Can current preclinical strategies for radiopharmaceutical development meet the needs of targeted alpha therapy?

Preclinical studies are essential for effectively evaluating TAT radiopharmaceuticals. Given the current suboptimal supply chain of these radionuclides, animal studies must be refined to produce the most translatable TAT agents with the greatest clinical potential. Vector design is pivotal, emphasizing harmonious physical and biological characteristics among the vector, target, and radionuclide. The scarcity of alpha-emitting radionuclides remains a significant consideration. Actinium-225 and lead-212 appear as the most readily available radionuclides at this stage. Available animal models for researchers encompass xenografts, allografts, and PDX (patient-derived xenograft) models. Emerging strategies for imaging alpha-emitters are also briefly explored. Ultimately, preclinical research must address two critical aspects: (1) offering valuable insights into balancing safety and efficacy, and (2) providing guidance on the optimal dosing of the TAT agent.

Tachykinin Receptor-Selectivity of the Potential Glioblastoma-Targeted Therapy, DOTA-[Thi8,Met(O2)11]-Substance P.

Radiopharmaceutical development hinges on the affinity and selectivity of the biological component for the intended target. An analogue of the neuropeptide Substance P (SP), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid-[Thi8,Met(O2)11]-SP (DOTA-[Thi8,Met(O2)11]SP), in the theranostic pair [68Ga]Ga-/ [213Bi]Bi-DOTA-[Thi8,Met(O2)11]SP has shown promising clinical results in the treatment of inoperable glioblastoma. As the theranostic targeting component, modifications to SP that affect the selectivity of the resulting analogue for the intended target (neurokinin-1 receptor [NK1R]) could be detrimental to its therapeutic potential. In addition to other closely related tachykinin receptors (neurokinin-2 receptor [NK2R] and neurokinin-3 receptor [NK3R]), SP can activate a mast cell expressed receptor Mas-related G protein-coupled receptor subtype 2 (MRGPRX2), which has been implicated in allergic-type reactions. Therefore, activation of these receptors by SP analogues has severe implications for their therapeutic potential. Here, the receptor selectivity of DOTA-[Thi8,Met(O2)11]SP was examined using inositol phosphate accumulation assay in HEK293-T cells expressing NK1R, NK2R, NK3R or MRGPRX2. DOTA-[Thi8,Met(O2)11]SP had similar efficacy and potency as native SP at NK1R, but displayed greater NK1R selectivity. DOTA-[Thi8,Met(O2)11]SP was unable to elicit significant activation of the other tachykinin receptors nor MRGPRX2 at high concentrations nor did it display antagonistic behaviour at these receptors. DOTA-[Thi8,Met(O2)11]SP, therefore has high potency and selectivity for NK1R, supporting its potential for targeted theranostic use in glioblastoma multiforme and other conditions characterised by NK1R overexpression.

Antibiotic-Derived Radiotracers for Positron Emission Tomography: Nuclear or "Unclear" Infection Imaging?

The excellent features of non-invasive molecular imaging, its progressive technology (real-time, whole-body imaging and quantification), and global impact by a growing infrastructure for positron emission tomography (PET) scanners are encouraging prospects to investigate new concepts, which could transform clinical care of complex infectious diseases. Researchers are aiming towards the extension beyond the routinely available radiopharmaceuticals and are looking for more effective tools that interact directly with causative pathogens. We reviewed and critically evaluated (challenges or pitfalls) antibiotic-derived PET radiopharmaceutical development efforts aimed at infection imaging. We considered both radiotracer development for infection imaging and radio-antibiotic PET imaging supplementing other tools for pharmacologic drug characterization; overall, a total of 20 original PET radiotracers derived from eleven approved antibiotics.

Non-oncological applications of RGD-based single-photon emission tomography and positron emission tomography agents.

INTRODUCTION: Non-invasive imaging techniques (especially single-photon emission tomography and positron emission tomography) apply several RGD-based imaging ligands developed during a vast number of preclinical and clinical investigations. The RGD (Arg-Gly-Asp) sequence is a binding moiety for a large selection of adhesive extracellular matrix and cell surface proteins. Since the first identification of this sequence as the shortest sequence required for recognition in fibronectin during the 1980s, fundamental research regarding the molecular mechanisms of integrin action have paved the way for development of several pharmaceuticals and radiopharmaceuticals with clinical applications. Ligands recognizing RGD may be developed for use in the monitoring of these interactions (benign or pathological). Although RGD-based molecular imaging has been actively investigated for oncological purposes, their utilization towards non-oncology applications remains relatively under-exploited. METHODS AND SCOPE: This review highlights the new non-oncologic applications of RGD-based tracers (with the focus on single-photon emission tomography and positron emission tomography). The focus is on the last 10 years of scientific literature (2009-2020). It is proposed that these imaging agents will be used for off-label indications that may provide options for disease monitoring where there are no approved tracers available, for instance Crohn's disease or osteoporosis. Fundamental science investigations have made progress in elucidating the involvement of integrin in various diseases not pertaining to oncology. Furthermore, RGD-based radiopharmaceuticals have been evaluated extensively for safety during clinical evaluations of various natures. CONCLUSION: Clinical translation of non-oncological applications for RGD-based radiopharmaceuticals and other imaging tracers without going through time-consuming extensive development is therefore highly plausible. Graphical abstract.

A prospective intra-individual comparison of [68Ga]Ga-PSMA-11 PET/CT, [68Ga]Ga-NODAGAZOL PET/CT, and [99mTc]Tc-MDP bone scintigraphy for radionuclide imaging of prostate cancer skeletal metastases.

PURPOSE: Prostate cancer (PCa) commonly metastasizes to the bones. There are several radionuclide techniques for imaging PCa skeletal metastases. We aimed to compare the lesion detection rate of [68Ga]Ga-PSMA-11 PET/CT, [68Ga]Ga-NODAGA-zoledronate ([68Ga]Ga-NODAGAZOL) PET/CT, and [99mTc]Tc-MDP bone scan in the assessment of bone metastases in patients with advanced PCa. METHODS: We prospectively recruited two cohorts of patients (staging and re-staging cohorts) with advanced prostate cancer. The staging cohort was treatment-naïve PCa patients who showed skeletal metastases on bone scan. These patients were subsequently imaged with [68Ga]Ga-PSMA-11 PET/CT and [68Ga]Ga-NODAGAZOL PET/CT. Re-staging cohort was patients who were previously treated with PSMA-based radioligand therapy and were experiencing PSA progression. The re-staging cohort was imaged with [68Ga]Ga-PSMA-11 PET/CT and [68Ga]Ga-NODAGAZOL PET/CT. We performed a per-patient and per-lesion analysis of skeletal metastases in both cohorts and made a comparison between scan findings. RESULTS: Eighteen patients were included with a median age of 68 years (range = 48-80) and a median Gleason score of 8. There were ten patients in the staging cohort with a median PSA of 119.26 ng/mL (range = 4.63-18,948.00) and eight patients in the re-staging cohort with a median PSA of 48.56 ng/mL (range = 6.51-3175.00). In the staging cohort, skeletal metastases detected by [68Ga]Ga-PSMA-11 PET/CT, [68Ga]Ga-NODAGAZOL PET/CT, and bone scan were 322, 288, and 261, respectively, p = 0.578. In the re-staging cohort, [68Ga]Ga-PSMA-11 PET/CT and [68Ga]Ga-NODAGAZOL PET/CT detected 152 and 191 skeletal metastases, respectively, p = 0.529. In two patients with negative [68Ga]Ga-PSMA-11 PET/CT findings, [68Ga]Ga-NODAGAZOL detected one skeletal metastasis in one patient and 12 skeletal metastases in the other. CONCLUSION: In patients with advanced prostate cancer, [68Ga]Ga-PSMA-11 PET/CT may detect more lesions than [68Ga]Ga-NODAGAZOL PET/CT and [99mTc]Tc-MDP bone scan for the staging of skeletal metastases. In patients who experience PSA progression on PSMA-based radioligand therapy, [68Ga]Ga-NODAGA PET/CT is a more suitable imaging modality for the detection of skeletal lesions not expressing PSMA. In the setting of re-staging, [68Ga]Ga-NODAGAZOL PET/CT may detect more lesions than [68Ga]Ga-PSMA-11 PET/CT.

Preclinical Assessment Addressing Intravenous Administration of a [68Ga]Ga-PSMA-617 Microemulsion: Acute In Vivo Toxicity, Tolerability, PET Imaging, and Biodistribution.

It has been herein presented that a microemulsion, known to be an effective and safe drug delivery system following intravenous administration, can be loaded with traces of [68Ga]Ga-PSMA-617 without losing its properties or causing toxicity. Following tolerated IV injections the capability of the microemulsion in altering [68Ga]Ga-PSMA-617 distribution was presented at 120 min post injection based on its ex vivo biodistribution results.

Microwave-assisted synthesis of meso-carboxyalkyl-BODIPYs and an application to fluorescence imaging.

In this study, a significantly improved method for the synthesis of modular meso-BODIPY (boron dipyrromethene) derivatives possessing a free carboxylic acid group (which was subsequently coupled to peptides), is disclosed. This method provides a vastly efficient synthetic route with a > threefold higher overall yield than other reports. The resultant meso-BODIPY acid allowed for further easy incorporation into peptides. The meso-BODIPY peptides showed absorption maxima from 495-498 nm and emission maxima from 504-506 nm, molar absorptivity coefficients from 33 383-80 434 M-1 cm-1 and fluorescent quantum yields from 0.508-0.849. The meso-BODIPY-c(RGDyK) peptide was evaluated for plasma stability and (proved to be durable even up to 4 h) was then assessed for its fluorescence imaging applicability in vivo and ex vivo. The optical imaging in vivo was limited due to autofluorescence, however, the ex vivo tissue analysis displayed BODIPY-c(RGDyK) internalization and cancer detection thereby making it a novel tumor-integrin associated fluorescent probe while displaying the lack of interference the dye has on the properties of this ligand to bind the receptor.

Production of [68 Ga]Ga-PSMA: Comparing a manual kit-based method with a module-based automated synthesis approach.

The labeling of peptides with gallium-68 is often initially performed by manual labeling, but with high clinical demand, other alternatives are needed. Cold-kits or automated synthesis are viable options for standardized methods and deemed pharmaceutically more acceptable. This study compares these [68 Ga]Ga-PSMA-11 production methods. Data from 40 kit-based and 40 automated syntheses of [68 Ga]Ga-PSMA-11 were analyzed. Pre-set criteria were evaluated including radiochemical purity, radionuclidic purity, chemical purity, physiological acceptability and sterility. The operator time and radiation dose received were measured. The robustness and repeatability of each method were assessed and a comparison of the running costs of each method is also provided. For both the methods all the analyzed products met the release criteria. No differences were found in radiochemical purity, radiochemical identity, radionuclidic purity, and sterility. However, radiochemical yield and apparent molar activity showed significant differences. For both methods, whole body radiation exposure to operators was lower than with manual labeling (25 - 40 µSv). The exposure during kit-based labeling (14.5 ± µSv) was seven times higher than that of automated synthesis (2.05 ± 0.99 µSv). The automated synthesis was the more expensive method. Both methods are sound alternatives to manual synthesis and offer higher quality, better radiation protection and a more reliable manufacturing of radiopharmaceuticals.

Preclinical assessment of 68 Ga-PSMA-617 entrapped in a microemulsion delivery system for applications in prostate cancer PET/CT imaging.

It has in recent years been reported that microemulsion (ME) delivery systems provide an opportunity to improve the efficacy of a therapeutic agent whilst minimising side effects and also offer the advantage of favourable treatment regimens. The prostate-specific membrane antigen (PSMA) targeting agents PSMA-11 and PSMA-617, which accumulate in prostate tumours, allow for [68 Ga]Ga3+ -radiolabelling and positron emission tomography/computed tomography (PET) imaging of PSMA expression in vivo. We herein report the formulation of [68 Ga]Ga-PSMA-617 into a ME ≤40 nm including its evaluation for improved cellular toxicity and in vivo biodistribution. The [68 Ga]Ga-PSMA-617-ME was tested in vitro for its cytotoxicity to HEK293 and PC3 cells. [68 Ga]Ga-PSMA-617-ME was administered intravenously in BALB/c mice followed by microPET/computed tomography (CT) imaging and ex vivo biodistribution determination. [68 Ga]Ga-PSMA-617-ME indicated negligible cellular toxicity at different concentrations. A statistically higher tolerance towards the [68 Ga]Ga-PSMA-617-ME occurred at 0.125 mg/mL by HEK293 cells compared with PC3 cells. The biodistribution in wild-type BALB/C mice showed the highest amounts of radioactivity (%ID/g) presented in the kidneys (31%) followed by the small intestine (10%) and stomach (9%); the lowest uptake was seen in the brain (0.5%). The incorporation of [68 Ga]Ga-PSMA-617 into ME was successfully demonstrated and resulted in a stable nontoxic formulation as evaluated by in vitro and in vivo means.

Diagnostic utility of 18F-FDG PET/CT in fever of unknown origin among patients with end-stage renal disease treated with renal replacement therapy.

OBJECTIVE: To evaluate the role of fluorine-18-fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) in identifying the cause of fever of unknown origin (FUO) in patients on renal replacement therapy (RRT) for end-stage renal disease (ESRD). SUBJECTS AND METHODS: We retrospectively reviewed the 18F-FDG PET/CT scans of 46 patients with a mean age of 39.28±12.50 years on RRT for ESRD. All patients with abnormal scans had histopathologic examination and microbial cultures of tissue samples from areas with increased standardized uptake value maximum (SUVmax) suggesting the cause of FUO in the 18F-FDG PET/CT scan. Fluorine-18-FDG PET/CT was considered helpful if it led to the diagnosis of the cause of FUO after histopathologic and microbiologic examinations. RESULTS: Fluorine-18-FDG PET/CT was helpful in identifying the cause of FUO in 22/46 patients (47.83%). Infection was the cause of fever in all these 22 patients. C-reactive protein (CRP) (P=0.003) and procalcitonin levels (P=0.021) were higher in patients with helpful 18F-FDG PET/CT. No significant difference was found in blood sugar levels and leucocytes counts between patients with helpful 18F-FDG PET/CT outcome and those without. By multiple regression analysis, the odds of a helpful 18F-FDG PET/CT increased with every unit increase in CRP level (OR: 1.009; 95% CI: 1.003-1.016; P=0.005). CONCLUSION: About half of the 18F-FDG-PET/CT scans (22/46) identified the cause of FUO in patients on RRT for ESRD. The clinical utility of 18F-FDG PET/CT in this group of patients is comparable to its average performance in the unselected patients' population evaluated for FUO. A higher CRP level was predictive of a positive 18F-FDG PET/CT outcome.

68Ga-PSMA-11 PET/CT in primary staging of prostate carcinoma: preliminary results on differences between black and white South-Africans.

PURPOSE: The incidence of prostate cancer is 60% higher and the mortality rate is two- to three-times greater in black versus white men. We report on differences in 68Ga-PSMA-11 PET/CT imaging findings in 77 black South-African (BSAs) and 18 white South-African (WSAs) treatment-naïve primary prostate carcinoma (PPC) patients. METHODS: 68Ga-PSMA-11 PET/CT imaging findings were compared to histological, biochemical and morphological imaging data. Patients were grouped into three Gleason grade groups (GG), GG 1 (scores 3 + 3 and 3 + 4), GG2 (scores 4 + 3 and 4 + 4) and GG3 (scores 9 and 10), and the PSA difference among the groups was determined. Inter-racial difference in SUVmax of the primary tumor as well as its correlation with serum PSA were also determined. RESULTS: Ninety-three out of 95 PPC where readily identified on 68Ga-PSMA-11 PET/CT imaging. Median PPC SUVmax and serum PSA values proved significantly higher (p = 0.033 and p = 0.003) in GG3 patients (median 16.4 and 180 ng/ml) when compared to GG1 patients (median 9.6 and 25.1 ng/ml) or GG2 patients (median 8.8 and 46.2 ng/ml). SUVmax significantly correlated with serum PSA-values (r = 0.377 (p = 0.0001)). Age, frequency of lymph node involvement and distant metastases, and GGs (p ≥ 0.153) were similar in BSAs and WSAs, both median serum PSA-values as well as SUVmax values proved significantly higher in BSAs when compared to WSAs, respectively, 81.6 ng/ml versus 14.5 ng/ml (p = 0.0001) and 11.9 versus 4.38 (p = 0.004). Moreover, Gleason-score normalized median SUVmax values proved 2.5 times higher in BSAs when compared to WSAs (p = 0.005). CONCLUSION: SUVmax values proved significantly related to GG and to be significantly higher in BSAs when compared to WSAs. Also, SUVmax significantly correlated with serum PSA values, which was significantly higher in BSAs when compared with WSAs.

68Ga-PSMA-HBED-CC PET imaging in breast carcinoma patients.

BACKGROUND: To report on imaging findings using 68Ga-PSMA-HBED-CC PET in a series of 19 breast carcinoma patients. METHODS: 68Ga-PSMA-HBED-CC PET imaging results obtained were compared to routinely performed staging examinations and analyzed as to lesion location and progesterone receptor status. RESULTS: Out of 81 tumor lesions identified, 84% were identified on 68Ga-PSMA-HBED-CC PET. 68Ga-PSMA-HBED-CC SUVmean values of distant metastases proved significantly higher (mean, 6.86, SD, 5.68) when compared to those of primary or local recurrences (mean, 2.45, SD, 2.55, p = 0.04) or involved lymph nodes (mean, 3.18, SD, 1.79, p = 0.011). SUVmean values of progesterone receptor-positive lesions proved not significantly different from progesterone receptor-negative lesions. SUV values derived from FDG PET/CT, available in seven patients, and 68Ga-PSMA-HBED-CC PET/CT imaging proved weakly correlated (r = 0.407, p = 0.015). CONCLUSIONS: 68Ga-PSMA-HBED-CC PET/CT imaging in breast carcinoma confirms the reported considerable variation of PSMA expression on human solid tumors using immunohistochemistry.

Preclinical Assessment of a 68Ga-DOTA-Functionalized Depsipeptide as a Radiodiagnostic Infection Imaging Agent.

The study assessed a radiolabeled depsipeptide conjugate (68Ga-DOTA-TBIA101) for its potential as an imaging agent targeting infection or infection-associated inflammation. 68Ga-labeled DOTA-TBIA101 imaging was performed in (NZR1) healthy rabbits; (NZR2) rabbits bearing muscular sterile inflammation and Staphylococcus aureus (SA) infection; and (NZR3) rabbits infected with Mycobacterium tuberculosis (MTB) combined with a subcutaneous scruff infection of SA in the same animal. All animals were imaged using a PET/CT scanner at 5 and 60 min post injection. Images showed elevated accumulation of 68Ga-DOTA-TBIA101 in the sterile muscular inflammation site (T/NT ratio = 2.6 ± 0.37 (5 min) and 2.8 ± 2.3 (60 min)) and muscles infected with MTB (T/NT ratio = 2.6 ± 0.35 (5 min) and 2.8 ± 0.16 (60 min)). The findings suggest that 68Ga-DOTA-TBIA101-PET/CT may detect MTB-associated inflammation, although more foundational studies need to be performed to rationalize the diagnostic value of this technique.

Gallium-68-dotatate PET/CT is better than CT in the management of somatostatin expressing tumors: First experience in Africa.

OBJECTIVE: In this study we aimed to present our experience on the use of Gallium-68-dotatate with positron emission tomography, computed tomography (68 Ga-dotatate PET/CT) in the management of neuroendocrine tumors (NET) and other somatostatin expressing tumors. SUBJECTS AND METHODS: We retrospectively reviewed patients with histologically confirmed or biochemically suspected NET and other somatostatin expressing (SSTR) tumors imaged at our department with 68Ga-dotatate PET/CT. We determined the performance of this imaging technique as well as its impact on patients management. A total of 203 patients were studied: 103 females, 100 males median age 52years. RESULTS: The commonest tumor type was gastroenteropancreatic NET (41% of patients) and the commonest sites of distant metastases were lymph nodes and the liver 34.0% and 30.5% respectively. Positron emission tomography detected foci of disease in 19 patients where CT was falsely negative. The sensitivity, specificity, positive predictive value, negative predictive value and accuracy of 68 Ga-dotatate PET/CT imaging of NET and other SST expressing tumors were 94.16%, 91.89%, 95.55%, 89.47% and 96.55% respectively. CONCLUSION: Gallium-68-dotatate PET/CT was better than CT in detecting primary sites of the disease and highly sensitive and specific for diagnosis and treatment of NET and other SSTR expressing tumors.

Development of a Single Vial Kit Solution for Radiolabeling of 68Ga-DKFZ-PSMA-11 and Its Performance in Prostate Cancer Patients.

Prostate-specific membrane antigen (PSMA), a type II glycoprotein, is highly expressed in almost all prostate cancers. By playing such a universal role in the disease, PSMA provides a target for diagnostic imaging of prostate cancer using positron emission tomography/computed tomography (PET/CT). The PSMA-targeting ligand Glu-NH-CO-NH-Lys-(Ahx)-HBED-CC (DKFZ-PSMA-11) has superior imaging properties and allows for highly-specific complexation of the generator-based radioisotope Gallium-68 ((68)Ga). However, only module-based radiolabeling procedures are currently available. This study intended to develop a single vial kit solution to radiolabel buffered DKFZ-PSMA-11 with (68)Ga. A (68)Ge/(68)Ga-generator was utilized to yield (68)GaCl3 and major aspects of the kit development were assessed, such as radiolabeling performance, quality assurance, and stability. The final product was injected into patients with prostate cancer for PET/CT imaging and the kit performance was evaluated on the basis of the expected biodistribution, lesion detection, and dose optimization. Kits containing 5 nmol DKFZ-PSMA-11 showed rapid, quantitative (68)Ga-complexation and all quality measurements met the release criteria for human application. The increased precursor content did not compromise the ability of (68)Ga-DKFZ-PSMA-11 PET/CT to detect primary prostate cancer and its advanced lymphatic- and metastatic lesions. The (68)Ga-DKFZ-PSMA-11 kit is a robust, ready-to-use diagnostic agent in prostate cancer with high diagnostic performance.

Fluorine-18-fluoroethylcholine PET/CT in the detection of prostate cancer: a South African experience.

OBJECTIVE: Imaging with fluorine-18-fluoro-2-deoxy-D-glucose positron emission tomography/computed tomography ((18)F-FDG PET/CT) has, until recently provided disappointing results with low sensitivity ranging from 31%-64% in patients with well-differentiated prostate cancer (PC) at all prostatic specific antigen (PSA) levels while fluorine-18-fluoroethylcholine ((18)F-FECh) PET/CT showed about 85% sensitivity in restaging patients after relapse. We present our experience of the sensitivity of (18)F-FECh PET/CT in the early stages of PC. SUBJECT AND METHODS: Fifty patients were prospectively recruited and imaged, of which 40 fulfilled all inclusion criteria. Our patients had an average age of 65.5 years. Fifteen patients were referred for initial staging, with the remaining 25 referred for restaging and all patients had histologically confirmed adenocarcinoma. Patients were imaged by (18)F-FECh PET/CT. Findings were evaluated qualitatively and quantitatively and compared to the results of histology, PSA, Gleason score and bone scintigraphy. The prostate SUVmax was also used. RESULTS: Thirty-one patients demonstrated abnormal pelvic- and or extra- pelvic findings on (18)F-FECh PET/CT, which was consistent with malignant or metastatic involvement. The prostate SUVmax could not be used to predict the presence or absence of metastatic disease. CONCLUSION: Findings of this paper suggest that (18)F-FECh PET/CT in 30/40 cases (estimated as 75%) was helpful in the initial staging, restaging and lymph node detection of patients with PC. The SUVmax was not helpful. We diagnosed more PC cases in our African-American patients as compared to the Caucasian patients.

Recently developed radiopharmaceuticals for bacterial infection imaging.

BACKGROUND: Infection remains a major cause of morbidity and mortality, regardless of advances in antimicrobial therapy and improved knowledge of microorganisms. With the major global threat posed by antimicrobial resistance, fast and accurate diagnosis of infections, and the reliable identification of intractable infection, are becoming more crucial for effective treatment and the application of antibiotic stewardship. Molecular imaging with the use of nuclear medicine allows early detection and localisation of infection and inflammatory processes, as well as accurate monitoring of treatment response. There has been a continuous search for more specific radiopharmaceuticals to be utilised for infection imaging. This review summarises the most prominent discoveries in specifically bacterial infection imaging agents over the last five years, since 2019. MAIN BODY: Some promising new radiopharmaceuticals evaluated in patient studies are reported here, including radiolabelled bacterial siderophores like [68Ga]Ga-DFO-B, radiolabelled antimicrobial peptide/peptide fragments like [68Ga]Ga-NOTA-UBI29-41, and agents that target bacterial synthesis pathways (folic acid and peptidoglycan) like [11C]para-aminobenzoic acid and D-methyl-[11C]-methionine, with clinical trials underway for [18F]fluorodeoxy-sorbitol, as well as for 11C- and 18F-labelled trimethoprim. CONCLUSION: It is evident that a great deal of effort has gone into the development of new radiopharmaceuticals for infection imaging over the last few years, with remarkable progress in preclinical investigations. However, translation to clinical trials, and eventually clinical Nuclear Medicine practice, is apparently slow. It is the authors' opinion that a more structured and harmonised preclinical setting and well-designed clinical investigations are the key to reliably evaluate the true potential of the newly proposed infection imaging agents.

Insights into Peptidoglycan-Targeting Radiotracers for Imaging Bacterial Infections: Updates, Challenges, and Future Perspectives.

The unique structural architecture of the peptidoglycan allows for the stratification of bacteria as either Gram-negative or Gram-positive, which makes bacterial cells distinguishable from mammalian cells. This classification has received attention as a potential target for diagnostic and therapeutic purposes. Bacteria's ability to metabolically integrate peptidoglycan precursors during cell wall biosynthesis and recycling offers an opportunity to target and image pathogens in their biological state. This Review explores the peptidoglycan biosynthesis for bacteria-specific targeting for infection imaging. Current and potential radiolabeled peptidoglycan precursors for bacterial infection imaging, their development status, and their performance in vitro and/or in vivo are highlighted. We conclude by providing our thoughts on how to shape this area of research for future clinical translation.

A modified technique for efficient radiolabeling of 68Ga-citrate from a SnO2-based 68Ge/68Ga generator for better infection imaging.

Our aim was to develop a practical method to prepare 68Ga-citrate using a SnO2-based 68Ge/68Ga generator and evaluate its use in infection imaging. 68Ga-citrate synthesis was performed in a straight forward, quantitative, one-step-aseptic procedure; an amended labeling method was applied using ACD-A buffered citrate as a precursor. Study participants were imaged on a Siemens Biograph 40 PET/CT scanner 60 min post intravenous injection. Our results showed: 90%-95% 68Ga-yield was obtained and subsequently used at 324-527 MBq to perform three to four parallel 68Ga-citrate syntheses. 68Ga-citrate of 96%-99% was yielded after 10 min incubation. The radiochemical purity was >99% with a pH value of 4.0-4.5. All other quality control requirements were met. The 68Ga-citrate stability was >96%. The final product was sterile, pyrogen and solvent-free, with very low 68Ge-levels, with 191±33 MBq in 6.6±2.8 mL. High quality images were obtained at 60 min post injection of 185 MBq of 68Ga-citrate. In conclusion, a fast, direct and cheap method with a quantitative preparation of 68Ga-citrate was described. We reported on the adaptations needed when using a SnO2-based 68Ge/68Ga generator and ACD-A buffered citrate as a precursor. This method allowed for multiple patient productions from one generator elution, with 300 MBq/patient of 68Ga-citrate produced in less than 30 min and excellent labeling reproducibility for routine infection imaging.