Le DOTATOC-(68Ga) pour l’imagerie TEP des tumeurs endocrines digestives : présentation d’un cas et revue de la littérature

⁶⁸Ga is a positron emitter, obtained from a ⁶⁸Ge/⁶⁸Ga generator, which can be used to label peptides of clinical interest. DOTATOC is a tracer of high affinity for the type 2 somatostatin receptors and is used for imaging of tumours which are expressing them, including endocrine tumours. We report on the case of a patient with a history of small bowel carcinoid tumour with hepatic metastases, treated by somatostatin analogues, in whom somatostatin receptor scintigraphy showed three liver foci and DOTATOC-(⁶⁸Ga) PET/CT highlighted much more liver lesions. Two recent studies emphasised on the superiority of DOTATOC-(⁶⁸Ga) PET over somatostatin receptor scintigraphy, and its complementarity with CT, especially for the diagnosis of bone metastases. DOTATOC-(⁶⁸Ga) PET/CT, which associates the specificity of somatostatin receptor scintigraphic detection with the spatial resolution of PET and the anatomical precision of CT, seems to be promised to a brilliant future, the more so as it offers many advantages to the patient: a shorter waiting time, one single image acquisition and a satisfying dosimetry.     

La TEP des tumeurs neuroendocrines de l’intestin grêle

This article focuses on the indication and the choice of tracer for PET/CT in case of neuroendocrine tumours (NET) of the small intestine, which are the most common digestive NETs. PET/CT can be used to search for the primary NET in case of detection of a metastasis, for staging and determination of resectability, for restaging, for optimising and determining the efficacy of therapeutic modalities in extended or recurrent forms. Currently, three types of PET tracers are routinely used: FDG can be useful in the case of aggressive NET especially the duodenum and proximal jejunum, FDOPA is the best tracer in the case of NET of distal jejunum or of ileum, the labeled somatostatin analogues ⁶⁸Ga in the case of well-differentiated NET from the duodenum or proximal jejunum, or irrespective of the location of primary NET if treatment with somatostatin analogue is intended, to confirm the overexpression of somatostatin receptors by lesions.     

Apport de la tomographie par émission de positons dans les tumeurs endocrines digestives : choix du traceur

Digestive endocrine tumors represent a heterogeneous group of neoplasm sharing common characteristics such as their high density of peptide receptors, their ability to take up amino acids and decarboxylate them into biogenic amines and their low glycolytic activity. These features are used for nuclear imaging targeting. To date, somatostatin receptor scintigraphy is considered the “gold standard” imaging procedure of well-differentiated tumors. Despite the significant contribution of SPECT/CT, the use of positron emission tomography imaging (PET) is growing rapidly. Three PET imaging modalities are currently available: 68Ga-labeled somatostatin analogs PET, 18F-dihydroxyphenylalanine PET (¹⁸F-DOPA) and 18F-deoxyglucose PET (¹⁸F-FDG). This article focuses on the current targets of molecular imaging and highlights the potential clinical applications of new targets.     

État actuel de l’utilisation en essais cliniques de molécules radiomarquées au 68Ga en France. Exemple du site de Bordeaux

Production of ⁶⁸Ga-radiopharmaceuticals for Positron Emission Tomography coupled with Computed Tomography (PET/CT) is increasing. These developments are today consolidated by the availability in France of a somatostatin receptor agonist (DOTATOC, Somakit^®), under marketed authorization, and two Prostate Specific Membrane Antigen (PSMA) inhibitors (PSMA-11 and PSMA-617) under nominative temporary authorization of use. The unquestionable success of these radiopharmaceuticals and their uses within diagnostic strategies represent clinical trials carried out using ⁶⁸Ga-DOTATOC and ⁶⁸Ga-PSMA-11 mainly. Today, new indications and new ⁶⁸Ga-radiopharmaceuticals arise to further promote PET/CT molecular imaging. In this article, we would share our experience to establish such clinical trials.     

A new 68Ga-labeled BBN peptide with a hydrophilic linker for GRPR-targeted tumor imaging

Bombesin (BBN) is a peptide exhibiting high affinity for the gastrin-releasing peptide receptor (GRPR), which is overexpressed on several types of cancers. Various GRPR antagonists and agonists have been labeled with radiometals for positron emission tomography (PET) imaging of GRPR-positive tumors. However, unfavorable hepatobiliary excretion such as high intestinal activity may prohibit their clinical utility for imaging abdominal cancer. In this study, the modified BBN peptide with a new hydrophilic linker was labeled with ⁶⁸Ga for PET imaging of GRPR-expressing PC-3 prostate cancer xenograft model. GRPR antagonists, MATBBN (Gly-Gly-Gly-Arg-Asp-Asn-d-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHCH₂CH₃) and ATBBN (d-Phe-Gln-Trp-Ala-Val-Gly-His-Leu-NHCH₂CH₃), were conjugated with 1,4,7-triazacyclononanetriacetic acid (NOTA) and labeled with ⁶⁸Ga. Partition coefficient and in vitro stability were also determined. GRPR binding affinity of both tracers was investigated by competitive radioligand binding assay. The in vivo receptor targeting potential and pharmacokinetic of ⁶⁸Ga-NOTA-MATBBN were also evaluated in PC-3 prostate tumor model and compared with those of ⁶⁸Ga-NOTA-ATBBN. NOTA-conjugated BBN analogs were labeled with ⁶⁸Ga within 20 min with a decay-corrected yield ranging from 90 to 95 % and a radiochemical purity of more than 98 %. The specific activity of ⁶⁸Ga-NOTA-MATBBN and ⁶⁸Ga-NOTA-ATBBN was at least 16.5 and 11.9 GBq/μmol, respectively. The radiotracers were stable in phosphate-buffered saline and human serum. ⁶⁸Ga-NOTA-MATBBN was more hydrophilic than ⁶⁸Ga-NOTA-ATBBN, as indicated by their log P values (?2.73 ± 0.02 vs. ?1.20 ± 0.03). The IC₅₀ values of NOTA-ATBBN and NOTA-MATBBN were similar (102.7 ± 1.18 and 124.6 ± 1.21 nM). The accumulation of ⁶⁸Ga-labeled GRPR antagonists in the subcutaneous PC-3 tumors could be visualized via small animal PET. The tumors were clearly visible, and the tumor uptakes of ⁶⁸Ga-NOTA-MATBBN and ⁶⁸Ga-NOTA-ATBBN were determined to be 4.19 ± 0.32, 4.00 ± 0.41, 2.93 ± 0.35 and 4.70 ± 0.40, 4.10 ± 0.30, 3.14 ± 0.30 %ID/g at 30, 60, and 120 min, respectively. There was considerable accumulation and retention of ⁶⁸Ga-NOTA-ATBBN in the liver and intestines. In contrast, the abdominal area does not have much retention of ⁶⁸Ga-NOTA-MATBBN. Biodistribution data were in accordance with the PET results, showing that ⁶⁸Ga-NOTA-MATBBN had more favorable pharmacokinetics and higher tumor to background ratios than those of ⁶⁸Ga-NOTA-ATBBN. At 1 h postinjection, the tumor to liver and intestine of ⁶⁸Ga-NOTA-MATBBN were 8.05 ± 0.56 and 21.72 ± 3.47 and the corresponding values of unmodified counterpart were 0.85 ± 0.23 and 3.45 ± 0.43, respectively. GRPR binding specificity was demonstrated by reduced tumor uptake of radiolabeled tracers after coinjection of an excess of unlabeled BBN peptides. ⁶⁸Ga-NOTA-MATBBN exhibited GRPR-targeting properties both in vitro and in vivo. The favorable characterizations of ⁶⁸Ga-NOTA-MATBBN such as convenient synthesis, specific GRPR targeting, high tumor uptake, and satisfactory pharmacokinetics warrant its further investigation for clinical cancer imaging.     

Comparison study of [18F]FAl-NOTA-PRGD2, [18F]FPPRGD2, and [68Ga]Ga-NOTA-PRGD2 for PET imaging of U87MG tumors in mice

[(18)F]FPPRGD2, an F-18 labeled dimeric cyclic RGDyK peptide, has favorable properties for PET imaging of angiogenesis by targeting the α(v)β(3) integrin receptor. This radiotracer has been approved by the FDA for use in clinical trials. However, the time-consuming multiple-step synthetic procedure required for its preparation may hinder the widespread usage of this tracer. The recent development of a method using an F-18 fluoride-aluminum complex to radiolabel peptides provides a strategy for simplifying the labeling procedure. On the other hand, the easy-to-prepare [(68)Ga]-labeled NOTA-RGD derivatives have also been reported to have promising properties for imaging α(v)β(3) integrin receptors. The purpose of this study was to prepare [(18)F]FPPRGD2 [corrected] , [(18)F]FAl-NOTA-PRGD2, and [(68)Ga]Ga-NOTA-PRGD2 and to compare their pharmacokinetics and tumor imaging properties using small animal PET. All three compounds showed rapid and high tracer uptake in U87MG tumors with high target-to-background ratios. The uptake in the liver, kidneys, and muscle were similar for all three tracers, and they all showed predominant renal clearance. In conclusion, [(18)F]FAl-NOTA-PRGD2 and [(68)Ga]Ga-NOTA-PRGD2 have imaging properties and pharmacokinetics comparable to those of [(18)F]FPPRGD2. Considering their ease of preparation and good imaging qualities, [(18)F]FAl-NOTA-PRGD2 and [(68)Ga]NOTA-PRGD2 are promising alternatives to [(18)F]FPPRGD2 for PET imaging of tumor α(v)β(3) integrin expression.     

Development of Novel Radiogallium-Labeled Bone Imaging Agents Using Oligo-Aspartic Acid Peptides as Carriers

⁶⁸Ga (T _1/2 = 68 min, a generator-produced nuclide) has great potential as a radionuclide for clinical positron emission tomography (PET). Because poly-glutamic and poly-aspartic acids have high affinity for hydroxyapatite, to develop new bone targeting ⁶⁸Ga-labeled bone imaging agents for PET, we used 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA) as a chelating site and conjugated aspartic acid peptides of varying lengths. Subsequently, we compared Ga complexes, Ga-DOTA-(Asp)_n (n = 2, 5, 8, 11, or 14) with easy-to-handle ⁶⁷Ga, with the previously described ⁶⁷Ga-DOTA complex conjugated bisphosphonate, ⁶⁷Ga-DOTA-Bn-SCN-HBP. After synthesizing DOTA-(Asp)_n by a Fmoc-based solid-phase method, complexes were formed with ⁶⁷Ga, resulting in ⁶⁷Ga-DOTA-(Asp)_n with a radiochemical purity of over 95% after HPLC purification. In hydroxyapatite binding assays, the binding rate of ⁶⁷Ga-DOTA-(Asp)_n increased with the increase in the length of the conjugated aspartate peptide. Moreover, in biodistribution experiments, ⁶⁷Ga-DOTA-(Asp)₈, ⁶⁷Ga-DOTA-(Asp)₁₁, and ⁶⁷Ga-DOTA-(Asp)₁₄ showed high accumulation in bone (10.5±1.5, 15.1±2.6, and 12.8±1.7% ID/g, respectively) but were barely observed in other tissues at 60 min after injection. Although bone accumulation of ⁶⁷Ga-DOTA-(Asp)_n was lower than that of ⁶⁷Ga-DOTA-Bn-SCN-HBP, blood clearance of ⁶⁷Ga-DOTA-(Asp)_n was more rapid. Accordingly, the bone/blood ratios of ⁶⁷Ga-DOTA-(Asp)₁₁ and ⁶⁷Ga-DOTA-(Asp)₁₄ were comparable with those of ⁶⁷Ga-DOTA-Bn-SCN-HBP. In conclusion, these data provide useful insights into the drug design of ⁶⁸Ga-PET tracers for the diagnosis of bone disorders, such as bone metastases.     

Preclinical evaluation of a dual sstr2 and integrin αvβ3-targeted heterodimer [68Ga]-NOTA-3PEG4-TATE-RGD

PurposeMultiple receptors are co-expressed in many types of cancers. Octreotate (TATE) and Arg-Gly-Asp (RGD) peptides target somatostatin receptor 2 (sstr2) and integrin α_vβ₃, respectively. We developed and synthesized a heterodimer NOTA-3PEG₄-TATE-RGD (3PTATE-RGD) and aimed to investigate its characteristics for dual-targeting sstr2 and integrin α_vβ₃.MethodsTATE and RGD peptides and 1,4,7-triazacylononane-N’,N’’,N’’’-triacetic acid (NOTA) were linked through a glutamate and polyethylene glycol (PEG) linker, then 3PTATE-RGD was labeled with ⁶⁸Ga ion. Receptor-binding characteristics and tumor-targeting efficacy were tested in vitro and in vivo using H69 and A549 lung cancer cell lines and tumor-bearing mice models.Results[⁶⁸Ga]-3PTATE-RGD had comparable sstr2 and integrin α_vβ₃-binding affinity with monomeric TATE and RGD in cell uptake and PET imaging study, respectively. In the competition study, H69 and A549 tumor uptake of [⁶⁸Ga]-3PTATE-RGD was completed inhibited in the presence of an excess amount of unlabeled TATE or RGD, respectively. The blocked level didn’t grow when both of TATE and RGD mixture was co-injected with [⁶⁸Ga]-3PTATE-RGD. The pharmacokinetics of [⁶⁸Ga]-3PTATE-RGD is comparable with [⁶⁸Ga]-TATE and [⁶⁸Ga]-RGD, resulting in a larger application.Conclusion[⁶⁸Ga]-3PTATE-RGD showed improved and wider tumor-targeting efficacy compared with monomeric TATE and RGD peptides, which warrants its further investigation in detection both of sstr2 and integrin α_vβ₃-related carcinomas.     

Y a t-il encore de la place pour la scintigraphie conventionnelle aux récepteurs de la somatostatine dans les tumeurs carcinoïdes à l’ère de la TEP ?

Our aim is to discuss, based on literature data, whether or not there is still a place for conventional somatostatin receptor scintigraphy (C-SRS) in the exploration of carcinoid tumours (CT) in the era of PET.MethodsBibliography was obtained by an interrogation of database: PubMed and Cochrane for the last 10 years. Keywords used were “neuroendocrine tumors”, “carcinoid tumors”, “pentetreotide”, “somatostatin”, “gallium-68” and “indium-111”.ResultsC-SRS visualized local or distant metastasis, with a sensitivity reaching 90% when size lesion is greater than 1 cm. It was more sensitive than morphologic exams in the detection of the primary lesion as well as the metastases and recurrent lesions. C-SRS had modified the therapeutic strategy in 21 to 53% of patients. It had determined resecability criteria and had predicted somatostatin analogue treatment efficiency. Furthermore, C-SRS was very useful in the follow-up of these tumours, mainly in the early detection of postoperative residues and recurrence. Recently, ⁶⁸Ga-DOTA-TOC PET had been used in some centers. According to many authors, it was superior to C-SRS for the detection of CT localization in the lung and skeleton and was similar for the detection of CT localization in liver and brain. According to these authors, ⁶⁸Ga-DOTA-TOC PET had evidenced lesions than C-SRS; nevertheless, there is always a global similar sensitivity in carcinoid tumours.Conclusion⁶⁸Ga-DOTA-TOC PET is surely more advantageous in guiding clinical management and follow-up, yet this imaging modality is expensive and not widespread. Nevertheless, C-SRS, which is cheaper, is an accurate technique in carcinoid tumours. Furthermore, if C-SRS proves negative, ⁶⁸Ga-DOTA-TOC PET should be indicated.     

Gallium-68 : considérations pratiques pour le succès des applications cliniques au sein d’un service de médecine nucléaire

Gallium-68 is a radionuclide, which has, because of its favorable physical characteristics similar to those of fluorine-18, gained a great interest for labeling PET tracers. Furthermore, it is available onsite at the radiopharmacy, by elution of a ⁶⁸Ge/⁶⁸Ga generator that has a shelf life of around one year, which approximates the versatility of 99mTc in the labeling of tracers for scintigraphy. After a brief historical overview, this article lists the necessary equipment and components, and the choices to be made (currently and in the near future) to implement, in a radiopharmacy, ⁶⁸Ga-labelling of PET tracers for a nuclear medicine department.     

Positron emission tomography imaging of prostate cancer

Prostate cancer (PCa) is the second leading cause of cancer death among men in the United States. Positron emission tomography (PET), a non-invasive, sensitive, and quantitative imaging technique, can facilitate personalized management of PCa patients. There are two critical needs for PET imaging of PCa, early detection of primary lesions and accurate imaging of PCa bone metastasis, the predominant cause of death in PCa. Because the most widely used PET tracer in the clinic, ¹⁸F-fluoro-2-deoxy-2-d-glucose (¹⁸F-FDG), does not meet these needs, a wide variety of PET tracers have been developed for PCa imaging that span an enormous size range from small molecules to intact antibodies. In this review, we will first summarize small-molecule-based PET tracers for PCa imaging, which measure certain biological events, such as cell membrane metabolism, fatty acid synthesis, and receptor expression. Next, we will discuss radiolabeled amino acid derivatives (e.g. methionine, leucine, tryptophan, and cysteine analogs), which are primarily based on the increased amino acid transport of PCa cells. Peptide-based tracers for PET imaging of PCa, mostly based on the bombesin peptide and its derivatives which bind to the gastrin-releasing peptide receptor, will then be presented in detail. We will also cover radiolabeled antibodies and antibody fragments (e.g. diabodies and minibodies) for PET imaging of PCa, targeting integrin α_vβ₃, EphA2, the epidermal growth factor receptor, or the prostate stem cell antigen. Lastly, we will identify future directions for the development of novel PET tracers for PCa imaging, which may eventually lead to personalized management of PCa patients.     

From scinti-mammography and metabolic imaging to receptor targeted PET-new principles of breast cancer detection

Early detection of breast cancer is a prerequisite for treatment success and improvement of survival. In tumors under 10mm diameter the standard morphological methods of imaging such as sonography, mammography and MRI imaging are of lesser specificity and loose sensitivity. Under 5mm detection of breast cancer remains a chalenge.Since recent years scinti-mammography using perfusion weighted enrichment of 99m-Tc-MIBI for imaging has become a standard technique indetection of breast cancer. It is superior when ever small lesions with increased perfusion are to be expected. it is used specially in dense breast patients. Other functional methods such as F-18-FDG-PET, C-11-Methionine-PET and the use of Ga-68-Somatostatin- or Ga-68-Bombesin-PET have been discussed for the early detection and therapy control of breast cancer patents. Especially the high specific low background receptor-PET imaging exels over the standard methods because of its ability to detect lesions even below 2 mm, as it has been shown for the Ga-68-DOTA-somatostatins. Because simple exchange of the diagnostic PET isotope against a therapeutical isotope like Lu-177, Y-90, Ga-67 or Cu-67 the receptor PET is directly linked to radio-peptide therapy.As the studies of J. C. Reubi et alii have been shown several peptide receptors are expressed in breast cancer, like the sms receptors and the gastrin releasing peptide receptors (bombesin receptors). One of the most widely expressed receptors expressed in breast cancer, which tends to be relatively selective, is NPY1 receptor. Intensive work had been done on the development of peptide ligands by A. Beck-Sicklinger and her group. These new developed peptides are very promising in combination with somatostatin and bombesin derivatives. Dedicated breast pet devices in combination with these high specific tracers have great potential to open and entire new quality in early detection of breast cancer and may lead to its radiopeptide therapy.     

Synthesis and evaluation of macrocyclic amino acid derivatives for tumor imaging by gallium-68 positron emission tomography

(68)Ga PET imaging in clinical oncology represents a notable development because the availability of (68)Ga is not dependent on a cyclotron. Furthermore, labeled amino acid derivatives have been proven to be useful for the imaging many tumor types. In the present study, we synthesized β-aminoalanine, γ-aminohomoalanine, and lysine conjugates of macrocyclic bifunctional chelating agents, such as, NOTA (1a-c) and DOTA (2a-c). The compounds produced were found to be potential useful as (68)Ga-PET imaging agents. In particular, they showed high tumor uptakes in vitro and in vivo, and had high labeling yields and excellent stabilities. The co-ordination chemistry of NOTA-monoamide compound 1a was studied by multinuclear NMR. In vitro studies showed that the synthesized compounds were taken up by cancer cells more than controls ((68)Ga-NOTA and (68)Ga-DOTA). Furthermore, in vivo studies showed that they have high tumor to muscle and tumor to blood ratios, and small-animal PET imaging revealed high tumor uptakes as compared with other organs, and high bladder activities, indicating rapid renal excretion. These results might motivate the use of (68)Ga amino acid PET for tumor diagnosis.     

Ciblage des récepteurs de la somatostatine dans les tumeurs neuroendocrines gastroentéropancréatiques (TNE-GEP) : quels radiotraceurs pour quelles tumeurs ?

Topographic and functional imaging hold a key position in endocrine oncology. In vivo somatostatin receptor scintigraphy using Indium-111 labeled DTPA-octreotide, a tracer with preferential affinity for the somatostatin receptor subtype 2 (sst2), is the gold-standard for initial diagnosis of gastroenteropancreatic neuroendocrine tumours (GEPNETs). Due to the detection limits of scintigraphy, other metabolic imaging modalities are required. Positron emission topography (PET) offers whole body scanning, facilitates tumour localization, and assesses the metastasis statement of the tumour. ¹⁸F-FDG is the most frequent radiotracer used in clinical practice because of its availability, but its interest is demonstrated only in undifferentiated GEPNETs. More recently, ¹⁸F-DOPA PET showed a high sensitivity in particular in carcinoid tumours detection. PET using different ⁶⁸Ga-labeled-somatostatin analogs with high affinity for sst2 displayed better results than SRS in GEPNETs primary tumour and metastasis detection, especially when fusion with TDM images was performed. Using similar metabolic targets, peptide receptor radionuclide therapy (PRRT) with ¹⁷⁷Lu-octreotate and ⁹⁰Y-DOTA-TOC, is indicated in disseminated GEPNETs forms with an efficiency of 30 % and a minor toxicity.     

Preclinical evaluation of a CXCR4-specific 68Ga-labelled TN14003 derivative for cancer PET imaging

Molecular imaging is an ideal platform for non-invasive detection and assessment of cancer. In recent years, the targeted imaging of CXCR4, a chemokine receptor that has been associated with tumour metastasis, has become an area of intensive research. In our pursuit of a CXCR4-specific radiotracer, we designed and synthesised a novel derivative of the CXCR4 peptidic antagonist TN14003, CCIC16, which is amenable to radiolabelling by chelation with a range of PET and SPECT radiometals, such as ⁶⁸Ga, ⁶⁴Cu and ¹¹¹In as well as ¹⁸F (Al¹⁸F). Potent in vitro binding affinity and inhibition of signalling-dependent cell migration by unlabelled CCIC16 were confirmed by a threefold uptake in CXCR4-over-expressing cells compared to their isogenic counterparts. Furthermore, in vivo experiments demonstrated the favourable pharmacokinetic properties of the ⁶⁸Ga-labelled tracer ⁶⁸Ga–CCIC16, along with its CXCR4-specific accumulation in tissues with desirable contrast (tumour-to-muscle ratio: 9.5). The specificity of our tracer was confirmed by blocking experiments. Taking into account the attractive intrinsic PET imaging properties of ⁶⁸Ga, the comprehensive preclinical evaluation presented here suggests that ⁶⁸Ga–CCIC16 is a promising PET tracer for the specific imaging of CXCR4-expressing tumours.     

Biases in Multicenter Longitudinal PET Standardized Uptake Value Measurements

This study investigates measurement biases in longitudinal positron-emission tomography/computed tomography (PET/CT) studies that are due to instrumentation variability including human error. Improved estimation of variability between patient scans is of particular importance for assessing response to therapy and multicenter trials. We used National Institute of Standards and Technology-traceable calibration methodology for solid germanium-68/gallium-68 (⁶⁸Ge/⁶⁸Ga) sources used as surrogates for fluorine-18 (¹⁸F) in radionuclide activity calibrators. One cross-calibration kit was constructed for both dose calibrators and PET scanners using the same 9-month half-life batch of ⁶⁸Ge/⁶⁸Ga in epoxy. Repeat measurements occurred in a local network of PET imaging sites to assess standardized uptake value (SUV) errors over time for six dose calibrators from two major manufacturers and for six PET/CT scanners from three major manufacturers. Bias in activity measures by dose calibrators ranged from -50% to 9% and was relatively stable over time except at one site that modified settings between measurements. Bias in activity concentration measures by PET scanners ranged from -27% to 13% with a median of 174 days between the six repeat scans (range, 29 to 226 days). Corresponding errors in SUV measurements ranged from -20% to 47%. SUV biases were not stable over time with longitudinal differences for individual scanners ranging from -11% to 59%. Bias in SUV measurements varied over time and between scanner sites. These results suggest that attention should be paid to PET scanner calibration for longitudinal studies and use of dose calibrator and scanner cross-calibration kits could be helpful for quality assurance and control.     

68Ga-DOTA and analogs: Current status and future perspectives

The construction of the ⁶⁸Ge/⁶⁸Ga generator has increased application of radiopharmaceuticals labeled with this isotope in medicine. ⁶⁸Ga-PET is widely employed in the management of neuroendocrine tumors but favorable chemistry with tri- and tetraaza-ring molecules has opened wide range of ⁶⁸Ga application in other fields of PET imaging. This review covers the radiopharmaceuticals labeled with gallium in molecular imaging and shows perspectives on the use of gallium-68 as a substitute for technetium-99, fluorine-18 and carbon-11 in some applications.     

Development and characterization of a 68Ga-labeled A20FMDV2 peptide probe for the PET imaging of αvβ6 integrin-positive pancreatic ductal adenocarcinoma

Pancreatic ductal adenocarcinoma (PDAC) is known to be one of the most lethal cancers. Since the majority of patients are diagnosed at an advanced stage, development of a detection method for PDAC at an earlier stage of disease progression is strongly desirable. Integrin α_Vβ6 is a promising target for early PDAC detection because its expression increases during precancerous changes. The present study aimed to develop an imaging probe for positron emission tomography (PET) which targets α_Vβ6 integrin-positive PDAC. We selected A20FMDV2 peptide, which binds specifically to αvβ6 integrin, as a probe scaffold, and ⁶⁸Ga as a radioisotope. A20FMDV2 peptide has not been previously labeled with ⁶⁸Ga. A cysteine residue was introduced to the N-terminus of the probe at a site-specific conjugation of maleimide-NOTA (mal-NOTA) chelate. Different numbers of glycine residues were also introduced between cysteine and the A20FMDV2 sequence as a spacer in order to reduce the steric hindrance of the mal-NOTA on the binding probe to αVβ6 integrin. In vitro, the competitive binding assay revealed that probes containing a 6-glycine linker ([^natGa]CG6 and [^natGa]Ac-CG6) showed high affinity to αVβ6 integrin. Both probes could be labeled by ^67/68Ga with high radiochemical yield (>50%) and purity (>98%). On biodistribution analysis, [⁶⁷Ga]Ac-CG6 showed higher tumor accumulation, faster blood clearance, and lower accumulation in the surrounding organs of pancreas than did [⁶⁷Ga]CG6. The α_Vβ6 integrin-positive xenografts were clearly visualized by PET imaging with [⁶⁸Ga]Ac-CG6. The intratumoral distribution of [⁶⁸Ga]Ac-CG6 coincided with the α_Vβ6 integrin-positive regions detected by immunohistochemistry. Thus, [⁶⁸Ga]Ac-CG6 is a useful peptide probe for the imaging of α_Vβ6 integrin in PDAC.     

Préparation et contrôle de qualité de la solution injectable de gallium-68 édotréotide (DOTATOC (68Ga))

Radiopharmacists of the Nuclear Medicine department of hospital Tenon have prepared and controlled the ⁶⁸Ga-labeled DOTATOC, for 4 years, as part of a clinical research study. The aim of this article is to share our experience, since this activity is not yet developed in France. Radiolabelling of DOTATOC (⁶⁸Ga) requires the settling of a ⁶⁸Ge/⁶⁸Ga generator, which is connected to an automated PC-controlled radiopharmaceutical labelling device (Elusynth ⁶⁸Ga, Iason) and comprises several steps. Performed quality controls (QC) are those commonly used for radiopharmaceuticals including: appearance, pH, radiochemical purity (RCP), radionuclide purity (PRN) and determination of the physical half-life. Bacterial endotoxins and sterility tests are systematically done. We obtained a mean value of radiolabelling yield around 45%. The results of QC are always in accordance with the specifications. The preparation failed in 7% of the 195 DOTATOC (⁶⁸Ga), over the last 4 years. It is important to note that the preparation of DOTATOC (⁶⁸Ga) monopolizes the radiopharmacist during 3 hours. This radiolabelling technique can be easily applied to other peptides, in order to develop other ⁶⁸Ga-labelled PET tracers.     

Multicenter study of quantitative PET system harmonization using NIST-traceable 68Ge/68Ga cross-calibration kit

PurposeThe present study aimed to define the errors in SUV and demonstrate the feasibility of SUV harmonization among contemporary PET/CT scanners using a novel National Institute of Standards and Technology (NIST)-traceable ⁶⁸Ge/⁶⁸Ga source as the reference standard.MethodsWe used ⁶⁸Ge/⁶⁸Ga dose calibrator and PET sources made with same batch of ⁶⁸Ge/⁶⁸Ga embedded in epoxy that is traceable to the NIST standard. Bias in the amount of radioactivity and the radioactive concentrations measured by the dose calibrators and PET/CT scanners, respectively, was determined at five Japanese sites. We adjusted optimal dial setting of the dose calibrators and PET reconstruction parameters to close the actual amount of radioactivity and the radioactive concentration, respectively, of the NIST-traceable ⁶⁸Ge/⁶⁸Ga sources to harmonize SUV. Errors in SUV before and after harmonization were then calculated at each site.ResultsThe average bias in the amount of radioactivity and the radioactive concentrations measured by dose calibrator and PET scanner was −4.94% and −12.22%, respectively, before, and −0.14% and −4.81%, respectively, after harmonization. Corresponding averaged errors in SUV measured under clinical conditions were underestimated by 7.66%, but improved by −4.70% under optimal conditions.ConclusionOur proposed method using an NIST-traceable ⁶⁸Ge/⁶⁸Ga source identified bias in values obtained using dose calibrators and PET scanners, and reduced SUV variability to within 5% across different models of PET scanners at five sites. Our protocol using a standard source has considerable potential for harmonizing the SUV when contemporary PET scanners are involved in multicenter studies.