeting via metal chelation is not feasible using this model. However, significant accumulation of "unchelated" 68Ga3+ in the tumour was found (12.9 %ID/g) even without prior administration of THPMe-NCS-huA33, though tumour-to-background contrast was impaired by residual activity in the blood. Therefore, the 68Ga-only experiment was repeated using THPMe (20 μg, 1 h after 68Ga3+ administration) to clear circulating 68Ga3+, producing a three-fold improvement of the tumour-to-blood activity concentration ratio. Although preliminary, these results highlight the potential of THPMe as a 68Ga clearing agent in imaging applications with gallium citrate. [ABSTRACT FROM AUTHOR]

Cover Feature: Versatile Bispidine-Based Bifunctional Chelators for 64CuII-Labelling of Biomolecules (Chem. Eur. J. 9/2020) Reductive alkylation at the relatively inert C9-position of bispidols paves the way for generating a number of derivatives ready to be coupled to a variety of targeting vector molecules. As these bispidine derivatives form highly stable complexes with the positron emitter SP 64 sp Cu SP II sp , they are virtually predestined for their application in the field of diagnostic positron emission tomography (PET). [Extracted from the article]