Current Radiopharmaceuticals - Volume 10, Issue 2, 2017

Although Somastostatin (SS) scintigraphy (SRS) has been introduced many years ago, it remains the most diffuse radionuclide diagnostic tool in patients with neuroendocrine tumours (NETs). Being SS receptors (SSTR) expressed in the majority of NETs, radiolabeled SS analogues (SS-A) provide high diagnostic accuracy, mainly in patients with gastro-entero-pancreatic (GEP) tumors. SSTR are the best target for radiotracers used either for diagnostic and therapeutic purposes in NETs due to their presence on the surface of neoplastic cells of clinical interest. 111 In- DTPA-octreotide (111In-Pentetreotide, Octreoscan®), may detect either primitive or secondary lesions in the presence of a satisfactory lesion/background ratio. The unsatisfactory diagnostic performance of 18F-Fluorodeoxyglucose (18), in NETs stimulated the synthesis of more specific positron-emitting tracers and SS-A labeled with 68 Gallium (DOTA-peptides) represent actually the best radionuclide procedure for NET imaging. Alternative radiotracers, labeled either with gamma or positron emitters and showing different uptake mechanisms, as 18F-DOPA (Fluorine- 18-L-dihydroxyphenylalanine), have also been proposed and clinically utilized. Octreoscan ®, despite its limitations, continue to represent the most frequently used method in evaluating the response to treatment and in follow-up of patients with NET, although the better diagnostic accuracy of DOTA-peptides.

Background and Objective: Breathing movement can introduce heavy bias in both image quality and quantitation in PET/CT. The aim of this paper is a review of the literature to evaluate the benefit of respiratory gating in terms of image quality, quantification and lesion detectability. Methods: A review of the literature published in the last 10 years and dealing with gated PET/CT technique has been performed, focusing on improvement in quantification, lesion detectability and diagnostic accuracy in neoplastic lesion. In addition, the improvement in the definition of radiotherapy planning has been evaluated. Results: There is a consistent increase of the Standardized Uptake Value (SUV) in gated PET images when compared to ungated ones, particularly for lesions located in liver and in lung. Respiratory gating can also increase sensitivity, specificity and accuracy of PET/CT. Gated PET/CT can be used for radiation therapy planning, reducing the uncertainty in target definition, optimizing the volume to be treated and reducing the possibility of “missing” during the dose delivery. Moreover, new technologies, able to define the movement of lesions and organs directly from the PET sinogram, can solve some problems that currently are limiting the clinical use of gated PET/CT (i.e.: extended acquisition time, radiation exposure). Conclusion: The published literature demonstrated that respiratory gating PET/CT is a valid technique to improve quantification, lesion detectability of lung and liver tumors and can better define the radiotherapy planning of moving lesions and organs. If new technical improvements for motion compensation will be clinically validated, gated technique could be applied routinely in any PET/CT scan.

Background: 1-α-D-(5-Deoxy-5-[¹⁸F]fluoroarabinofuranosyl)-2-nitroimidazole([¹⁸F] FAZA) is a PET radiotracer that demonstrates excellent potential in imaging regional hypoxia, and is clinically used in diagnosing a wide range of solid tumors in cancer patients. [¹⁸F]FAZA, however, is radiofluorinated in only moderate recovered radiochemical yield (rRCY, ~12%). It is postulated that the relative stability of the C1' β-anomeric bond at C5' will make 1-β-D-(5-fluoro-5-deoxyarabinofuranosyl)-2-nitroimidazole (β-FAZA), the β-conformer of FAZA, an attractive candidate for clinical hypoxia imaging. Objectives: The principle goals were to synthesize β-FAZA and β-Ac2TsAZA, the radiofluorination precursor, to establish the radiofluorination chemistry leading toβ-[¹⁸F]FAZA, and to investigate the biodistribution of β-[¹⁸F]FAZA in an animal tumor-bearing model using PET imaging. Methods: The appropriately-protected furanose sugar was coupled with 2-nitroimidazole to afford 1-β-D-(2,3-di-O-acetylarabinofuranosyl)-2-nitroimidazole (β-Ac2AZA). Fluorination of β-Ac2AZA with DAST, followed by alkaline hydrolysis, afforded β-FAZA (21%). The radiolabeling synthon, 1-β-D-(5-O-toluenesulfonyl-2,3-di-O-acetylarabinofuranosyl)-2-nitroimidazole (β-Ac2TsAZA), on radiofluorination using the ¹⁸F/K222 complex under various reaction conditions, followed by base-catalyzed deacetylation, afforded β-[¹⁸F]FAZA. β-[¹⁸F]FAZA was radiochemically stable for at least 8 h when stored in aqueous ethanol (8%) at 22 °C. A preliminary PET imaging-based biodistribution study of β-[¹⁸F]FAZA was performed in A431 tumor-bearing nude mice. Results: β-FAZA and β-Ac2TsAZA were synthesized in satisfactory yield. Radiochemistry of [¹⁸F]FAZA was established. PET images showed strong uptake in hypoxic regions of the tumor. Conclusion:The synthesis of β-FAZA and β-[18F]FAZA are reported. Radiofluorination of β-Ac2TsAZA and the deprotection of β-Ac2[18F]FAZA were facile, but led to a more complex mixture of radiofluorinated by-products than observed with the corresponding precursor of β-[18F]FAZA. PET images were indicative of hypoxia-selective accumulation of β-[18F]FAZA in tumor.>

Objective: To evaluate the predictive value of FDG-PET/CT parameters on outcome of oropharyngeal squamocellular cancer (OSCC) patients undergoing helical tomotherapy (HTT), with dose escalation to FDG-PET/CT positive tumour volumes using the simultaneous integrated boost (SIB) technique. Materials and Methods: We analysed 41 patients studied by FDG-PET/CT and treated with radical intent between 2005 and 2014 for OSCC. HTT-SIB was delivered in 30 fractions concomitantly: 69 Gy, as SIB, to the PET-positive volume (biological target volume – BTV-PET), both to the primary tumour (T) and lymph nodes (N), 66 Gy to the T and positive N, 54 Gy to the laterocervical nodes at risk. Selected PET parameters were recovered: maximum and mean standardized uptake values (SUVmax and SUVmean, respectively), metabolic tumour volume (MTV) and total lesion glycolysis (TLG) obtained with different thresholds (40-50-60% of the SUVmax) for T and N. The correlation between these parameters and the 3-year overall (OS), cancer specific (CSS), disease free (DFS), local relapse free for T and N (LRFS-T and LRFS-N) and distant metastasis free (DMFS) survivals was investigated. Results: The median follow-up was 37 months (range: 3-125). The 3-year OS, CSS, DFS, LRFST, LRFS-N and DMFS were 86%, 88%, 76%, 83%, 88% and 91%, respectively. BTVT+ N>30.9cc and BTV-T>22.4cc were correlated with CSS (p=0.02) and OS (p=0.006) respectively;vTLG-T-60>34.6cc was correlated with CSS (p=0.04) and OS (p=0.01). MTV-T-60>4.4cc could predict a higher risk of relapse/death (CSS: p=0.033; hazard ratio (HR) =10.92; OS: p=0.01; HR=16.4; LRFS-T: p=0.02; HR=13.90; LRFS-T+N: p=0.03; HR=6.50). Conclusion: PET parameters predicted survival outcomes and may be considered in the future in the implementation of more personalized treatment schedules in patients affected by OSCC undergoing radiotherapy. FDG-PET/CT dose escalated HTT-SIB allowed very promising 3-year disease control rates in OSCC patients.

Background: Ultrasound or stereotactic guided hook-wire localisation has been the standard-of-care for the pre-surgical localisation of impalpable breast lesions, which account for approximately a third of all breast cancer. Radioguided occult lesion localisation using I-125 seeds (ROLLIS) is a relatively new technique for guiding surgical excision of impalpable breast lesions, and is a promising alternative to the traditional hook-wire method. When combined with Tc-99m labelled colloid for sentinel node mapping in clinically indicated cases, there has been uncertainty regarding whether the downscatter of Tc-99m into the I-125 energy spectrum could adversely affect the intra-operative detection of the I-125 seed, especially pertaining to a peritumoral injection. Objective: To evaluate the percentage contribution of downscattered activity from Tc-99m into the I-125 energy spectrum in simulated intra-operative resections of an I-125 seed following different sentinel node injection techniques. Method: Two scenarios were simulated using breast phantoms with lean chicken breast. The first scenario, with a 2cm distance between the Tc-99m injection site and the I-125 seed, simulated a periareolar ipsiquadrant injection with the subdermal or intradermal technique. The second scenario simulated a peritumoral injection technique with the Tc-99m bolus and an I-125 seed at the same site. Count rates were acquired with a hand-held gamma probe, and the percentage contribution of downscattered Tc-99m gamma photons to the I-125 energy window was calculated. Results: In scenarios one and two, downscattered Tc-99m activity contributed 0.5% and 33% respectively to the detected count rate in the I-125 energy window. In both scenarios, the I-125 seed was successfully localised and removed using the gamma probe. Conclusion: There is no significant contribution of downscattered activity associated with a peritumoral injection of Tc-99m to adversely affect the accurate intra-operative localisation of an I-125 seed.

Background and Objective: In a security ward we assessed the diagnostic contribution of single photon scintigraphy [SPECT] in our diagnostic pathway for patients with serious mental disease and a history of violence. Methods: Twenty patients were examined between 2012 and 2015 and the findings compared to those in nine patients with the same diagnosis, but no history of violence. Results: All violent patients had areas with reduced accumulation of 99mTc-HMPAO frontally and in the temporal lobe, in the non-violent group only two patients demonstrated these findings. Conclusion: Traditionally, low accumulation of the tracer in SPECT is related to reduced perfusion of brain tissue. We discuss our findings in the light of other possible pathophysiological mechanisms.

Background: D4 small peptide (Leu-Ala-Arg-Leu-Leu-Thr) was selected as an appropriate agent for specific targeting of epidermal growth factor receptor (EGFR). Objective: The aim of study was to investigate the ^99mTc-labeled D4 peptide for non-small cell lung tumor targeting. Method: HYNIC-(Ser)3-D4 peptide was labeled with ^99mTc using mixture of tricine and ethylenediamine diacetic acid (EDDA) as co-ligands. The in vitro cellular uptake of radiolabeled peptide was evaluated by blocking test on human non-small cell lung cancer (A-549) cell line and its biodistribution was evaluated in A-549 xenografted nude mice. Results: This conjugated peptide was labeled with 99mTc in high radiochemical purity and it was highly stable in buffer and serum. The un-blocked to blocked cellular radioactivity ratio was 4-fold that showed a specific binding of this radiolabeled peptide on A-549 cell. Animal biodistribution in A-549 xenografted nude mice showed rapid clearance from blood and other non-target organs. Tumor uptake values as %ID/g (percentage of injection dose per gram of tissue) were 2.47% and 1.30% at 1 and 4 h after injection. Conclusion: This study showed the ^99mTc-EDDA/tricine-HYNIC-(Ser)3-D4 peptide had tumor targeting on the non-small cell lung tumor.

The aim of this work was to assess the influence of treatment with U-Caspofungin, on the quality of diagnostic scintigraphic images of induced lesions in nude mice undergoing both bacterial and fungal infections and to determine the level of specificity of 99mTc-tricarbonyl-Caspofungin to discriminate between fungal or bacterial infections. In vitro studies on the behaviour of the 99mTc-tricarbonyl-Caspofungin complex binding percentage at different yeast concentrations of Candida albicans or Staphyolococcus aureus were determined. The incubation was performed with and without U-Caspofungin. In vivo evaluation was performed of 6 groups of athymic mice: sham, inflammation (LPS), fungal infection with Candida albicans (CA) and bacterial infection with Staphylocuccus aureus (SA). In vitro studies showed that the uptake of the complex by both yeasts and bacteria, depends on the concentration of colony forming units (cfu), and that this uptake is favoured by the presence of UCaspofungin that increases the membrane permeability to the 99mTc-tricarbonyl-Caspofungin complex. In vivo evaluation showed low uptake in sterile inflammation model and moderate to high uptake in infections models both treated or not with U-Caspofungin. The results of biodistributions were compatible with scintigraphic images. Conclusion: The uptake of the complex depends on the load of microorganisms, but it presents high sensibility, even at low concentrations of the infecting agent. The treatment with U-Caspofungin has no influence on the quality of the scintigraphic images used for diagnosis and localization of infection foci.

Background: Labeled RGD peptide that specifically targets ανβ3 integrin has great potential for the early diagnosis of malignant tumors.αvβ3 integrin receptors appear specifically more on the surface of glioblastoma (malignant glioma) cells rather than normal cells. Objective: The aim of this study was to identify a novel RGD that can be radiolabeled with 99mTc with in vitro assessment of its targeting ability for U87MG human brain cancer cells. Method: Novel RGD was designed by Amino Acid retro-inversion technique. The peptide HYNIC conjugate was radiolabeled with 99mTc at 95°C for 10 min and radiochemical analysis was performed using ITLC and HPLC methods. The stability of the radiopeptide was checked in the presence of human serum at 37°C up to 24 h. Binding properties and internalization were studied with U87MG cells. Results: Novel HYNIC-RGD has shown high radiochemical purity over 98%. Radioconjugate binding and internalization in U87MG cells were high and specific (13.96% and 12.38% at 4 h respectively). The radiolabeled peptide revealed good affinity for glioblastoma cells (Kd=1.46± 0.26nM). Conclusion: The in vitro study demonstrated the targeting ability of novel 99mTc-HYNIC-RGD for glioblastoma cells. Therefore, more in vivo studies are required.