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Here we describe an anti-prostate-specific membrane antigen (PSMA) minibody (IAB2MA) conjugated to an octadentate, macrocyclic chelator based on four 1-hydroxypyridin-2-one coordinating units (Lumi804 [L804]) labeled with 89 Zr (PET imaging) and 177 Lu (radiopharmaceutical therapy), with the goal of developing safer and more efficacious treatment options for prostate cancer. Methods: L804 was compared with the current gold standard chelators, DOTA and deferoxamine (DFO), conjugated to IAB2MA for radiolabeling with 177 Lu and 89 Zr in cell binding, preclinical biodistribution, imaging, dosimetry, and efficacy studies in the PSMA-positive PC3-PIP tumor-bearing mouse model of prostate cancer. Results: Quantitative radiolabeling (>99% radiochemical yield) of L804-IAB2MA with 177 Lu or 89 Zr was achieved at ambient temperature in under 30 min, comparable to 89 Zr labeling of DFO-IAB2MA. In contrast, DOTA-IAB2MA was radiolabeled with 177 Lu for 30 min at 37°C in approximately 90% radiochemical yield, requiring further purification. Using europium(III) as a luminescent surrogate, high binding affinity of Eu-L804-IAB2MA to PSMA was demonstrated in PC3-PIP cells (dissociation constant, 4.6 ± 0.6 nM). All 4 radiolabeled constructs showed significantly higher levels of internalization after 30 min in the PC3-PIP cells than in PSMA-negative PC3-FLU cells. The accumulation of 177 Lu- and 89 Zr-L804-IAB2MA in PC3-PIP tumors and all organs examined (i.e., heart, liver, spleen, kidney, muscle, salivary glands, lacrimal glands, carcass, and bone) was significantly lower than that of 177 Lu-DOTA-IAB2MA and 89 Zr-DFO-IAB2MA at 96 and 72 h after injection, respectively. Generally, SPECT/CT and PET/CT imaging data showed no significant difference in the SUV mean of the tumors or muscle between the radiotracers. Dosimetry analysis via both organ-level and voxel-level dose calculation methods indicated significantly higher absorbed doses of 177 Lu-DOTA-IAB2MA in tumors, kidney, liver, muscle, and spleen than of 177 Lu-L804-IAB2MA. PC3-PIP tumor-bearing mice treated with single doses of 177 Lu-L804-IAB2MA (18.4 or 22.2 MBq) exhibited significantly prolonged survival and reduced tumor volume compared with unlabeled minibody control. No significant difference in survival was observed between groups of mice treated with 177 Lu-L804-IAB2MA or 177 Lu-DOTA-IAB2MA (18.4 or 22.2 MBq). Treatment with 177 Lu-L804-IAB2MA resulted in lower absorbed doses in tumors and less toxicity than that of 177 Lu-DOTA-IAB2MA. Conclusion: 89 Zr- and 177 Lu-L804-IAB2MA may be a promising theranostic pair for imaging and therapy of prostate cancer., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

The demand for PET tracers that target prostate-specific membrane antigen (PSMA) continues to increase. Meeting this demand with approved 68 Ga- and 18 F-labeled PSMA tracers is challenging outside of major urban centers. This is because the short physical half-life of these radionuclides makes it necessary to produce them near their sites of usage. To overcome this challenge, we propose cyclotron-produced 61 Cu for labeling PSMA PET tracers. 61 Cu can be produced on a large scale, and its 3.33-h half-life allows shipping over considerably longer distances than possible for 68 Ga and 18 F. Production of true theranostic twins using 61 Cu and the β - -emitter 67 Cu is also feasible. Methods: PSMA-I&T (DOTAGA-(l-y)fk(sub-KuE)) and its derivative in which the DOTAGA chelator was replaced by NODAGA (NODAGA-(l-y)fk(sub-KuE)), herein reported as DOTAGA-PSMA-I&T and NODAGA-PSMA-I&T, respectively, were labeled with 61 Cu and compared with [ 68 Ga]Ga-DOTAGA-PSMA-I&T, [ 68 Ga]Ga-NODAGA-PSMA-I&T, [ 68 Ga]Ga-PSMA-11, and [ 18 F]PSMA-1007. In vitro (lipophilicity, affinity, cellular uptake, and distribution) and in vivo (PET/CT, biodistribution, and stability) studies were performed in LNCaP cells and xenografts. Human dosimetry estimates were calculated for [ 61 Cu]Cu-NODAGA-PSMA-I&T. First-in-human imaging with [ 61 Cu]Cu-NODAGA-PSMA-I&T was performed in a patient with metastatic prostate cancer. Results: [ 61 Cu]Cu-DOTAGA-PSMA-I&T and [ 61 Cu]Cu-NODAGA-PSMA-I&T were synthesized with radiochemical purity of more than 97%, at an apparent molar activity of 24 MBq/nmol, without purification after labeling. In vitro, natural Cu ( nat Cu)-DOTAGA-PSMA-I&T and nat Cu-NODAGA-PSMA-I&T showed high affinity for PSMA (inhibitory concentration of 50%, 11.2 ± 2.3 and 9.3 ± 1.8 nM, respectively), although lower than the reference nat Ga-PSMA-11 (inhibitory concentration of 50%, 2.4 ± 0.4 nM). Their cellular uptake and distribution were comparable to those of [ 68 Ga]Ga-PSMA-11. In vivo, [ 61 Cu]Cu-NODAGA-PSMA-I&T showed significantly lower uptake in nontargeted tissues than [ 61 Cu]Cu-DOTAGA-PSMA-I&T and higher tumor uptake (14.0 ± 5.0 percentage injected activity per gram of tissue [%IA/g]) than [ 61 Cu]Cu-DOTAGA-PSMA-I&T (6.06 ± 0.25 %IA/g, P = 0.0059), [ 68 Ga]Ga-PSMA-11 (10.2 ± 1.5 %IA/g, P = 0.0972), and [ 18 F]PSMA-1007 (9.70 ± 2.57 %IA/g, P = 0.080) at 1 h after injection. Tumor uptake was also higher for [ 61 Cu]Cu-NODAGA-PSMA-I&T at 4 h after injection (10.7 ± 3.3 %IA/g) than for [ 61 Cu]Cu-DOTAGA-PSMA-I&T (4.88 ± 0.63 %IA/g, P = 0.0014) and [ 18 F]PSMA-1007 (6.28 ± 2.19 %IA/g, P = 0.0145). Tumor-to-nontumor ratios of [ 61 Cu]Cu-NODAGA-PSMA-I&T were superior to those of [ 61 Cu]Cu-DOTAGA-PSMA-I&T and comparable to those of [ 68 Ga]Ga-PSMA-11 and [ 18 F]PSMA-1007 at 1 h after injection and increased significantly between 1 and 4 h after injection in most cases. Human dosimetry estimates for [ 61 Cu]Cu-NODAGA-PSMA-I&T were similar to the ones reported for 18 F-PSMA ligands. First-in-human imaging demonstrated multifocal osseous and hepatic metastases. Conclusion: [ 61 Cu]Cu-NODAGA-PSMA-I&T is a promising PSMA radiotracer that compares favorably with [ 68 Ga]Ga-PSMA-11 and [ 18 F]PSMA-1007, while allowing delayed imaging., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

Occult nodal spread and metastatic disease require longstanding imaging and biochemical assessments for thyroid cancer, a disease that has a propensity for diffuse, small-volume disease. We have developed a 64 Cu-labeled platelet-derived growth factor receptor α (PDGFRA) antibody for immuno-PET of PDGFRA in metastatic papillary thyroid cancer (PTC). The present work describes the discovery of small cyclic PDGFRA-targeting peptides, their binding features, and radiolabeling with positron emitter gallium-68 ( 68 Ga) for in vitro and in vivo characterization in thyroid cancer models. Phage-display technology with two separate libraries and seven different cell lines was used through three rounds of biopanning as well as flow cytometry and comparative analysis with recombinant protein to select specific peptide sequences. Phenotypic binding analysis was completed by using phosphorylation and cell migration assays. In vitro protein binding was analyzed with thermophoresis and flow cytometry using the fluorescent-labeled PDGFRA peptide. Peptide candidates were modified with the NOTA chelator for radiolabeling with 68 Ga. In vitro cell uptake was studied in various thyroid cancer cell lines. In vivo studies of 68 Ga-labeled peptides included metabolic stability and PET imaging. From the original library (10 13 compounds), five different peptide groups were identified based on biopanning experiments with and without the α subunit of PDGFR, leading to ∼50 peptides. Subsequent phenotypic screening revealed two core peptide sequences ( CP16 and CP18 ) that demonstrated significant changes in the level of PDGFRA phosphorylation and cell migration. Alanine scan sublibraries were created from these two lead peptide sequences, and peptides were radiolabeled using 68 Ga-GaCl 3 at pH 4.5, resulting in RCP > 95% within 34-40 min, including SPE purification. Cyclic peptide CP18.5 showed the strongest effects on cell migration, flow cytometry, and binding by visual interference color assay. 68 Ga-labeled PDGFRA-targeting peptides showed elevated cell and tumor uptake in models of thyroid cancer, with 68 Ga-NOTA-CP18.5 being the lead candidate. However, metabolic stability in vivo was compromised for 68 Ga-NOTA-CP18.5 vs 68 Ga-NOTA-CP18 but without impacting tumor uptake or clearance profiles. First-generation radiolabeled cyclic peptides have been developed as novel radiotracers, particularly 68 Ga-NOTA-CP18.5 , for the molecular imaging of PDGFRA in thyroid cancer.

The aim of this study was to evaluate the preclinical efficacy of [ 89 Zr]Zr-DFO-Ab253 as a novel positron emission tomography (PET) tracer for CD146-positive malignant melanoma imaging. Considering the high expression of CD146 in malignant melanoma, this study investigated the effect of different CD146 expression levels on the tumor uptake of [ 89 Zr]Zr-DFO-Ab253. CD146 selectivity was investigated by using the CD146-positive human melanoma cell A375 and the CD146-negative human alveolar epithelial cell A549. The cell uptake of [ 89 Zr]Zr-DFO-Ab253 tracers was investigated, and receptor-binding affinities were measured by radioactive enzyme-linked immunosorbent assay. Biodistribution studies and micro-PET imaging of the radiotracers were performed on mice bearing A375 and A549 xenografts under baseline and blocking conditions. An immunohistochemical test was performed using A375 and A549 tissue sections for CD146 expression level analysis. [ 89 Zr]Zr-DFO-Ab253 was obtained with a high radiochemical yield (87.86 ± 4.66%) and a satisfactory radiochemical purity (>98.0%). The specificity and affinity of [ 89 Zr]Zr-DFO-Ab253 were confirmed in melanoma A375 cells and in vivo PET imaging of A375 tumor models. [ 89 Zr]Zr-DFO-IgG and A549 lung tumors were prepared as control radiotracers and negative models to verify the specificity of [ 89 Zr]Zr-DFO-Ab253 on CD146. [ 89 Zr]Zr-DFO-Ab253 has a K d of 4.01 ± 0.50 nM. PET imaging and biodistribution showed a higher uptake of [ 89 Zr]Zr-DFO-Ab253 in A375 melanomas than that in A549 tumors (42.1 ± 4.04% vs 7.87 ± 1.30% ID/g at 120 h, P < 0.05). A low tumor uptake of [ 89 Zr]Zr-DFO-IgG was observed with uptakes of 1.91 ± 0.41 and 2.80 ± 0.14 ID%/g when blocked at 120 h. The radiation-absorbed dose was calculated to be 0.13 mSv/MBq. This study demonstrates the synthesis and preclinical evaluation of [ 89 Zr]Zr-DFO-Ab253 and indicates that the novel tracer has promising applications in malignant melanoma-specific PET imaging because of its high uptake and long-time retention in malignant melanoma. It also provides feasibility for the development of integrated molecular probes for diagnosis and treatment based on the CD146 target.

Nectin cell adhesion molecule 4 (Nectin-4) is overexpressed in various malignant tumors and has emerged as a promising target for tumor imaging. Bicyclic peptides, known for their conformational rigidity, metabolic stability, and membrane permeability, are ideal tracers for positron emission tomography (PET) imaging. In this study, we evaluated the feasibility of visualizing Nectin-4-positive tumors using radiolabeled bicyclic peptide derivatives and optimized the pharmacokinetics of radiotracers by introducing PEG chains of different lengths. Five PEGylated radiotracers radiolabeled with 68 Ga 3+ exhibited high radiochemical purity and stability. As the chain length increased, the Log  D values decreased from -2.32 ± 0.13 to -2.50 ± 0.16, indicating a gradual increase in the hydrophilicity of the radiotracers. In vitro cell-binding assay results showed that the PEGylated bicyclic peptide exhibits nanomolar affinity, and blocking experiments confirmed the specific binding of the tracers to the Nectin-4 receptor. In vivo PET imaging and biodistribution studies in SW780 and 5637 xenograft mice showed that [ 68 Ga]Ga-NOTA-PEG 12 -BP demonstrated optimal pharmacokinetics, characterized by rapid and good tumor uptake, faster background clearance, and improved tumor-to-tissue contrast. Finally, compared with 18 F-FDG, PET imaging, in vivo blocking assays of [ 68 Ga]Ga-NOTA-PEG 12 -BP and histological staining confirmed that specific tumor uptake was mediated by Nectin-4 receptors. The results indicated that [ 68 Ga]Ga-NOTA-PEG 12 -BP was a promising PET radiotracer for Nectin-4 targeting, with applications for clinical translation.

This study aimed to evaluate a novel albumin-binding strategy for addressing the challenge of insufficient tumor retention of fibroblast activation protein inhibitors (FAPIs). Maleimide, a molecule capable of covalent binding to free thiol groups, was modified to conjugate with FAPI-04 in order to enhance its binding to endogenous albumin, resulting in an extended blood circulation half-life and increased tumor uptake. DOTA-FAPI-maleimide was prepared and radiolabeled with Ga-68 and Lu-177, followed by cellular assays, pharmacokinetic analysis, PET/CT, and SPECT/CT imaging to assess the probe distribution in various tumor-bearing models. Radiolabeling of the modified probe was successfully achieved with a radiochemical yield of over 99% and remained stable for 144 h. Cellular assays showed that the ligand concentration required for 50% inhibition of the probe was 1.20 ± 0.31 nM, and the K d was 0.70 ± 0.07 nM with a B max of 7.94 ± 0.16 fmol/cell, indicative of higher specificity and affinity of DOTA-FAPI-maleimide compared to other FAPI-04 variants. In addition, DOTA-FAPI-maleimide exhibited a persistent blood clearance half-life of 7.11 ± 0.34 h. PET/CT images showed a tumor uptake of 2.20 ± 0.44%ID/g at 0.5 h p.i., with a tumor/muscle ratio of 5.64 in HT-1080-FAP tumor-bearing models. SPECT/CT images demonstrated long-lasting tumor retention. At 24 h p.i., the tumor uptake of [ 177 Lu]Lu-DOTA-FAPI-maleimide reached 5.04 ± 1.67%ID/g, with stable tumor retention of 3.40 ± 1.95%ID/g after 4 days p.i. In conclusion, we developed and evaluated the thiol group-attaching strategy, which significantly extended the circulation and tumor retention of the adapted FAPI tracer. We envision its potential application for clinical cancer theranostics.

Purpose: Accumulating evidence suggests that neurotensin (NTS) and neurotensin receptors (NTSRs) play key roles in lung cancer progression by triggering multiple oncogenic signaling pathways. This study aims to develop Cu-labeled neurotensin receptor 1 (NTSR1)-targeting agents with the potential for both imaging and therapeutic applications., Method: A series of neurotensin receptor antagonists (NRAs) with variable propylamine (PA) linker length and different chelators were synthesized, including [ 64 Cu]Cu-CB-TE2A-iPA-NRA ([ 64 Cu]Cu-4a-c, i = 1, 2, 3), [ 64 Cu]Cu-NOTA-2PA-NRA ([ 64 Cu]Cu-4d), [ 64 Cu]Cu-DOTA-2PA-NRA ([ 64 Cu]Cu-4e, also known as [ 64 Cu]Cu-3BP-227), and [ 64 Cu]Cu-DOTA-VS-2PA-NRA ([ 64 Cu]Cu-4f). The series of small animal PET/CT were conducted in H1299 lung cancer model. The expression profile of NTSR1 was also confirmed by IHC using patient tissue samples., Results: For most of the compounds studied, PET/CT showed prominent tumor uptake and high tumor-to-background contrast, but the tumor retention was strongly influenced by the chelators used. For previously reported 4e, [ 64 Cu]Cu-labeled derivative showed initial high tumor uptake accompanied by rapid tumor washout at 24 h. The newly developed [ 64 Cu]Cu-4d and [ 64 Cu]Cu-4f demonstrated good tumor uptake and tumor-to-background contrast at early time points, but were less promising in tumor retention. In contrast, our lead compound [ 64 Cu]Cu-4b demonstrated 9.57 ± 1.35, 9.44 ± 2.38 and 9.72 ± 4.89%ID/g tumor uptake at 4, 24, and 48 h p.i., respectively. Moderate liver uptake (11.97 ± 3.85, 9.80 ± 3.63, and 7.72 ± 4.68%ID/g at 4, 24, and 48 h p.i.) was observed with low uptake in most other organs. The PA linker was found to have a significant effect on drug distribution. Compared to [ 64 Cu]Cu-4b, [ 64 Cu]Cu-4a had a lower background, including a greatly reduced liver uptake, while the tumor uptake was only moderately reduced. Meanwhile, [ 64 Cu]Cu-4c showed increased uptake in both the tumor and the liver. The clinical relevance of NTSR1 was also demonstrated by the elevated tumor expression in patient tissue samples., Conclusions: Through the side-by-side comparison, [ 64 Cu]Cu-4b was identified as the lead agent for further evaluation based on its high and sustained tumor uptake and moderate liver uptake. It can not only be used to efficiently detect NTSR1 expression in lung cancer (for diagnosis, patient screening, and treatment monitoring), but also has the great potential to treat NTSR-positive lesions once chelating to the beta emitter 67 Cu., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: The advancement of heterodimeric tracers, renowned for their high sensitivity, marks a significant trend in the development of radiotracers for cancer diagnosis. Our prior work on [ 68 Ga]Ga-HX01, a heterodimeric tracer targeting CD13 and integrin α v β 3 , led to its approval for phase I clinical trials by the China National Medical Production Administration (NMPA). However, its fast clearance and limited tumor retention pose challenges for broader clinical application in cancer treatment. This study aims to develop a new radiopharmaceutical with increased tumor uptake and prolonged retention, rendering it a potential therapeutic candidate., Methods: New albumin binder-conjugated compounds were synthesized based on the structure of HX01. In vitro and in vivo evaluation of these new compounds were performed after labelling with 68 Ga. Small-animal PET/CT imaging were conducted at different time points at 0.5-6 h post injection (p.i.) using BxPC-3 xenograft mice models. The one with the best imaging performance was further radiolabeled with 177 Lu for small-animal SPECT/CT and ex vivo biodistribution investigation., Results: We have synthesized novel albumin binder-conjugated compounds, building upon the structure of HX01. When radiolabeled with 68 Ga, all compounds demonstrated improved pharmacokinetics (PK). Small-animal PET/CT studies revealed that these new albumin binder-conjugated compounds, particularly [ 68 Ga]Ga-L6, exhibited significantly enhanced tumor accumulation and retention compared with [ 68 Ga]Ga-L0 without an albumin binder. [ 68 Ga]Ga-L6 outperformed [ 68 Ga]Ga-L7, a compound developed using a previously reported albumin binder. Furthermore, [ 177 Lu]Lu-L6 demonstrated rapid clearance from normal tissues, high tumor uptake, and prolonged retention in small-animal SPECT/CT and biodistribution studies, positioning it as an ideal candidate for radiotherapeutic applications., Conclusion: A new integrin α v β 3 and CD13 targeting compound was screened out. This compound bears a novel albumin binder and exhibits increased tumor uptake and prolonged tumor retention in BxPC-3 tumors and low background in normal organs, making it a perfect candidate for radiotherapy when radiolabeled with 177 Lu., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Purpose: The unsatisfactory efficacy of PD-L1 antibodies in glioblastoma (GBM) is largely due to the temporal and spatial heterogeneity of PD-L1 expression. Molecular imaging can enhance understanding of the tumor immune microenvironment and guide immunotherapy. However, highly sensitive imaging agents capable of effectively visualizing PD-L1 heterogeneity are limited. This study introduces a novel PET tracer, offering improved imaging of PD-L1 heterogeneity in GBM xenografts, with a comparative analysis to [ 18 F]AlF-NOTA-WL12., Methods: [ 18 F]AlF-NOTA-PCP2 was synthesized with high purity and its affinity for PD-L1 was characterized using surface plasmon resonance (SPR) and cell binding assays. Its specificity for PD-L1 was evaluated both in vitro using various cell lines and in vivo with GBM xenograft models in NOD/SCID mice. PET/CT imaging was conducted to evaluate the tracer's biodistribution, pharmacokinetics, and ability to quantify tumoral spatial heterogeneity of PD-L1 expression. A focused comparative analysis between [ 18 F]AlF-NOTA-PCP2 and [ 18 F]AlF-NOTA-WL12 was conducted, examining binding affinity, biodistribution, pharmacokinetics, and imaging effectiveness in GBM xenografts. Additionally, human radiation dosimetry estimates compared the safety profiles of both tracers., Results: [ 18 F]AlF-NOTA-PCP2 demonstrated high radiochemical purity (> 95%) and a strong affinity for PD-L1, comparable to [ 18 F]AlF-NOTA-WL12. In vitro and in vivo studies confirmed its specificity for PD-L1, with increased uptake in PD-L1 expressing cells and tumors. Toxicological profiles indicated no significant abnormalities in serum biochemical indicators or major organ tissues. MicroPET/CT imaging showed [ 18 F]AlF-NOTA-PCP2's effectiveness in visualizing PD-L1 expression levels and spatial heterogeneity in GBM xenografts. Comparative studies revealed [ 18 F]AlF-NOTA-PCP2's improved pharmacokinetic properties, including higher tumor-to-blood ratios and lower nonspecific liver uptake, as well as reduced radiation exposure compared to [ 18 F]AlF-NOTA-WL12., Conclusion: [ 18 F]AlF-NOTA-PCP2 distinguishes itself as an exceptionally sensitive PET/CT tracer, adept at non-invasively and accurately quantifying PD-L1 expression and its spatial heterogeneity in tumors, especially in GBM. Its favorable pharmacokinetic properties, safety profile, and high affinity for PD-L1 highlight its potential for enhancing the precision of cancer immunotherapy and guiding individualized treatment strategies. While promising, its clinical translation, especially in brain imaging, necessitates further validation in clinical trials., (© 2024. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Despite the availability of various 11 C-labeled positron emission tomography (PET) tracers for assessing P-glycoprotein (P-gp) function, there are still limitations related to complex metabolism, high lipophilicity, and low baseline uptake. This study aimed to address these issues by exploring a series of customized dihydropyridines (DHPs) with enhanced stability and reduced lipophilicity as alternative PET tracers for P-gp dysfunction. Compared with verapamil and the rest DHPs, dimethyl 4-(4-fluorophenyl)-2,6-dimethyl-1,4-dihydropyridine-3,5-dicarboxylate (1) exhibited superior cellular uptake differences between the human gastric cancer cell line SGC7901 and its drug-resistant counterpart. [ 18 F]1 is successfully synthesized using a novel "hot-Hantzsch" approach in 22.1 ± 0.1 % radiochemical yields. MicroPET/CT imaging demonstrated that the uptake of [ 18 F]1 in the brains of P-gp blocked mice increased by > 3 times compared to the control group. Additionally, [ 18 F]1 displayed favorable lipophilicity (log D = 2.3) and excellent clearance characteristics, making it a promising tracer candidate with low background noise and high contrast., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Ltd. All rights reserved.)

The radiohybrid (rh) concept to design targeted (and chemically identical) radiotracers for imaging or radionuclide therapy of tumors has gained momentum. For this strategy, a new bifunctional Silicon-based Fluoride Acceptor (SiFA) moiety (SiFA)SeFe was synthesized, endowed with improved hydrophilicity and high versatility of integration into rh-compounds. Preliminary radiolabeling and stability studies under different conditions were conducted using model bioconjugate peptides. Further, three somatostatin receptor 2 (sstR2)-targeted rh-compounds ( (SiFA)SeFe-rhTATE1-3 , TATE = (Tyr 3 )-octreotate) were developed. Compound (SiFA)SeFe-rhTATE3 , enables labeling with 18 F for PET imaging or chelation of 177 Lu for therapy. The rh-compounds possess comparable receptor binding affinity and in vitro performance as good as the clinically proven gold standards. SstR2-specificity was further shown for (SiFA)SeFe-rhTATE2 using the chicken chorioallantoic membrane (CAM) model. The biodistribution of two compounds in mice showed high accumulation in tumors and excretion via the kidneys, demonstrating the clinical applicability of the (SiFA)SeFe moiety.

Ligand-based virtual screening (LBVS) has rarely been tested as a method for discovering new structural scaffolds for PET radioligand development. This study used LBVS to discover potential chemotype leads for developing radioligands for PET imaging of tauopathies. ZINC12, a free database of over 12 million commercially available compounds, was searched to discover novel scaffolds based on similarities to four query compounds. Thirteen high-ranking hits were purchased and assayed for their ability to compete against three tritiated radioligands at their distinct binding sites in Alzheimer's disease brain tissue. Three hits were 2-substituted 6-methoxy naphthalenes. Synthetic elaboration of this new chemotype yielded three new ligands ( 25 , 26 , and 28 ) with high affinity for the [ 3 H] 6 (flortaucipur) neurofibrillary tangle binding site. Compound 28 showed remarkably high affinity ( K i , 7 nM) and other desirable properties for a candidate PET radioligand, including low topological polar surface area, moderate computed log  D , and amenability for labeling with carbon-11. LBVS appears to be uniquely valuable for discovering new chemotypes for candidate PET radioligands.

d-Amino acids such as d-alanine are substrates for bacterial peptidoglycan biosynthesis and are selectively taken up by bacteria and not mammalian cells. Consequently, d-amino acid metabolism is an attractive target for antibiotic discovery and the development of bacteria-specific imaging agents. d-Fluoroalanine and the deuterium-labeled analogue fludalanine (MK641) were originally explored as antibiotics by Merck but failed in clinical trials due to unaccepted toxicity. Herein, we synthesized a fluorine-18 labeled d-fluoroalanine, d-3-[ 18 F]fluoroalanine (d-[ 18 F]FAla), and its deuterated analogue, d-3-[ 18 F]fluoroalanine- d 3 (d-[ 18 F]FAla- d 3 ), and evaluated their capability to image bacterial infection. Both d-[ 18 F]FAla and d-[ 18 F]FAla- d 3 can accumulate up to 0.64-0.78% ID/cc in the infectious area at 15 min postinjection. Despite the reduction of in vivo defluorination not being observed for deuterated 18 F-labeled d-fluoroalanine, these radiolabeled d-alanine analogues were able to differentiate bacterial infection from sterile inflammation in a soft-tissue model of S. aureus infection.

Mutations of isocitrate dehydrogenase 1 (IDH1) are key biomarkers for glioma classification, but current methods for detection of mutated IDH1 (mIDH1) require invasive tissue sampling and cannot be used for longitudinal studies. Positron emission tomography (PET) imaging with mIDH1-selective radioligands is a promising alternative approach that could enable non-invasive assessment of the IDH status. In the present work, we developed efficient protocols for the preparation of four 18 F-labeled derivatives of the mIDH1-selective inhibitor olutasidenib. All four probes were characterized by cellular uptake studies with U87 glioma cells harboring a heterozygous IDH1 mutation (U87-mIDH) and the corresponding wildtype cells (U87-WT). In addition, the most promising probe was evaluated by PET imaging in healthy mice and mice bearing subcutaneous U87-mIDH and U87-WT tumors. Although all four probes inhibited mIDH1 with variable potencies, only one of them ([ 18 F]mIDH-138) showed significantly higher in vitro uptake into U87-mIDH compared to U87-WT cells. In addition, PET imaging with [ 18 F]mIDH-138 in mice demonstrated good in vivo stability and low non-specific uptake of the probe, but also revealed significantly higher uptake into U87-WT compared to U87-mIDH tumors. Finally, application of a two-tissue compartment model (2TCM) to the PET data indicated that preferential tracer uptake into U87-WT tumors results from higher specific binding rather than from differences in tracer perfusion. In conclusion, these results corroborate recent findings that mIDH1-selective inhibition may not directly correlate with mIDH1-selective target engagement and indicate that in vivo engagement of wildtype and mutated IDH1 may be governed by factors that are not faithfully reproduced by in vitro assays, both of which could complicate development of PET probes.

Photoredox is a powerful synthetic tool in organic chemistry and has been widely used in various fields, including nuclear medicine and molecular imaging. In particular, acridinium-based organophotoredox radiolabeling has significantly impacted the production and discovery of positron emission tomography (PET) agents. Despite their extensive use in preclinical research, no PET agents synthesized by acridinium photoredox labeling have been tested in humans. [ 18 F]FDOPA is clinically used for tumor diagnosis and the evaluation of neuropsychiatric disorders, but its application is limited by complex synthesis methods, the need for expensive modules, and/or the high cost of consumable materials/cassettes. In this report, we integrated a photoredox labeling unit with an automated module and produced [ 18 F]FDOPA for human study. This research not only represents the first human study of a PET agent generated by acridinium-based organophotoredox reactions but also demonstrates the safety of this novel labeling method, serving as a milestone/reference for the clinical translation of other PET agents generated by this technique in the future.

Radiolabelled puromycin analogues will allow the quantification of protein synthesis through nuclear medicine-based imaging. A particularly useful application could be the non-invasive longitudinal visualisation of mycobacterial activity through direct quantification of puromycin binding. This study assesses the value of [ 68 Ga]Ga-DOTA-puromycin in the visualisation of mycobacteria through positron emission tomography combined with magnetic resonance imaging (µPET/MRI). The radiopharmaceutical was produced by previously published and validated methods. [ 68 Ga]Ga-DOTA-Puromycin imaging was performed on severe immunodeficient mice infected with Bacille Calmette-Guérin-derived M. Bovis (BCG). Acute and chronic infection stages were examined by µPET/MRI. A follow-up group of animals acted as controls (animals bearing S. aureus-derived infection and sterile inflammation) to assess tracer selectivity. [ 68 Ga]Ga-DOTA-puromycin-µPET/MRI images revealed the acute, widespread infection within the right upper shoulder and armpit. Also, [ 68 Ga]Ga-DOTA-puromycin signal sensitivity measured after a 12-week period was lower than that of [ 18 F]FDG-PET in the same animals. A suitable correlation between normalised uptake values (NUV) and gold standard histopathological analysis confirms accurate tracer accumulation in viable bacteria. The radiopharmaceutical showed infection selectivity over inflammation but accumulated in both M. Bovis and S. Aureus, lacking pathogen specificity. Overall, [ 68 Ga]Ga-DOTA-puromycin exhibits potential as a tool for non-invasive protein synthesis visualization, albeit without pathogen selectivity., (© 2024. The Author(s).)

Naphthalocyanine-based agents exhibit huge potential in photodynamic therapy, yet their photodynamic performance is restricted by the penetration depth of the external laser. Herein, we employed 18 F-FDG as an internal light source to excite silicon naphthalocyanine nanoparticles to simultaneously circumvent radiative transition and boost 1 O 2 generation for tumor suppression.

Cardiovascular diseases, including fatal myocardial infarctions from atheromatous plaques, are the primary global mortality cause. Detecting stenotic atheromatous plaques is possible through coronary angiography, but vulnerable plaques with eccentric remodeling are undetectable with current diagnostic methods. Addressing this challenge, our group developed a radiopharmaceutical drug targeting vascular cell adhesion molecule 1 (VCAM-1), radiolabeled with technetium-99m. Given the absence of a monograph in the European Pharmacopoeia, and in order to draft the investigational medicinal product documentation, analytical methods had to be validated by high performance liquid chromatography (HPLC) and thin layer chromatography (TLC) to determine the radiochemical purity (RCP) of 99m Tc-cAbVCAM1-5. This study therefore presents the results of the validation of analytical methods obtained in this context. The method validation followed the European Association of Nuclear Medicine (EANM) recommendations adapted from ICH Q2(R1), ensuring conformity with specificity, accuracy, repeatability and intermediate precision, linearity, robustness, quantification limit (LoQ), and range criteria. Regarding the results of specificity, both HPLC and TLC methods demonstrated excellent separation of 99m Tc-cAbVCAM1-5 from impurities 99m TcO4 - . Accuracy results indicated recovery percentages within the range of 99.52-101.40% for the HPLC and 99.51-101.97% for TLC, ensuring reliable measurements for each concentration of 99m TcO 4 - . Precision of the methods was validated by assessing repeatability and intermediate precision. Linearity was determined over the usual concentrations range and the correlation coefficient was greater than 0.99 for both methods. The limit of quantification was measured by diluting the 99m TcO 4 - to obtain a signal-to-noise ratio of around 10:1. Under these conditions, we obtained an LOQ of 2.10 MBq/mL for HPLC and 2Mbq/mL for TLC. In conclusion, the analytical methods developed in this study comply with EANM recommendations. This therefore allows us to correctly assess the radiochemical purity of 99m Tc-cAbVCAM1-5, a new radiotracer targeting inflammation in vulnerable plaques., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Targeted Radionuclide Therapies (TRT) involve the tailored combination of a therapeutic radionuclide and a targeting molecule, as for instance antibodies or fragments thereof. Despite their short shelf-life, these drug products must meet stringent regulatory standards before use. We introduce a novel, efficient method utilizing Bio-Layer Interferometry (BLI) for rapid identity testing of TRT drug products in less than five minutes. This approach not only reduces radioactive waste but also minimizes operator exposure to radiation. This label-free method has been successfully developed and validated for three different TRT products, ensuring compliance with Good Manufacturing Practices (GMP). Furthermore, we outline our strategic approach to the production and testing of custom biosensors for each product, firmly grounded in Quality-by-Design (QbD) principles., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier B.V. All rights reserved.)

The global incidence of invasive fungal infections (IFIs) has increased over the past few decades, mainly in immunocompromised patients, and is associated with high mortality and morbidity. Aspergillus fumigatus is one of the most common and deadliest IFI pathogens. Major hurdles to treating fungal infections remain the lack of rapid and definitive diagnosis, including the frequent need for invasive procedures to provide microbiological confirmation, and the lack of specificity of structural imaging methods. To develop an Aspergillus -specific positron emission tomography (PET) imaging agent, we focused on fungal-specific sugar metabolism. We radiolabeled cellobiose, a disaccharide known to be metabolized by Aspergillus species, and synthesized 2-deoxy-2-[ 18 F]fluorocellobiose ([ 18 F]FCB) by enzymatic conversion of 2-deoxy-2-[ 18 F]fluoroglucose ([ 18 F]FDG) with a radiochemical yield of 60 to 70%, a radiochemical purity of >98%, and 1.5 hours of synthesis time. Two hours after [ 18 F]FCB injection in A. fumigatus pneumonia as well as A. fumigatus , bacterial, and sterile inflammation myositis mouse models, retained radioactivity was only seen in foci with live A. fumigatus infection. In vitro testing confirmed production of β-glucosidase enzyme by A. fumigatus and not by bacteria, resulting in hydrolysis of [ 18 F]FCB into glucose and [ 18 F]FDG, the latter being retained by the live fungus. The parent molecule was otherwise promptly excreted through the kidneys, resulting in low background radioactivity and high target-to-nontarget ratios at A. fumigatus infectious sites. We conclude that [ 18 F]FCB is a promising and clinically translatable Aspergillus -specific PET tracer.

Gallium-68-labeled siderophores as radiotracers have gained interest for the development of in situ infection-specific imaging diagnostics. Here, we report radiolabeling, in vitro screening, and in vivo pharmacokinetics (PK) of gallium-68-labeled schizokinen ([ 68 Ga]Ga-SKN) as a new potential radiotracer for imaging bacterial infections. We radiolabeled SKN with ≥95% radiochemical purity. Our in vitro studies demonstrated its hydrophilic characteristics, neutral pH stability, and short-term stability in human serum and toward transchelation. In vitro uptake of [ 68 Ga]Ga-SKN by Escherichia coli , Pseudomonas aeruginosa , Staphylococcus aureus , and S. epidermidis , but no uptake by Candida glabrata , C. albicans , or Aspergillus fumigatus , demonstrated its specificity to bacterial species. Whole-body [ 68 Ga]Ga-SKN positron emission tomography (PET) combined with computerized tomography (CT) in healthy mice showed rapid renal excretion with no or minimal organ uptake. The subsequent ex vivo biodistribution resembled this fast PK with rapid renal excretion with minimal blood retention and no major organ uptake and showed some dissociation of the tracer in the urine after 60 min postinjection. These findings warrant further evaluation of [ 68 Ga]Ga-SKN as a bacteria-specific radiotracer for infection imaging.

The overexpression of HER2 is pivotal in the initiation and progression of breast cancer. Developing HER2-targeted radiotracers is crucial for noninvasive assessment of HER2 expression, patient selection for HER2-targeted therapy, monitoring treatment response, and identifying resistance. Here, we reported a nonsite-specific coupled radiotracer, 68 Ga-NOTA-SNA004-His 6 , and a site-specific coupled radiotracer, 68 Ga-NODAGA-SNA004-GSC, based on a novel HER2 nanobody, SNA004. Both radiotracers exhibited high affinity, specific targeting, and rapid clearance in vitro and in vivo. Additionally, these tracers and trastuzumab showed noncompetitive binding to HER2. Compared to 68 Ga-NOTA-SNA004-His 6 , 68 Ga-NODAGA-SNA004-GSC demonstrated significantly reduced renal and liver uptake. PET/CT imaging with 68 Ga-NODAGA-SNA004-GSC sensitively detected the responsiveness of various tumor models to trastuzumab and its antibody-drug conjugates (ADCs). Overall, the site-specific coupled radiotracer 68 Ga-NODAGA-SNA004-GSC offered significant advantages in biodistribution and signal-to-noise ratio, making it a valuable tool for monitoring HER2 expression levels before, during, and after trastuzumab and ADC treatment.

α-synuclein (α-syn) pathologies are central to the development of synucleinopathies including Parkinson's disease (PD). Positron emission tomography (PET) imaging of α-syn pathologies is one strategy to facilitate the diagnosis, understanding, and treatment of synucleinopathies, but has been restricted by the lack of specific α-syn PET probes. In this work, we identified 2,6-disubstituted imidazo[2,1- b ][1,3,4]thiadiazole (ITA) as a new α-syn-binding scaffold. Through autoradiography studies, we discovered an iodinated lead compound [ 125 I] ITA-3 , with moderate binding affinity (IC 50 = 55 nM) to α-syn pathologies in human PD brain sections. Modified from [ 125 I] ITA-3 , we developed a potential PET tracer, [ 18 F] FITA-2 (radiochemical yield >25%, molar activity >110 GBq/μmol), which demonstrated clear signals in α-syn-rich regions in human PD brain tissues (IC 50 = 245 nM), good brain uptake (SUV peak = 2.80 ± 0.45), and fast clearance rate in rats. Overall, [ 18 F] FITA-2 appears to be a promising candidate for α-syn PET imaging and merits further development.

Prostate-specific membrane antigen (PSMA) is an excellent target for cancer detection and therapy. Hypoxia is prevalent in solid tumors, and various nitroimidazole (NI) radioligands can be trapped inside hypoxic cells for diagnosis and therapy. To enhance tumor uptake and retention, we designed bivalent agents (compounds 1 - 8 ) incorporating a hypoxia-sensitive NI-moiety and a PSMA-targeting group. Ligands 1 - 8 were successfully prepared and labeled with 68 Ga or 177 Lu. Among them, [ 68 Ga]Ga- 8 ([ 68 Ga]Ga-AAZTA-NI-PSMA-093) demonstrated significantly higher cellular accumulation under hypoxic conditions than under normoxic conditions, suggesting hypoxia-selective trapping by the introduction of NI group. PET/CT imaging at 60 min postinjection of [ 68 Ga]Ga- 8 revealed high tumor uptake (SUV max : 10.68%ID/mL) in the tumor-bearing mice model. SPECT/CT imaging of [ 177 Lu]Lu- 8 at 24 and 48 h postinjection demonstrated excellent accumulation and retention. Preliminary studies indicate that [ 68 Ga]Ga/[ 177 Lu]Lu- 8 may be promising bivalent agents targeting hypoxia and PSMA binding for diagnosis and radiotherapy.

Activation of the adenosine 2A receptor (A 2A R) can lead to tumor immunosuppression, which results in poor prognosis of immunotherapy. The aim of this study was to design novel 18 F-labeled probes ([ 18 F]F-PFP 2 and [ 18 F]F-PFP 4 ) to visualize A 2A R in the tumor. The uptake of radioprobes in A 2A R-negative 4T1 breast tumor was lower than that of A 2A R-positive B16F10 melanoma at 1 h p.i. (1.22 ± 0.36% ID/g vs 2.80 ± 0.72% ID/g), 2 h p.i. (1.09 ± 0.20% ID/g vs 2.93 ± 0.76% ID/g) and 3 h p.i. (0.89 ± 0.27% ID/g vs 2.73 ± 0.58% ID/g), respectively. B16F10 lung metastasis models were employed to expand the application scenarios, observing significantly higher uptake of [ 18 F]F-PFP 2 in metastatic lesions compared to normal lung tissue (5.55 ± 2.18% ID/g vs 1.89 ± 0.65% ID/g, tumor/lung ratio ∼3). It is given that [ 18 F]F-PFP 2 might lay the foundation for establishing an A 2A R-targeted imaging evaluation system for tumors, which will provide more precise guidance for personalized treatment.

Despite the development of various novel therapies, glioblastoma (GBM) remains a devastating disease, with a median survival of less than 15 months. Recently, targeted radionuclide therapy has shown significant progress in treating solid tumors, with the approval of Lutathera for neuroendocrine tumors and Pluvicto for prostate cancer by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA). This achievement has shed light on the potential of targeted radionuclide therapy for other solid tumors, including GBM. This review presents the current status of targeted radionuclide therapy in GBM, highlighting the commonly used therapeutic radionuclides emitting alpha, beta particles, and Auger electrons that could induce potent molecular and cellular damage to treat GBM. We then explore a range of targeting vectors, including small molecules, peptides, and antibodies, which selectively target antigen-expressing tumor cells with minimal or no binding to healthy tissues. Considering that radiopharmaceuticals for GBM are often administered locoregionally to bypass the blood-brain barrier (BBB), we review prominent delivery methods such as convection-enhanced delivery, local implantation, and stereotactic injections. Finally, we address the challenges of this therapeutic approach for GBM and propose potential solutions.

The burgeoning field of cancer theranostics has witnessed advancements through the development of targeted molecular agents, particularly peptides. These agents exploit the overexpression or mutations of specific receptors, such as the Epidermal Growth Factor receptor (EGFR) and α V β 3 integrin, which are pivotal in tumor growth, angiogenesis, and metastasis. Despite the extensive research into and promising outcomes associated with antibody-based therapies, peptides offer a compelling alternative due to their smaller size, ease of modification, and rapid bioavailability, factors which potentially enhance tumor penetration and reduce systemic toxicity. However, the application of peptides in clinical settings has challenges. Their lower binding affinity and rapid clearance from the bloodstream compared to antibodies often limit their therapeutic efficacy and diagnostic accuracy. This overview sets the stage for a comprehensive review of the current research landscape as it relates to EGFR- and integrin α V β 3 -targeting peptides. We aim to delve into their synthesis, radiolabeling techniques, and preclinical and clinical evaluations, highlighting their potential and limitations in cancer theranostics. This review not only synthesizes the extant literature to outline the advancements in peptide-based agents targeting EGFR and integrin α V β 3 but also identifies critical gaps that could inform future research directions. By addressing these gaps, we contribute to the broader discourse on enhancing the diagnostic precision and therapeutic outcomes of cancer treatments.

Fatty acid binding protein 3 (FABP3) is expressed both in tumor cells and in the tumor vasculature, making it a potential target for medical imaging and therapy. In this study, we aimed to radiolabel a CooP peptide with a free amino and thiol group, and evaluate the radiolabeled product [ 18 F]FNA- N -CooP for imaging FABP3 expression in breast cancer brain metastases by positron emission tomography. [ 18 F]FNA- N -CooP was prepared by highly chemoselective N -acylation and characterized using different chemical approaches. We validated its binding to the target using in vitro tissue section autoradiography and performed stability tests in vitro and in vivo. [ 18 F]FNA- N -CooP was successfully synthesized in 16.8% decay-corrected radiochemical yield with high radiochemical purity (98.5%). It exhibited heterogeneous binding on brain metastasis tissue sections from a patient with breast cancer, with foci of radioactivity binding corresponding to FABP3 positivity. Furthermore, the tracer binding was reduced by 55% in the presence of nonradioactive FNA- N -CooP a blocker, indicating specific tracer binding and that FABP3 is a viable target for [ 18 F]FNA- N -CooP. Favorably, the tracer did not bind to necrotic tumor tissue. However, [ 18 F]FNA- N -CooP displayed limited stability both in vitro in mouse plasma or human serum and in vivo in mouse, therefore further studies are needed to improve the stability [ 18 F]FNA- N -CooP to be used for in vivo applications.

Thyroid cancer is the most common endocrine cancer, with differentiated thyroid cancers (DTCs) accounting for 95% of diagnoses. While most DTC patients are diagnosed and treated with radioiodine (RAI), up to 20% of DTC patients become RAI refractory (RAI-R). RAI-R patients have significantly reduced survival rates compared to patients who remain RAI-avid. This study explores [ 89 Zr]Zr-TR1402 as a thyroid-stimulating hormone receptor (TSHR)-targeted PET radiopharmaceutical for DTC. [ 89 Zr]Zr-TR1402 was synthesized with a molar activity of 25.9 MBq/nmol by conjugating recombinant human TSH (rhTSH) analogue TR1402 to chelator p-SCN-Bn-deferoxamine (DFO) in a molar ratio of 3:1 (DFO/TR1402) and radiolabeling with 89 Zr ( t 1/2 = 78.4 h, β + = 22.7%). As TSHR is absent in commonly available DTC-derived cell lines, TSHR was reintroduced via stable transduction by delivering a lentivirus containing the full-length coding region of the human TSHR gene. Receptor-mediated uptake of [ 89 Zr]Zr-TR1402 was evaluated in vitro in stably transduced TSHR+ and wild-type TSHR- DTC cell lines. In vivo PET imaging was performed on Days 1-3 postinjection in male and female athymic nude mice bearing TSHR+ and TSHR- xenografts, along with ex vivo biodistribution on Day 3 postinjection. In vitro uptake of 1 nM [ 89 Zr]Zr-TR1402 was significantly higher in TSHR+ THJ529T ( P < 0.0001) and FTC133 ( P < 0.01) cells than in TSHR- THJ529T and FTC133 cells. This uptake was shown to be specific in both TSHR+ THJ529T ( P < 0.0001) and TSHR+ FTC133 ( P < 0.0001) cells by blocking uptake with 250 nm DFO-TR1402. In vivo PET imaging showed accumulation of [ 89 Zr]Zr-TR1402 in TSHR+ tumors, which was the highest on Day 1. In the male FTC133 xenograft model, ex vivo biodistribution confirmed a significant difference ( P < 0.001) in uptake between FTC133+ (1.3 ± 0.1%ID/g) and FTC133- (0.8 ± 0.1%ID/g) tumors. A significant difference ( P < 0.05) in uptake was also seen in the male THJ529T xenograft model between THJ529T+ (1.8 ± 0.6%ID/g) and THJ529T- (0.8 ± 0.4%ID/g) tumors. The in vitro and in vivo accumulation of [ 89 Zr]Zr-TR1402 in TSHR-expressing DTC cell lines support the continued preclinical optimization of this approach.

The purpose of this study was to examine how the introduction of ibuprofen (IBU) affected tumor-targeting and biodistribution properties of 177 Lu-labeled IBU-conjugated alpha-melanocyte-stimulating hormone peptides. The IBU was used as an albumin binder and conjugated to the DOTA-Lys moiety without or with a linker to yield DOTA-Lys(IBU)-GG-Nle-CycMSH hex {1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-Lys(IBU)-Gly-Gly-Nle-c[Asp-His-DPhe-Arg-Trp-Lys]-CONH 2 }, DOTA-Lys(Asp-IBU)-GGNle-CycMSH hex , DOTA-Lys(Asn-IBU)-GGNle-CycMSH hex , and DOTA-Lys(Dab-IBU)-GGNle-CycMSH hex peptides. Their melanocortin-receptor 1 (MC1R) binding affinities were determined on B16/F10 melanoma cells first. Then the biodistribution of 177 Lu-labeled peptides was determined on B16/F10 melanoma-bearing C57 mice at 2 h postinjection to choose the lead peptide for further examination. The full biodistribution and melanoma imaging properties of 177 Lu-DOTA-Lys(Asp-IBU)-GGNle-CycMSH hex were further evaluated using B16/F10 melanoma-bearing C57 mice. DOTA-Lys(IBU)-GG-Nle-CycMSH hex , DOTA-Lys(Asp-IBU)-GGNle-CycMSH hex , DOTA-Lys(Asn-IBU)-GGNle-CycMSH hex , and DOTA-Lys(Dab-IBU)-GGNle-CycMSH hex displayed the IC 50 values of 1.41 ± 0.37, 1.52 ± 0.08, 0.03 ± 0.01, and 0.58 ± 0.06 nM on B16/F10 melanoma cells, respectively. 177 Lu-DOTA-Lys(Asp-IBU)-GGNle-CycMSH hex exhibited the lowest liver and kidney uptake among all four designed 177 Lu peptides. Therefore, 177 Lu-DOTA-Lys(Asp-IBU)-GGNle-CycMSH hex was further evaluated for its full biodistribution and melanoma imaging properties. The B16/F10 melanoma uptake of 177 Lu-DOTA-Lys(Asp-IBU)-GGNle-CycMSH hex was 19.5 ± 3.12, 24.12 ± 3.35, 23.85 ± 2.08, and 10.80 ± 2.89% ID/g at 0.5, 2, 4, and 24 h postinjection, respectively. Moreover, 177 Lu-DOTA-Lys(Asp-IBU)-GGNle-CycMSH hex could clearly visualize the B16/F10 melanoma lesions at 2 h postinjection. The conjugation of IBU with or without a linker to GGNle-CycMSH hex affected the MC1R binding affinities of the designed peptides. The charge of the linker played a key role in the liver and kidney uptake of 177 Lu-Asp-IBU, 177 Lu-Asn-IBU, and 177 Lu-Dab-IBU. 177 Lu-Asp-IBU exhibited higher tumor/liver and tumor/kidney uptake ratios than those of 177 Lu-Asn-IBU and 177 Lu-Dab-IBU, underscoring its potential evaluation for melanoma therapy in the future.

Claudin18.2 ( CLDN18.2), due to its high expression in various gastric cancer tissues, is considered an optimal target for antitumor drug molecules. In this study, we obtained the labeled compounds of [ 125 I]I-zolbetuximab using the Iodogen method. Under the optimum labeling conditions, the molar activity of [ 125 I]I-zolbetuximab was 1.75 × 10 2 GBq/μmol, and the labeling efficiency was more than 99%. The labeled compounds exhibited excellent in vitro stability in both phosphate buffer saline (PBS, pH = 7.4) and fetal bovine serum systems (FBS) (radiochemical purity >90% at 72 h). The uptake percentage of [ 125 I]I-zolbetuximab in MKN45-CLDN18.2 cells is 24.69 ± 0.84% after 6 h. The saturation binding assay and specificity assay further demonstrated the high specificity of [ 125 I]I-zolbetuximab for CLDN18.2. The long retention at the tumor site and rapid metabolic clearance at other organ sites of [ 125 I]I-zolbetuximab were observed in small-animal SPECT-CT imaging. The same trend was also observed in the biodistribution study. Due to the excellent targeting ability of zolbetuximab for CLDN18.2, [ 125 I]I-zolbetuximab exhibits strong specific binding and retention with cells and tumors highly expressing CLDN18.2. However, the balance between mAb's longer cycle time in vivo and targeting binding and retention ability should be intensively considered for using this kind of radiopharmaceutical in the diagnosis and treatment of CLDN18.2-positive gastric cancer.

Prostate cancer (PCa) is one of the most common tumors in men, with the overexpression of prostate-specific membrane. In this study, we developed four new 68 Ga-labeled PSMA-targeting tracers by introducing quinoline, phenylalanine and decanoic acid groups to enhance their lipophilicity, strategically limiting their metabolic pathway through the urinary system. Four radiotracers were synthesized with radiochemical purity >95 %, and exhibited high stability in vivo and in vitro. The inhibition constants (K i ) of SDTWS01-04 to PSMA were in the nanomolar range (<10 nM). Micro PET/CT imaging and biodistribution analysis revealed that 68 Ga-SDTWS01 enabled clear tumor visualization in PET images at 1.5 h post-injection, with excellent pharmacokinetic properties. Notably, the kidney uptake of 68 Ga-SDTWS01 significantly reduced, with higher tumor-to-kidney ratio (0.36 ± 0.02), tumor-to-muscle ratio (24.31 ± 2.10), compared with 68 Ga-PSMA-11 (T/K: 0.15 ± 0.01; T/M: 14.97 ± 1.40), suggesting that 68 Ga-SDTWS01 is a promising radiotracer for the diagnosis of PCa. Moreover, SDTWS01 with a chelator DOTA could also label 177 Lu and 225 Ac, which could be used for the treatment of PCa., Competing Interests: Declaration of competing interest There is no conflict of interests regarding our manuscript entitled “Synthesis and preclinical evaluation of (68)Ga-labeled PSMA tracers with improved pharmacological properties”., (Copyright © 2024 Elsevier Masson SAS. All rights reserved.)

Radioimmunoconjugates (RICs) composed of tumor-targeting monoclonal antibodies and radionuclides have been developed for diagnostic and therapeutic application. A new radiolabeling method using microfluidic devices is expected to facilitate simpler and more rapid synthesis of RICs. In the microfluidic method, microfluidic chips can promote the reaction between reactants by mixing them efficiently, and pumping systems enable automated synthesis. In this study, we synthesized RICs by the pre-labeling method, in which the radiometal is coordinated to the chelator and then the radiolabeled chelator is incorporated into the antibodies, using microfluidic devices for the first time. As a result of examining the reaction parameters including the material of mixing units, reaction temperature, and flow rate, RICs with radiochemical purity (RCP) exceeding 90% were obtained. These high-purity RICs were successfully synthesized without any purification simply by pumping three solutions of a chelating agent, radiometal, and antibody into microfluidic devices. Under the same conditions, the RCP of RICs labeled by conventional methods was below 50%. These findings indicate the utility of microfluidic devices for automatic and rapid synthesis of high-quality RICs., (© 2024 John Wiley & Sons Ltd.)

Recently, the folate receptor (FR) has become an exciting target for the diagnosis of FR-positive malignancies. Nevertheless, suboptimal in vivo pharmacokinetic properties, particularly high uptake in the renal and hepatobiliary systems, are important limiting factors for the clinical translation of most FR-based radiotracers. In this study, we developed a novel 18 F-labeled FR-targeted positron emission tomography (PET) tracer [ 18 F]AlF-NOTA-Asp 2 -PEG 2 -Folate modified with a hydrophilic linker (-Asp 2 -PEG 2 ) to optimize its pharmacokinetic properties and conducted a comprehensive preclinical assessment. The [ 18 F]AlF-NOTA-Asp 2 -PEG 2 -Folate was manually synthesized within 30 min with a non-decay-corrected radiochemical yield of 16.3 ± 2.0% (n = 5). Among KB cells, [ 18 F]AlF-NOTA-Asp 2 -PEG 2 -Folate exhibited high specificity and affinity for FR. PET/CT imaging and biodistribution experiments in KB tumor-bearing mice showed decent tumor uptake (1.7 ± 0.3% ID/g) and significantly decreased uptake in kidneys and liver (22.2 ± 2.1 and 0.3 ± 0.1% ID/g at 60 min p.i., respectively) of [ 18 F]AlF-NOTA-Asp 2 -PEG 2 -Folate, compared to the known tracer [ 18 F]AlF-NOTA-Folate (78.6 ± 5.1 and 5.3 ± 0.5 % ID/g at 90 min p.i., respectively). The favorable properties of [ 18 F]AlF-NOTA-Asp 2 -PEG 2 -Folate, including its efficient synthesis, decent tumor uptake, relatively low renal uptake, and rapid clearance from most normal organs, portray it as a promising PET tracer for FR-positive tumors., (© 2024 John Wiley & Sons Ltd.)

Molecular imaging using positron emission tomography (PET) can serve as a promising tool for visualizing biological targets in the brain. Insights into the expression pattern and the in vivo imaging of the G protein-coupled orexin receptors OX1R and OX2R will further our understanding of the orexin system and its role in various physiological and pathophysiological processes. Guided by crystal structures of our lead compound JH112 and the approved hypnotic drug suvorexant bound to OX1R and OX2R, respectively, we herein describe the design and synthesis of two novel radioligands, [ 18 F]KD23 and [ 18 F]KD10. Key to the success of our structural modifications was a bioisosteric replacement of the triazole moiety with a fluorophenyl group. The 19 F-substituted analog KD23 showed high affinity for the OX1R and selectivity over OX2R, while the high affinity ligand KD10 displayed similar K i values for both subtypes. Radiolabeling starting from the respective pinacol ester precursors resulted in excellent radiochemical yields of 93% and 88% for [ 18 F]KD23 and [ 18 F]KD10, respectively, within 20 min. The new compounds will be useful in PET studies aimed at subtype-selective imaging of orexin receptors in brain tissue., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: There is currently no ideal radiotracer for imaging bacterial infections. Radiolabelled D-amino acids are promising candidates because they are actively incorporated into the peptidoglycan of the bacterial cell wall, a structural feature which is absent in human cells. This work describes fluorine-18 labelled analogues of D-tyrosine and D-methionine, O-(2-[ 18 F]fluoroethyl)-D-tyrosine (D-[ 18 F]FET) and S-(3-[ 18 F]fluoropropyl)-D-homocysteine (D-[ 18 F]FPHCys), and their pilot evaluation studies as potential radiotracers for imaging bacterial infection., Procedures: D-[ 18 F]FET and D-[ 18 F]FPHCys were prepared in classical fluorination-deprotection reactions, and their uptake in Staphylococcus aureus and Pseudomonas aeruginosa was evaluated over 2 h. Heat killed bacteria were used as controls. A clinically-relevant foreign body model of S. aureus infection was established in Balb/c mice, as well as a sterile foreign body to mimic inflammation. The ex vivo biodistribution of D-[ 18 F]FPHCys in the infected and inflamed mice was evaluated after 1 h, by dissection and gamma counting. The uptake was compared to that of [ 18 F]FDG., Results: In vitro uptake of both D-[ 18 F]FET and D-[ 18 F]FPHCys was specific to live bacteria. Uptake was higher in S. aureus than in P. aeruginosa for both radiotracers, and of the two, higher for D-[ 18 F]FPHCys than D-[ 18 F]FET. Blocking experiments with non-radioactive D-[ 19 F]FPHCys confirmed specificity of uptake. In vivo, D-[ 18 F]FPHCys had greater accumulation in S. aureus infection compared with sterile inflammation, which was statistically significant. As anticipated, [ 18 F]FDG showed no significant difference in uptake between infection and inflammation., Conclusions: D-[ 18 F]FPHCys uptake was higher in infected tissues than inflammation, and represents a fluorine-18 labelled D-AA with potential to detect a S. aureus reference strain (Xen29) in vivo. Additional studies are needed to evaluate uptake of this radiotracer in clinical isolates., (© 2024. The Author(s).)

Background: The recent emergence of targeted radionuclide therapy has increased the demand for imagers capable of visualizing pharmacokinetics in developing radiopharmaceuticals in the preclinical phase. Some radionuclides emit hard x-rays and gamma-rays below 100 keV, in which energy range the performance of conventional NaI scintillators is poor. Multipinhole collimators are also used for small animal imaging with a good spatial resolution but have a limited field of view (FOV)., Purpose: In this study, a new imager with high sensitivity over a wide FOV in the low-energy band ( < $&lt;$ 100 keV) was developed for the pharmacokinetic study., Methods: We developed an x-ray and gamma-ray camera for high-resolution spectroscopy, named "CdTe XG-Cam," equipped with a cadmium telluride semiconductor detector and a parallel-hole collimator using a metal 3D printer. To evaluate the camera-system performance, phantom measurements with single and dual nuclides ( 99 m Tc $^{\rm 99m}{\rm Tc}$ , 111 In $^{111}{\rm In}$ , and 125 I ) $^{125}{\rm I)}$ were performed. The performance for in vivo imaging was evaluated using tumor-bearing mice to which a nuclide ( 99 m Tc $^{\rm 99m}{\rm Tc}$ or 125 I ) $^{125}{\rm I)}$  administered., Results: We simultaneously obtained information on 111 In $^{111}{\rm In}$ and 125 I $^{125}{\rm I}$ , which emit emission lines in the low-energy band with peak energies close to each other (23-26 keV for 111 In $^{111}{\rm In}$ and 27-31 keV for 125 I ) $^{125}{\rm I)}$ , and applied an analytical method based on spectral model fitting to determine the individual radioactivities accurately. In the small animal imaging, the distributions of the nuclide in tumors were accurately quantified and time-activity curves in tumors are obtained., Conclusions: The demonstrated capability of our system to perform in vivo imaging suggests that the camera can be used for applications of pharmacokinetics research., (© 2024 American Association of Physicists in Medicine.)

Imaging agents for positron emission tomography (PET) and single-photon emission computerized tomography (SPECT) have shown their utility in many situations, answering clinical questions related to drug development and medical considerations. The discovery and development of imaging agents follow a well-understood process, with variations related to available starting points and to the envisaged imaging application. This article describes the general development path leading from the expression of an imaging need and project initiation to a clinically usable imaging agent. The definition of the project rationale, the design and optimization of early leads, and the assessment of the imaging potential of an imaging agent candidate are followed by preclinical and clinical development activities that differ from those required for therapeutic agents. These include radiolabeling with a positron emitter and first-in-human clinical studies, to rapidly evaluate the ability of a new imaging agent to address the questions it was designed to answer., (© 2024 Wiley-VCH GmbH.)

Monoclonal antibodies and antibody fragments have proven to be highly effective vectors for the delivery of radionuclides to target tissues for positron emission tomography (PET) and single-photon emission computed tomography (SPECT). However, the stochastic methods that have traditionally been used to attach radioisotopes to these biomolecules inevitably produce poorly defined and heterogeneous probes and can impair the ability of the immunoglobulins to bind their molecular targets. In response to this challenge, an array of innovative site-specific and site-selective bioconjugation strategies have been developed, and these approaches have repeatedly been shown to yield better-defined and more homogeneous radioimmunoconjugates with superior in vivo performance than their randomly modified progenitors. In this Current Opinion in Chemical Biology review, we will examine recent advances in this field, including the development - and, in some cases, clinical translation - of nuclear imaging agents radiolabeled using strategies that target the heavy chain glycans, peptide tags, and unnatural amino acids., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Brian Zeglis has patent #US11000604B2 issued to None. Brian Zeglis has patent #CA3230848A1 pending to Zentera Therapeutics. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The development of theranostic radiotracers relies on their binding to specific molecular markers of a particular disease and the use of corresponding radiopharmaceutical pairs thereafter. This study reports the use of multiamine macrocyclic moieties (MAs), as linkers or chelators, in tracers targeting the neurotensin receptor-1 (NTSR-1). The goal is to achieve elevated tumor uptake, minimal background interference, and prolonged tumor retention in NTSR-1-positive tumors. Methods: We synthesized a series of neurotensin antagonists bearing MA linkers and metal chelators. The MA unit is hypothesized to establish a strong interaction with the cell membrane, and the addition of a second chelator may enhance water solubility, consequently reducing liver uptake. Small-animal PET/CT imaging of [ 64 Cu]Cu-DOTA-SR-3MA, [ 64 Cu]Cu-NT-CB-NOTA, [ 68 Ga]Ga-NT-CB-NOTA, [ 64 Cu]Cu-NT-CB-DOTA, and [ 64 Cu]Cu-NT-Sarcage was acquired at 1, 4, 24, and 48 h after injection using H1299 tumor models. [ 55 Co]Co-NT-CB-NOTA was also tested in HT29 (high NTSR-1 expression) and Caco2 (low NTSR-1 expression) colorectal adenocarcinoma tumor models. Saturation binding assay and internalization of [ 55 Co]Co-NT-CB-NOTA were used to test tracer specificity and internalization in HT29 cells. Results: In vivo PET imaging with [ 64 Cu]Cu-NT-CB-NOTA, [ 68 Ga]Ga-NT-CB-NOTA, and [ 55 Co]Co-NT-CB-NOTA revealed high tumor uptake, high tumor-to-background contrast, and sustained tumor retention (≤48 h after injection) in NTSR-1-positive tumors. Tumor uptake of [ 64 Cu]Cu-NT-CB-NOTA remained at 76.9% at 48 h after injection compared with uptake 1 h after injection in H1299 tumor models, and [ 55 Co]Co-NT-CB-NOTA was retained at 60.2% at 24 h compared with uptake 1 h after injection in HT29 tumor models. [ 64 Cu]Cu-NT-Sarcage also showed high tumor uptake with low background and high tumor retention 48 h after injection Conclusion: Tumor uptake and pharmacokinetic properties of NTSR-1-targeting radiopharmaceuticals were greatly improved when attached with different nitrogen-containing macrocyclic moieties. The study results suggest that NT-CB-NOTA labeled with either 64 Cu/ 67 Cu, 55 Co/ 58m Co, or 68 Ga (effect of 177 Lu in tumor to be determined in future studies) and NT-Sarcage labeled with 64 Cu/ 67 Cu or 55 Co/ 58m Co may be excellent diagnostic and therapeutic radiopharmaceuticals targeting NTSR-1-positive cancers. Also, the introduction of MA units to other ligands is warranted in future studies to test the generality of this approach., (© 2024 by the Society of Nuclear Medicine and Molecular Imaging.)

To investigate the feasibility of detection of apoptosis in vivo by 99mTc-HYNIC-Annexin V, Annexin V was labeled with 99mTc through HYNIC. 18 New Zealand rabbits implanted VX-2 were randomly divided into control (n = 8) and paclitaxel (PAC, n = 10) groups, given 2 mL/kg of normal saline or 2.4 mg/kg of PAC intravenously. The liver tumor imaging was detected by SPECT through intravenous injection of 99mTc-HYNIC-Annexin V before treatment, 24 hours and 48 hours after treatment respectively. Tumor radioactive count proportion to non-tumor sites was calculated. When the last imaging was finished, the rabbits were sacrificed. The tumor was taken out and divided into two pieces, one for TUNEL immunohistochemical analysis and the other for flow cytometry (FCM). We found that the rate of Annexin V labeled with 99mTc through HYNIC was more than 95%, and radiochemical purity was above 95%. The SPECT showed that two groups had no significant tumor imaging before the treatment. There is no significant tumor imaging in control group, while the PAC group 24 h and 48 h after treatment showed significant accumulation. The Tumor/non-Tumor (T/NT) in PAC group at 24 h and 48 h after chemotherapy was significantly different from that in the control group and PAC group prior to treatment. There was no significant difference between 24 h and 48 h in PAC group. The TUNEL-positive cells detected by immunohistochemistry and apoptotic rate detected by FCM in PAC group were significant different from those in control group. The T/NT was significantly correlated to TUNEL-positive cells and apoptotic rate of the tumor. PAC can induce apoptosis of rabbit VX-2 liver cancer cells. 24-48 h after paclitaxel chemotherapy is a window time for apoptosis detection. Apoptotic cells in vivo can be detected by SPECT through 99mTc-HYNIC-Annexin V.

Fibroblast activation protein (FAP) has attracted considerable attention as a possible target for the radiotherapy of solid tumors. Unfortunately, initial efforts to treat solid tumors with FAP-targeted radionuclides have yielded only modest clinical responses, suggesting that further improvements in the molecular design of FAP-targeted radiopharmaceutical therapies (RPT) are warranted. In this study, we report several advances on the previously described FAP6 radioligand that increase tumor retention and accelerate healthy tissue clearance. Seven FAP6 derivatives with different linkers or albumin binders were synthesized, radiolabeled, and investigated for their effects on binding and cellular uptake. The radioligands were then characterized in 4T1 tumor-bearing Balb/c mice using both single-photon emission computed tomography (SPECT) and ex vivo biodistribution analyses to identify the conjugate with the best tumor retention and tumor-to-healthy organ ratios. The results reveal an optimized FAP6 radioligand that exhibits efficacy and safety properties that potentially justify its translation into the clinic.

A folic acid-targeted polyurea (PURE) dendrimer was easily radiolabelled with Technetium-99m ( 99m Tc-PURE G4 -FA 2 ) avoiding the use of additional ligands and bioconjugation chemistry. This straightforward strategy is enabled in PURE dendrimers due to their favourable surface terminal groups configuration, showing coordination capabilities and turning these biodendrimers into attractive platforms for nanoradiotheranostics.

Granzyme B is an immune-related biomarker that closely correlates with cytotoxic T lymphocytes (CTLs), and hence detecting the expression level of granzyme B can provide a dependable scheme for clinical immune response assessment. In this study, two positron emission tomography (PET) probes [ 18 F]SF-M-14 and [ 18 F]SF-H-14 targeting granzyme B are designed based on the intramolecular cyclization scaffold SF. [ 18 F]SF-M-14 and [ 18 F]SF-H-14 can respond to granzyme B and glutathione (GSH) to conduct intramolecular cyclization and self-assemble into nanoaggregates to enhance the retention of probe at the target site. Both probes are prepared with high radiochemical purity (>98%) and high stability in PBS and mouse serum. In 4T1 cells cocultured with T lymphocytes, [ 18 F]SF-M-14 and [ 18 F]SF-H-14 reach the maximum uptake of 6.71 ± 0.29 and 3.47 ± 0.09% ID/mg at 0.5 h, respectively, but they remain below 1.95 ± 0.22 and 1.47 ± 0.21% ID/mg in 4T1 cells without coculture of T lymphocytes. In vivo PET imaging shows that the tumor uptake in 4T1-tumor-bearing mice after immunotherapy is significantly higher (3.5 times) than that in the untreated group. The maximum tumor uptake of [ 18 F]SF-M-14 and [ 18 F]SF-H-14 in the mice treated with BEC was 4.08 ± 0.16 and 3.43 ± 0.12% ID/g, respectively, while that in the untreated mice was 1.04 ± 0.79 and 1.41 ± 0.11% ID/g, respectively. These results indicate that both probes have great potential in the early evaluation of clinical immunotherapy efficacy.

Aims: PET myocardial perfusion imaging (MPI) is the gold standard for the noninvasive diagnosis of ischemic myocardial. Construction of 18 F-labeled PET MPI probe showed benefits to reduce the imaging cost, and enhance the image quality and patient-friendliness., Methods: Two 18 F-labeled MPI probes ( 18 F-BoMPI) were developed. Detailed in vitro/vivo evaluation including photophysical properties, in vitro stability, myocardial cell uptake kinetics and mechanisms, cytotoxicity and IC50, biodistribution and plasma clearance curve were investigated. Resting and stressing myocardial perfusion PET imaging were performed in healthy and myocardial ischemic mice., Results: 18 F-BoMPI could be quickly labeled and easily postprocessed, and demonstrated excellent in vitro stability. Cell assays indicated that 18 F-BoMPI exhibited mitochondria-targeting but potential-independent myocardial uptake. In vivo evaluation revealed the effective myocardial uptake and rapid background clearance. PET MPI confirmed effective probe accumulation in the healthy heart, but rapidly clearance in the background, making heart clearly delineated in the images. Ischemic myocardial could be clearly distinguished as the region of radioactivity sparsity in PET MPI., Conclusion: The 18 F-labeled probes showed great potentials to reduce the practicability threshold of PET MPI.

Bruton's tyrosine kinase (BTK) is pivotal in B-cell signaling and a target for potential anti-cancer and immunological disorder therapies. Improved selective reversible BTK inhibitors are in demand due to the absence of direct BTK engagement measurement tools. Promisingly, PET imaging can non-invasively evaluate BTK expression. In this study, radiolabeled BIO-2008846 ([ 11 C]BIO-2008846-A), a BTK inhibitor, was used for PET imaging in NHPs to track brain biodistribution. Radiolabeling BIO-2008846 with carbon-11, alongside four PET scans on two NHPs each, showed a homogeneous distribution of [ 11 C]BIO-2008846-A in NHP brains. Brain uptake ranged from 1.8% ID at baseline to a maximum of 3.2% post-pretreatment. The study found no significant decrease in regional VT values post-dose, implying minimal specific binding of [ 11 C]BIO-2008846-A compared to free and non-specific components in the brain. Radiometabolite analysis revealed polar metabolites with 10% unchanged radioligand after 30 min. The research highlighted strong brain uptake despite minor distribution variability, confirming passive diffusion kinetics dominated by free and non-specific binding.

[ 123 I]β-methyl-p-iodophenyl-pentadecanoic acid ([ 123 I]BMIPP), which is used for nuclear medicine imaging of myocardial fatty acid metabolism, accumulates in cancer cells. However, the mechanism of accumulation remains unknown. Therefore, this study aimed to elucidate the accumulation and accumulation mechanism of [ 123 I]BMIPP in cancer cells. We compared the accumulation of [ 123 I]BMIPP in cancer cells with that of [ 18 F]FDG and found that [ 123 I]BMIPP was a much higher accumulation than [ 18 F]FDG. The accumulation of [ 123 I]BMIPP was evaluated in the presence of sulfosuccinimidyl oleate (SSO), a CD36 inhibitor, and lipofermata, a fatty acid transport protein (FATP) inhibitor, under low-temperature conditions and in the presence of etomoxir, a carnitine palmitoyl transferase I (CPT1) inhibitor. The results showed that [ 123 I]BMIPP accumulation was decreased in the presence of SSO and lipofermata in H441, LS180, and DLD-1 cells, suggesting that FATPs and CD36 are involved in [ 123 I]BMIPP uptake in cancer cells. [ 123 I]BMIPP accumulation in all cancer cell lines was significantly decreased at 4 °C compared to that at 37 °C and increased in the presence of etomoxir in all cancer cell lines, suggesting that the accumulation of [ 123 I]BMIPP in cancer cells is metabolically dependent. In a biological distribution study conducted using tumor-bearing mice transplanted with LS180 cells, [ 123 I]BMIPP highly accumulated in not only LS180 cells but also normal tissues and organs (including blood and muscle). The tumor-to-intestine or large intestine ratios of [ 123 I]BMIPP were similar to those of [ 18 F]FDG, and the tumor-to-large-intestine ratios exceeded 1.0 during 30 min after [ 123 I]BMIPP administration in the in vivo study. [ 123 I]BMIPP is taken up by cancer cells via CD36 and FATP and incorporated into mitochondria via CPT1. Therefore, [ 123 I]BMIPP may be useful for imaging cancers with activated fatty acid metabolism, such as colon cancer. However, the development of novel imaging radiotracers based on the chemical structure analog of [ 123 I]BMIPP is needed.

Targeted alpha therapy (TAT) pairs the specificity of antigen targeting with the lethality of alpha particles to eradicate cancerous cells. Actinium-225 [ 225 Ac; t 1/2  = 9.920(3) days] is an alpha-emitting radioisotope driving the next generation of TAT radiopharmaceuticals. Despite promising clinical results, a fundamental understanding of Ac coordination chemistry lags behind the rest of the Periodic Table due to its limited availability, lack of stable isotopes, and inadequate systems poised to probe the chemical behavior of this radionuclide. In this work, we demonstrate a platform that combines an 8-coordinate synthetic ligand and a mammalian protein to characterize the solution and solid-state behavior of the longest-lived Ac isotope, 227 Ac [t 1/2  = 21.772(3) years]. We expect these results to direct renewed efforts for 225 Ac-TAT development, aid in understanding Ac coordination behavior relative to other +3 lanthanides and actinides, and more broadly inform this element's position on the Periodic Table., (© 2024. The Author(s).)

Radiolabeling of bionanomaterials with technetium-99m ( 99m Tc) has become a promising approach in combining the benefits of nanotechnology and nuclear medicine for diagnostic and therapeutic purposes. This review is intended to provide a comprehensive overview of the state-of-the-art of radiolabeling of bionanomaterials with 99m Tc, highlighting the synthesis methods, labeling mechanisms, biological evaluation, physicochemical characterization and clinical applications of 99m Tc-labeled bionanomaterials. Various types of nanomaterials are considered in the review, including lipid- and protein-based nanosystems, dendrimers and polymeric nanomaterials. Moreover, the review assesses the challenges presented by this emerging field, such as stability of the radiolabel, potential toxicity of the nanomaterials and regulatory aspects. Finally, promising future perspectives and areas of research development in 99m Tc-labeled bionanomaterials are discussed.