68Ga‐PET: a powerful generator‐based alternative to cyclotron‐based PET radiopharmaceuticals

PET (positron emission tomography) is a powerful diagnostic and imaging technique which requires short‐lived positron emitting isotopes. The most commonly used are accelerator‐produced ¹¹C and ¹⁸F. An alternative is the use of metallic positron emitters. Among them ⁶⁸Ga deserves special attention because of its availability from long‐lived ⁶⁸Ge/⁶⁸Ga generator systems which render ⁶⁸Ga radiopharmacy independent of an onsite cyclotron. The coordination chemistry of Ga³⁺ is dominated by its hard acid character. A variety of mono‐ and bifunctional chelators have been developed which allow the formation of stable ⁶⁸Ga³⁺complexes and convenient coupling to biomolecules. ⁶⁸Ga coupling to small biomolecules is potentially an alternative to ¹⁸F‐ and ¹¹C‐based radiopharmacy. In particular, peptides targeting G‐protein coupled receptors overexpressed on human tumour cells have shown preclinically and clinically high and specific tumour uptake. Kit‐formulated precursors along with the generator may be provided, similar to the ⁹⁹Mo/^99mTc‐based radiopharmacy, still the mainstay of nuclear medicine. Copyright © 2008 John Wiley & Sons, Ltd.     

[68Ga]‐HP‐DO3A‐nitroimidazole: a promising agent for PET detection of tumor hypoxia

The goal of this study is to evaluate a new ⁶⁸Ga‐based imaging agent for detecting tumor hypoxia using positron emission tomography (PET). The new hypoxia targeting agent reported here, [⁶⁸Ga]‐HP‐DO3A‐nitroimidazole ([⁶⁸Ga]‐HP‐DO3A‐NI), was constructed by linking a nitroimidazole moiety with the macrocyclic ligand component of ProHance®, HP‐DO3A. The hypoxia targeting capability of this agent was evaluated in A549 lung cancer cells in vitro and in SCID mice bearing subcutaneous A549 tumor xenografts. The cellular uptake assays showed that significantly more [⁶⁸Ga]‐HP‐DO3A‐NI accumulates in hypoxic tumor cells at 30, 60 and 120 min than in the same cells exposed to 21% O₂. The agent also accumulated in hypoxic tumors in vivo to give a tumor/muscle ratio (T/M) of 5.0 ± 1.2 (n = 3) as measured by PET at 2 h post‐injection (p.i.). This was further confirmed by ex vivo biodistribution data. In addition, [⁶⁸Ga]‐HP‐DO3A‐NI displayed very favorable pharmacokinetic properties, as it was cleared largely through the kidneys with little to no accumulation in liver, heart or lung (%ID/g < 0.5%) at 2 h p.i. The specificity of the agent for hypoxic tissues was further validated in a comparative study with a control compound, [⁶⁸Ga]‐HP‐DO3A, which lacks the nitroimidazole moiety, and by PET imaging of tumor‐bearing mice breathing air versus 100% O₂. Given the commercial availability of cGMP ⁶⁸Ge/⁶⁸Ga generators and the ease of ⁶⁸Ga labeling, the new agent could potentially be widely applied for imaging tumor hypoxia prior to radiation therapy. Copyright © 2015 John Wiley & Sons, Ltd.     

Topical Sensor for the Assessment of Injection Quality for 18F-FDG, 68Ga-PSMA and 68Ga-DOTATATE Positron Emission Tomography

IntroductionCalculation of the standard uptake value (SUV) and image quality in positron emission tomography (PET) hinges on accurate dose delivery. Extravasation or partial extravasation of the radiopharmaceutical dose can undermine SUV and image quality, and contribute to unnecessary imaging (time and CT dose). Topical sensor characterisation of injections has been reported, with extravasation rates ranging from 9% to 23% for 18F-FDG after manual injection.MethodA single site, single PET/CT scanner was used to characterise injections using an autoinjector with standardised apparatus, flush volume and infusion rate using 18F-FDG, 68Ga-PSMA and 68Ga-DOTATATE; more reflective of Australian PET facilities. 296 patients with topical application of LARA sensors were retrospectively analysed.ResultsOnly 1.1% of studies showed evidence of partial dose extravasation. In total, 9.1% were identified to have an injection anomaly (including venous retention). No statistically significant differences were noted across the radiopharmaceuticals for demographic data. Although not demonstrating a statistically significant correlation, there was more extravasated doses associated with female patients (P = .334), right side (P = .372), and hand injections (P = .539). Extravasation was independent of dose administered (P = .495), the radiopharmaceutical (P = .887), who injected the dose (P = .343), height (P = .438), weight (P = .607) or age (P = .716). Extravasation was associated with higher glucose levels (P < .001), higher t-half (P = .019) and higher aUCR10, tc50, aUCR1 and c1 (all P < .001).ConclusionTopical monitoring and characterisation of PET dose administration is possible and practical with the LARA device. Extravasation and partial extravasation of PET doses are not only readily detected but they are also preventable. The LARA device can provide the insights into variables that could eliminate extravasation as a cause of image quality or SUV accuracy issues.     

Evaluation of unusual neuroendocrine tumours by means of Ga-DOTA-NOC PET

¹⁸F-FDG PET value for the assessment of neuroendocrine tumours (NET) is limited. Preliminary studies indicate that somatostatin receptor PET using ⁶⁸Ga-DOTA-peptides is more accurate for disease assessment and provide additional data on receptor status, that are crucial for targeted radionuclide therapy. At present, however, few papers investigated the role of ⁶⁸Ga-DOTA-NOC PET in NET, especially in unusual situations. The purpose of the present study was to evaluate ⁶⁸Ga-DOTA-NOC for the evaluation of NET of uncommon presentation. Patients with biopsy-proven NET were scheduled for ⁶⁸Ga-DOTA-NOC PET; we excluded from further evaluation cases with most common NET tumours (gastro-entero-pancreatic and pulmonary localization of primary lesion, MEN syndromes, medullary thyroid carcinoma, pheochromocytomas). PET results were compared with findings of conventional imaging, including CT, ultrasonography, MR and somatostatin receptor scintigraphy; finally PET results were compared with follow-up data with respect to the impact on patient management. Fourteen patients were finally enrolled; primary tumours were located at uterine level (3 cases), prostate (3 cases), ovary (1 case), kidney (1 case), breast (1 case), ear (1 case); also 3 cases of paraganglioma (at neck, abdominal and mediastinum level) and 1 case of lymphoma were included. ⁶⁸Ga-DOTA-NOC PET was positive, showing at least 1 lesion, in 6/14 cases while 5 cases turned out negative and 2 inconclusive. On a clinical basis, ⁶⁸Ga-DOTA-NOC provided additional information in comparison to conventional imaging procedures in 7/14 cases, and was considered useful in 12/14 patients, with 8 patients in which ⁶⁸Ga-DOTA-NOC PET was determinant for patient's management. Although the number of patients studied is limited, our data show that ⁶⁸Ga-DOTA-NOC can be usefully applied for the evaluation of NET of uncommon presentation; in particular very promising results were obtained in paraganglioma. On the other hand, care has to be paid when studying lesions localized at sites of physiological concentration of the tracer, and in presence of inflammation.     

Fast synthesis and bioconjugation of 68Ga core‐doped extremely small iron oxide nanoparticles for PET/MR imaging

Combination of complementary imaging techniques, like hybrid PET/MRI, allows protocols to be developed that exploit the best features of both. In order to get the best of these combinations the use of dual probes is highly desirable. On this sense the combination of biocompatible iron oxide nanoparticles and 68Ga isotope is a powerful development for the new generation of hybrid systems and multimodality approaches. Our objective was the synthesis and application of a chelator‐free 68Ga‐iron oxide nanotracer with improved stability, radiolabeling yield and in vivo performance in dual PET/MRI. We carried out the core doping of iron oxide nanoparticles, without the use of any chelator, by a microwave‐driven protocol. The synthesis allowed the production of extremely small (2.5 nm) 68Ga core‐doped iron oxide nanoparticles. The microwave approach allowed an extremely fast synthesis with a 90% radiolabeling yield and T1 contrast in MRI. With the same microwave approach the nano‐radiotracer was functionalized in a fast and efficient way. We finally evaluated these dual targeting nanoparticles in an angiogenesis murine model by PET/MR imaging. Copyright © 2016 John Wiley & Sons, Ltd.     

Ultrasmall particles for Gd‐MRI and 68Ga‐PET dual imaging

Nanoparticles made of a polysiloxane matrix and surrounded by 1,4,7,10‐tetraazacyclododecane‐1‐glutaric anhydride‐4,7,10‐triacetic acid (DOTAGA)[Gd³⁺] and 2,2'‐(7‐(1‐carboxy‐4‐((2,5‐dioxopyrrolidin‐1‐yl)oxy)‐4‐oxobutyl)‐1,4,7‐triazonane‐1,4‐diyl)diacetic acid) NODAGA[⁶⁸Ga³⁺] have been synthesized for positron emission tomography/magnetic resonance (PET/MRI) dual imaging. Characterizations were carried out in order to determine the nature of the ligands available for radiolabelling and to quantify them. High radiolabelling purity (>95%) after ⁶⁸Ga labelling was obtained. The MR and PET images demonstrate the possibility of using the nanoparticles for a combined PET/MR imaging scanner. The images show fast renal elimination of the nanoparticles after intravenous injection.Copyright © 2014 John Wiley & Sons, Ltd.     

Small animal PET for the evaluation of an animal model of genital infection

Background: [¹⁸F]‐FDG is a widely used tracer for the non‐invasive evaluation of hypermetabolic processes like cancer and inflammation. However, [¹⁸F]‐FDG is considered inaccurate for the diagnosis of urinary tract and genital infections because of its urinary excretion. Since the 1970s, Gallium scintigraphy is a well established test that has been used for the evaluation of inflammation and infection in human patients. Aim: The aim of this study was to assess the feasibility of ⁶⁸Ga‐Chloride small animal PET for the analysis of an animal model of genital infection, induced after the vaginal inoculum of Chlamydia muridarum. Material and methods: Thirty mice were infected by placing 15 μl of sucrose phosphate glutamic acid (SPG) 10⁷ inclusion forming units of C. muridarum into the vaginal vault. As controls of inflammation, three animals were challenged with 15 μl of SPG and one healthy animal was used to assess the tracer biodistribution. Four animals died during the experiment. Eleven animals were evaluated with ⁶⁸Ga‐Chloride small animal PET (GE, eXplore Vista) 3–5, 10–12, 17–19 days after infection, as well as three controls of inflammation and one healthy animal. Infection was monitored by obtaining cervical‐vaginal swabs from all the animals on the day of each PET procedure. Moreover, five groups of three animals each were killed at 6, 13, 20, 27 and 34 days after infection were studied. Results: ⁶⁸Ga‐PET turned out positive in all the infected animals, concordantly to data obtained by the cervical swabs and by the ex vivo analysis. The tumour‐to‐background ratio (TBR) decreased over time as the inflammation tended to naturally extinguish. The controls showed a slightly increased uptake of tracer due to the aseptic inflammation caused by SPG and frequent cervical swabs. The healthy control did not show any pelvic uptake. Conclusion: ⁶⁸Ga‐Chloride is a promising tracer for the assessment of genital infection in a mouse animal model.     

Bone Metabolism after Total Hip Revision Surgery with Impacted Grafting: Evaluation using H<Subscript>2</Subscript><Superscript>15</Superscript>O and [<Superscript>18</Superscript>F]fluoride PET; A Pilot Study

PURPOSE: To evaluate bone blood flow and bone formation in patients after total hip revision surgery with impacted bone grafting using H(2) (15)O and [(18)F]fluoride positron emission tomography (PET). PROCEDURES: To asses bone blood flow and bone metabolism in bone allograft after impaction grafting, four patients treated with total hip revision surgery were enrolled prospectively in this study. Six patients scheduled for primary hip arthroplasties were included as a control group. The study protocol consisted of three H(2) (15)O and [(18)F]fluoride PET scans in each patient. RESULTS: Bone blood flow increased significantly compared to the preoperative state in patients treated for primary hip arthroplasty. In patients undergoing revision surgery, bone blood flow was twofold to threefold higher compared to the preoperative state, but did not reach significance. Bone metabolism in patients undergoing revision was threefold higher 2 weeks postoperatively compared to the primary hip group. We found a significant correlation between Ki and bone blood flow. CONCLUSIONS: Allogeneic bone grafts induce a higher rate of local periprosthetic bone formation compared to periprosthetic bone formation after a primary total hip placement. In vivo coupling between bone blood flow and bone metabolism suggests that bone metabolism in allogeneic bone grafts may partly rely on bone blood flow adaptations.     

18F-FDG PET/CT及68Ga-FAPI PET/CT在淋巴瘤诊断中的价值对比

目的  比较¹⁸F-FDG PET/CT及⁶⁸Ga-FAPI PET/CT对淋巴瘤的诊断价值,探究⁶⁸Ga-FAPI PET/CT在淋巴瘤诊断中的应用前景。方法  回顾性分析我院2020年1月~2022年12月淋巴瘤待诊的37例患者,对比其¹⁸F-FDG PET/CT及⁶⁸Ga-FAPI PET/CT的最大标准摄取值（SUV_max）值及TBR值的差异,分别研究两种检查方法的SUV_max及TBR值与Ki67之间的相关性,并比较两种检查方法在淋巴瘤分期及浸润灶诊断上的差异。结果  37例患者中有30例确诊为淋巴瘤。¹⁸F-FDG PET/CT的诊断效能高于⁶⁸Ga-FAPI PET/CT。淋巴瘤患者中SUV_max-FDG>SUV_max-FAPI（17.35 vs 4.80）,差异有统计学意义（P < 0.05）;淋巴瘤患者中TBR-FDG>TBR-FAPI（29.35 vs 7.05）,差异有统计学意义（P < 0.05）。SUV_max-FDG、TBR-FDG与Ki67之间呈正相关关系（SUV_max-FDG：R²=0.28,P < 0.05;TBR-FDG：R²=0.19,P < 0.05）,SUV_max-FAPI、TBR-FAPI Ki67之间无相关性（P>0.05）。在检测淋巴瘤浸润方面,¹⁸F-FDG PET/CT优于⁶⁸Ga-FAPI PET/CT。结论  ¹⁸F-FDG PET/CT诊断淋巴瘤的SUV_max及TBR值高于⁶⁸Ga-FAPI PET/CT,在淋巴瘤的诊断和分期中具有更好的效果,可以更好地指导淋巴瘤的临床诊疗,但⁶⁸Ga-FAPI PET/CT在淋巴瘤的诊断中仍具有很大的指导作用。     

A novel PET tracer for the imaging of αvβ3 and αvβ5 integrins in experimental breast cancer bone metastases

The aim of this study was the evaluation of ⁶⁸Ga‐DOTA‐E‐[c(RGDfK)]₂ as a novel PET tracer to image αvβ3 and αvβ5 integrins. For this purpose, DOTA‐E‐[c(RGDfK)]₂ was labeled with ⁶⁸Ga, which was obtained from a ⁶⁸Ge/⁶⁸Ga generator, purified by solid‐phase extraction and the radiochemical purity analyzed by radio‐RP‐HPLC. ⁶⁸Ga‐DOTA‐E‐[c(RGDfK)]₂ was obtained reproducibly in radiochemical yields of 60 ± 6% and with an excellent radiochemical purity of >99%. In nude rats bearing bone metastases after injection of MDA‐MB‐231 human breast cancer cells, biodistribution studies were performed to evaluate the accumulation of the radiotracer in selected organs, blood and bone metastases 0.5, 1, 2 and 3 h post injection. A rapid uptake into the bone metastases and rapid blood clearance was observed, resulting in tumor–blood ratios of up to 26.6 (3 h post injection) and tumor–muscle ratios of up to 7.9 (3 h post injection). A blocking experiment with coinjected αvβ3/αvβ5 antagonist showed the tumor uptake to be receptor‐specific. In an initial in vivo micro PET evaluation of the tracer using the same animal model, the bone metastasis was clearly visualized. These results suggest that ⁶⁸Ga‐DOTA‐E‐[c(RGDfK)]₂ is a promising PET tracer suitable for the imaging of αvβ3 and αvβ5 integrins in bone metastases. This novel PET tracer should be further evaluated concerning its usefulness for early detection of bone metastases and monitoring treatment response of these lesions. Copyright © 2011 John Wiley & Sons, Ltd.     

Gallium(III) complexes of NOTA‐bis (phosphonate) conjugates as PET radiotracers for bone imaging

Ligands with geminal bis(phosphonic acid) appended to 1,4,7‐triazacyclonone‐1,4‐diacetic acid fragment through acetamide (NOTAM^BP) or methylenephosphinate (NO2AP^BP) spacers designed for ⁶⁸Ga were prepared. Ga^III complexation is much faster for ligand with methylenephosphinate spacer than that with acetamide one, in both chemical (high reactant concentrations) and radiolabeling studies with no‐carrier‐added ⁶⁸Ga. For both ligands, formation of Ga^III complex was slower than that with NOTA owing to the strong out‐of‐cage binding of bis(phosphonate) group. Radiolabeling was efficient and fast only above 60 °C and in a narrow acidity region (pH ~3). At higher temperature, hydrolysis of amide bond of the carboxamide‐bis(phosphonate) conjugate was observed during complexation reaction leading to Ga–NOTA complex. In vitro sorption studies confirmed effective binding of the ⁶⁸Ga complexes to hydroxyapatite being comparable with that found for common bis(phosphonate) drugs such as pamindronate. Selective bone uptake was confirmed in healthy rats by biodistribution studies ex vivo and by positron emission tomography imaging in vivo. Bone uptake was very high, with SUV (standardized uptake value) of 6.19 ± 1.27 for [⁶⁸Ga]NO2AP^BP) at 60 min p.i., which is superior to uptake of ⁶⁸Ga–DOTA‐based bis(phosphonates) and [¹⁸F]NaF reported earlier (SUV of 4.63 ± 0.38 and SUV of 4.87 ± 0.32 for [⁶⁸Ga]DO3AP^BP and [¹⁸F]NaF, respectively, at 60 min p.i.). Coincidently, accumulation in soft tissue is generally low (e.g. for kidneys SUV of 0.26 ± 0.09 for [⁶⁸Ga]NO2AP^BP at 60 min p.i.), revealing the new ⁶⁸Ga complexes as ideal tracers for noninvasive, fast and quantitative imaging of calcified tissue and for metastatic lesions using PET or PET/CT. Copyright © 2014 John Wiley & Sons, Ltd.     

前列腺癌的骨转移:MRI 与核素骨扫描的对照分析

目的　比较分析MRI与核素骨扫描(BS)在前列腺癌骨转移诊断方面的敏感性、特异性与准确性。方法　71例经病理证实的前列腺癌,在治疗前分别行核素骨扫描和盆腔MRI检查。比较两种方法对盆腔范围内骨转移显示情况。结果　71例前列腺癌患者,以盆腔范围为观察目标,确诊为骨转移瘤者19例。MRI正确诊断18例,假阴性1例,无假阳性,其诊断敏感性为947%,特异性为100%,正确诊断率为986%;核素骨扫描正确诊断17例,假阴性2例,假阳性8例,其诊断敏感性为895%,特异性846%,正确诊断率859%。以病灶为统计单位,在盆腔范围内,共92个病灶确诊为转移;MRI诊断正确91个病灶,假阴性1个;核素骨扫描诊断正确66个病灶,假阴性26个,假阳性18个。敏感性MRI为989%,而核素骨扫描为717%。结论　在显示骨转移瘤方面,MRI较核素骨扫描具有更高的敏感性、特异性与准确性,但受扫描范围限制。     

18F-FDG PET/CT与99Tcm-MDP骨显像诊断肿瘤骨转移价值的Meta分析

目的评价18F-FDG PET/CT与99Tcm-MDP骨显像对肿瘤骨转移早期诊断的价值。方法计算机检索MEDLINE、PubMend、EMbase、Ovid、Cochrane Library数据库,检索时间截至2010年,搜集18F-FDG PET/CT与99Tcm-MDP骨显像诊断恶性肿瘤骨转移的文献。由3位研究者根据纳入与排除标准独立筛选文献、提取资料和评价质量后,采用MetaDisc软件进行Meta分析,计算合并敏感性、特异性、诊断优势比(DOR),并绘制SROC曲线,计算曲线下面积(AUC)与Q*。结果最终纳入5个研究。Meta分析结果显示:18F-FDG PET/CT与99Tcm-MDP骨显像在诊断肿瘤骨转移的敏感性合并分别为0.95[95%CI(0.90,0.97)]和0.77[95%CI(0.71,0.83)],特异性合并分别为0.98[95%CI(0.97,0.99)]和0.90[95%CI(0.88,0.92)],DOR合并分别为602.81[95%CI(214.07,1 697.51)]和41.37[95%CI(8.15,210.05)];SROC AUC与Q*分别为0.984 2、0.901 7和0.945 4、0.833 1。结论应用18F-FDG PET/CT早期诊断肿瘤骨转移明显优于99Tcm-MDP骨显像。     

Signal of Interest Selection Standard for Ultrasonic Backscatter in Cancellous Bone Evaluation

The aim of this study was to examine the effect of the backscattered signal of interest (SOI) on ultrasonic cancellous bone evaluation. In vitro backscatter measurements were performed using 16 bovine cancellous bone specimens and six different transducers with central frequencies of 0.5, 1, 2.25, 3.5, 5 and 10 MHz. The SOI for signal analysis was selected by a rectangular window. The delay (T1) and duration (T2) of the time window were varied, and the apparent integrated backscatter (AIB) and its correlation to bone volume fraction (BV/TV) were calculated. The results indicate that in addition to affecting the measured value of AIB, the SOI influences the observed correlation between AIB and BV/TV. Strong positive correlations were observed for short T1 (0.5 MHz: ≤6 μs, 1 MHz: ≤3 μs, 2.25 and 3.5 MHz: ≤2 μs, 5 and 10 MHz: ≤1 μs). However, strong negative correlations were observed when T1 was long (0.5 MHz: >9 μs, 1 MHz: >7 μs, 2.25 and 3.5 MHz: >3 μs, 5 and 10 MHz: >2 μs). The T2 value, especially low values (≤3 μs), also influenced the correlation coefficients. Positive correlations were more commonly observed at lower frequencies (i.e., 0.5–1 MHz), whereas negative correlations were more common at higher frequencies (i.e., 2.25–10 MHz). An explicit standard for in vitro SOI selection and cancellous bone assessment was proposed for a broad frequency range (0.5–10 MHz). Current conflicting findings are explained, and constructive suggestions for ultrasonic backscatter cancellous bone evaluation are provided.     

放射性核素骨显像评估血管化组织工程骨修复兔长段骨缺损

目的:研究间充质干细胞(MSCs)和其诱导内皮细胞(ECs)联合种植于多孔β-TCP构筑血管化组织工程骨修复兔长段骨缺损的作用及放射性核素骨显像(ECT)在此过程中的监测效果。方法:制备兔双侧尺骨1.5 cm骨缺损共48侧,分4组修复(每组12侧),A血管化组织工程骨组(MSCs ECs β-TCP),B组织工程骨组(MSCs β-TCP),C单纯材料组(β-TCP),D空白组。术后4、8、12周行ECT、组织切片等检查,观察各组骨缺损修复效能及移植物血管化情况。结果:D组骨缺损未修复,A组骨缺损修复效能及血管化情况优于B组,而B组又优于C组,各结果有显著差异(P<0.05)。结论:MSCs和其诱导ECs共培养构筑的血管化组织工程骨能促进成骨过程和新生骨的血管化,显著提高组织工程骨修复长段骨缺损的能力,ECT在修复过程中有较准确预测效果。     

[68Ga]Ga-P16-093 as a PSMA-Targeted PET Radiopharmaceutical for Detection of Cancer: Initial Evaluation and Comparison with [68Ga]Ga-PSMA-11 in Prostate Cancer Patients Presenting with Biochemical Recurrence

Molecular Imaging and Biology - This study was undertaken to evaluate radiation dosimetry for the prostate-specific membrane antigen targeted [68Ga]Ga-P16-093 radiopharmaceutical, and to initially...