Current Radiopharmaceuticals - Volume 4, Issue 2, 2011

Molecular imaging, in particular positron emission tomography (PET), plays pivotal roles in 21st century personalized medicine. PET has been used in the clinic for decades and 18F-FDG has become indispensible in many facets of patient management, such as cancer staging and treatment monitoring. Commonly used PET tracers are typically labeled with 15O (t1/2: 122.2 s), 13N (t1/2: 10.0 min), 11C (t1/2: 20.4 min), or 18F (t1/2: 109.7 min). Driven by the ever-increasing availability of preclinical/ clinical PET scanners and radioisotopes, research on nonstandard PET nuclides has flourished over the last decade. Since the abovementioned four standard radionuclides all have relatively short half-lives, a wide variety of nonstandard radionuclides (typically with half-lives in the order of hours to days) have been explored for labeling larger molecules to interrogate a variety of biological events through PET imaging. This special issue of Current Radiopharmaceuticals is focused on the PET tracers based on nonstandard radionuclides. In the first article of this issue, Dr. Tolmachev gave a comprehensive overview on the use of two positron-emitting isotopes of bromine, 75Br (t1/2: 96.7 min) and 76Br (t1/2: 16.2 h), for PET imaging applications. Next, Dr. Wuest and co-workers provided a thorough survey on applications of 94mTc-based PET, where the production/processing of 94mTc (t1/2: 52.5 min) and its coordination chemistry were both described in detail. Dr. Nickles and co-workers discussed in depth about the unrealized potential of 34mCl (t1/2: 32.2 min) for PET imaging. Recent improvements in accelerator targetry have made radiochlorine available from small cyclotrons, which can be used for the synthesis of novel imaging probes through both electrophilic and nucleophilic avenues. In the next review, Dr. Sun and co-workers summarized the recent advances in copper radiopharmaceuticals, which are composed of five radioisotopes: 60Cu (t1/2: 23.7 min), 61Cu (t1/2: 3.4 h), 62Cu (t1/2: 9.9 min), 64Cu (t1/2: 12.7 h), and 67Cu (t1/2: 2.6 d). Due to the availability and production cost, the research efforts in copper radiopharmaceuticals are mainly focused on the use of 64Cu, which has low positron energy thus is ideal for PET imaging quantification. The article by Dr. Liu and co-workers is an excellent summary on 86Y (t1/2: 14.7 h)-based PET tracers, which have gained increasing attention since they are ideal surrogates for in vivo determination of biodistribution and dosimetry of therapeutic 90Y (pure β emitter; t1/2: 2.7 d)-based radiopharmaceuticals. Lastly, the current status of PET imaging with 89Zr (t1/2: 3.3 d) was described by Dr. Cai and co-workers. With decay half-life well matched to the circulation half-lives of antibodies, 89Zr has been extensively studied over the last decade and successful pilot studies in cancer patients have already been reported. Initially, I intended to also cover a few other nonstandard radionuclides in this special issue, such as 55Co (t1/2: 17.5 h), 68Ga (t1/2: 67.7 min), 82Rb (t1/2: 75.0 s), 124I (t1/2: 4.2 d), arsenic isotopes, among others. However, many of the experts that were invited were not able to contribute due to their tight schedule and various other commitments. With more and more promising PET tracers being developed using nonstandard radionuclides, clinical translation is key. Over the last decade, the field of molecular imaging has witnessed tremendous expansion. The next decade of the 21st century will likely see more and more nonstandard radionuclide-based PET tracers enter clinical trials and benefit cancer patients, which will usher in a brand new era of PET imaging beyond 18F-FDG.

The use of positron emission tomography (PET) for radionuclide imaging provides better sensitivity, better spatial and temporal resolution and better quantification accuracy in comparison with single photon emission computed tomography (SPECT). One limitation of PET is the predominant use of short-lived (with half-life up to 2 h) radionuclides. Extension of PET utility might be achieved by the use of more long-lived, “non-conventional” positron emitters. Two positron-emitting isotopes of bromine, 75Br (T1/2 = 96.7 min) and 76Br (T1/2 = 16.2 h), can be considered as labels for targeting proteins and peptides, and for small molecules, which have an optimal imaging time outside the time frame provided by conventional biogenic positron emitters. Variety of tracers might be labelled by electrophilic bromination of activated phenolic rings, electrophilic bromodestannylation and halogen exchange. A major problem is that in vivo metabolism of tracers might lead to formation of radiobromide as a main radiocatabolite. Radiobromide is very slowly excreted, and is distributed in the extracellular space creating high background. Careful tracer design optimisation is required to avoid this obstacle in the introduction of bromine isotopes into PET practice.

This review gives a survey on the use and applications of technetium-94m (94mTc) as a non-conventional positron emission tomography (PET) radionuclide for molecular imaging. The first part of this review describes the production and processing of 94mTc. The second part covers basic concepts of technetium coordination chemistry with a special focus on the synthesis of 94mTc-labeled compounds for molecular imaging purposes. The review concludes with a summary and an outlook on the prospects of using 94mTc in the field of PET chemistry and molecular imaging.

The unstable isotopes of chlorine have a brief history limited largely to production from sulphur isotopes. Recent improvements in accelerator targetry have made radiochlorine available from small cyclotrons, and concurrent research into labeling chemistry suggests both electrophilic and nucleophilic avenues for the synthesis of novel imaging probes. The prevalence of chlorine compounds from anthropogenic and natural sources offers varied and fertile ground for future scientific explanation with their radiolabeled counterparts.

Copper has five radioisotopes (60Cu, 61Cu, 62Cu, 64Cu, and 67Cu) that can be used in copper radiopharmaceuticals. These radioisotopes decay by mixed emissions of β+, β-, and γ with a wide range of half-lives from 9.74 min (62Cu) to 2.58 d (67Cu), which enable the design and synthesis of a variety of radiopharmaceuticals for different biomedical applications in diagnostic and therapeutic nuclear medicine. However, due to the availability and production cost, the research efforts in copper radiopharmaceuticals are mainly focused on the use of 64Cu (t1/2 = 12.7 h; 17.4% β+, 43% EC, 39% β-), a radioisotope with low positron energy (E β+max = 0.656 MeV) that is ideal for positron emission tomography (PET) imaging quantification and β- emissions along with Auger electron for radiotherapy. Driven by the ever-increasing availability of preclinical and clinical PET scanners, a considerable interest has been seen in the development of novel copper radiopharmaceuticals in the past decade for a variety of diseases as represented by PET imaging of cancer. To avoid unnecessary literature redundancy, this review focuses on the unrepresented research aspects of copper chemistry (e.g. electrochemistry) and their uses in the evaluation of novel nuclear imaging probe design and recent advances in the field towards the practical use of copper radiopharmaceuticals.

Positron emission tomography (PET) has become a powerful tool for probing biochemical processes in living subjects. PET imaging depends largely on the development of novel PET tracers labeled with positron-emitting radionuclides. Since the four traditional PET isotopes (18F, 11C, 13N, and 15O) are produced in a cyclotron and are short-lived, their use for long-term observation of biological processes in vivo is limited. In the last decades, extensive research in the development of other unconventional radionuclides (such as 64Cu, 68Ga, 89Zr, 86Y, and 124I) labeled tracers with half-lives complementary to the biological properties of their targeting agents has been conducted. Among these tracers, 86Y-based PET tracers have gained increasing attention since they are ideal surrogates for in vivo determination of biodistribution and dosimetry of therapeutic 90Y (pure β- emitter) pharmaceuticals. In this review article, we will brief introduce the physical characteristics, production, and radiochemistry of 86Y, and will summarize the current 86Y-based PET tracers used for molecular imaging and cancer detection in animal studies and in clinical trials.

Positron emission tomography (PET) imaging with radiolabeled monoclonal antibodies has always been a dynamic area in molecular imaging. With decay half-life (3.3 d) well matched to the circulation half-lives of antibodies (usually on the order of days), 89Zr has been extensively studied over the last decade. This review article will give a brief overview on 89Zr isotope production, the radiochemistry generally used for 89Zr-labeling, and the PET tracers that have been developed using 89Zr. To date, 89Zr-based PET imaging has been investigated for a wide variety of cancer-related targets, which include human epidermal growth factor receptor 2, epidermal growth factor receptor, prostate-specific membrane antigen, splice variant v6 of CD44, vascular endothelial growth factor, carbonic anhydrase IX, insulin-like growth factor 1 receptor, among others. With well-developed radiochemistry, commercial availability of chelating agents for 89Zr labeling, increasingly widely available isotope supply, as well as successful proof-of-principle in pilot human studies, it is expected that PET imaging with 89Zr-based tracers will be a constantly evolving and highly vibrant field in the near future.

New advances in nanotechnology has been responsible for the development of a new science called nanomedicine. In the recent years many discoveries as nanotubes and nanoparticles, especially for pharmaceuticals use, has increasing the application of nanotechnology for medical purposes. In this direction the development of nanoradiopharmaceuticals are also promising as novel radiopharmaceuticals. In this study we made an extensive overview of the most recent advantages in this field of nanotechnology and a fully application to radiopharmaceuticals. Despite, we gaive some nanoradiopharmaceuticals already developed and under investigation for clinical use. The results described that is possible to make nanoradiopharmaceuticals of two ways. The first one directly: nanoencapsulating an already radioactive radiopharmaceuticals. And the second way is nanoencapsulating a non-radioactive ligand for posterior labeling with a radioisotope alikes 99mTc. In both cases the nanoradiopharmaceuticals are acquired. We ended that nanoradiopharmaceuticals are feasible and may represent the future of the nuclear medicine.

Background: More than 25% of 99mTc colloidal rhenium sulphide preparations have been reported to have a radiochemical purity of <95% in 11 radiopharmacies. Objectives: To identify the key parameters involved in radiochemical purity, different preparation procedures were analysed to develop an optimised preparation method. Methods: In the first part of this study, various data such as the Nanocis kit batch number, the eluate volume, the time between the two final elutions, the temperature and duration of heating were collected and analysed to determine the critical parameters that significantly decrease radiochemical purity. In the second part, a new procedure was applied and then the same parameters and radiochemical purity values were collected and compared with the results before the new procedure. Results: Among 184 preparations, 137 (75%) had a radiochemical purity exceeding 95%, 25 (13.6%) were between 90 and 95% pure and 22 (12%) were below 90%. Significantly higher radiochemical purity was observed after the implementation of the new preparation procedure (89.5% of 374 preparations had radiochemical purities of >95%). This new procedure consists in lowering the 99mTc eluate volume and time of heating. Conclusions: The implementation of a new method for the preparation of 99mTc colloidal rhenium sulphide based on a comparison of practices in various radiopharmacies resulted in: i) a determination of the critical points of this preparation, ii) an optimised labelling technique to harmonise different practices, and iii) a significant improvement in the preparations radiochemical purity and the quality of the lymphoscintigraphy in the location of sentinel node.

Objective: The aim of the present study was to develop a 177Lu-labeled porphyrin derivative having favorable characteristics for use in targeted radiotherapy of cancer and to evaluate its biological behavior in mouse tumor models with respect to its effectiveness in tumor regression. Owing to the inherent affinity of porphyrins to accumulate in the tumors, suitably modified porphyrin derivative was chosen as the vehicle for the targeted delivery of the radionuclide. 177Lu was preferred as the radionuclide of choice due to its suitable nuclear decay characteristics [Eβ(max) = 497 keV, Eγ = 208 keV (11%), 113 keV (6.4%)], comparatively longer half-life (6.73 d) and ease of production in adequate quantity and sufficiently high specific activity using medium flux research reactors. Methods: A novel porphyrin analogue, 5,10,15,20-tetrakis[4-carboxymethyleneoxyphenyl]porphyrin was synthesized inhouse and coupled with a macrocyclic bi-functional chelating agent, namely p-amino-benzyl-1,4,7,10- tetraazacyclododecane-1,4,7,10-tetraacetic acid. The porphyrin-BFCA conjugate was labeled with 177Lu and the biological behavior of the radiolabeled conjugate was studied by biodistribution and imaging in Swiss mice bearing either fibrosarcoma or thymic lymphoma tumors. Effectiveness of the agent in controlling the growth of tumor volumes was also studied by administering various doses of the radiolabeled preparation in the mouse tumor models. Results: 177Lu-labeled porphyrin-BFCA conjugate was prepared with high radiochemical purity (>99%) and adequate invitro stability. Biodistribution and imaging studies revealed good uptake and retention of the agent in the tumors with encouraging tumor to blood and tumor to muscle ratios at various post-administration time points. Tumor regression studies showed that the administration of the agent increased the average tumor doubling time and decreased the average specific growth rate substantially in both the types of tumors. However, thymic lymphoma was found to be more sensitive to the radiolabeled conjugate compared to fibrosarcoma. Conclusion: Preliminary biological evaluation and tumor regression studies carried out in two different tumor models in Swiss mice exhibited the promising nature of 177Lu-labeled porphyrin-BFCA conjugate as an agent for targeted tumor therapy. However, further detailed investigations are warranted to evaluate the true potential of the developed agent.

99mTc-macroaggregated albumin is widely used to diagnose pulmonary embolism. To control the radiochemical purity of this radiopharmaceutical, three rapid control methods using filter, thin layer chromatography or centrifugation, are described in the academic literature. In this paper, the interactions between impurities and 99mTc-macroaggregated albumin were presented. For each control method, the influence of these interactions on the determination of the radiochemical purity of labeled macroaggregated albumin was evaluated. Then, a comparison of radiochemical purity obtained by these three methods was performed in normal condition and with different addition of pertechnetate. Finally, a correlation between these three methods was investigated. The results show a specificity difference between these three control methods. However in practice, this difference has no impact on the evaluation of the radiochemical purity of 99mTcmacroaggregated albumin by these three methods. In additions, methods are still correlated with pertechnetate additions in 99mTc-macroaggregated albumin suspension. Thus, this study demonstrates that these three control methods are exchangeable in radiopharmacy.

Purpose: The almost constant presence of apparent metabolic hypermetabolism of cerebellar vermis seen on 18FDG PET in a population of injured brains has been reported in a previous paper. Aim of this paper is to determine a) whether there is a correlation between the entity of this sign, semi quantitatively determined, and the severity of the trauma at its onset, and b) whether the entity of the relative enhancement correlates with the medium and long term clinical outcome. Methods: A group of 45 consecutive patients admitted to the Acquired Brain Injury Unit of our Hospital for recent, major head trauma, underwent a basal 18FDG PET/CT scan of the brain; the presence of relative hypermetabolism of the vermis cerebelli was visually assessed and semi quantitatively determined (vermis/cerebellum ratio: V/C); the median V/C value was used as a divide between low V/C ratios (group A) and high V/C ratios (group B). During one year after trauma, every patient from both groups received an extensive testing to evaluate cognitive and behavioral performances and evolution: Disability Rating Scale (DRS) and Levels of Cognitive Function (LCF) were administered monthly from month 1 to month 6, and at 12 months from the trauma; Glasgow Outcome Scale (GOS) was administered at 3, 6 and 12 months from the head trauma. Numerical scores from each of these performance-testing protocols were cross-matched with values derived from the V/C 18FDG PET/CT determinations. A relative risk estimate via Chi-square testing was performed on the results of both groups for LCF and DRS scales at 1, 6 and 12 months from trauma. Results: At one month after trauma, overall LCF (LCF1) values ranged from 2 to 8, avg. 3.77, SD ± 2.10; the average value in group A was 5.21, SD ± 2.09, in B group 2.47, SD ± 0.98 (F=17.5, P = 0). At this time, overall average DRS (DRS1) was 6.7, SD ± 2.05, ranging from 2 to 9; the average value was 5.52, SD ± 0.47 in group A, and 7.72, SD ± 0.30 in group B (F = 6.3, P = 0.01). Relative risk estimates for patients with higher V/C ratios for poor performance in DRS scale were: 2.46 at 1 month (confidence boundaries 1.66 - 3.64), 3.75 (c.b. 1.64 - 8.64) at 6 months, 5.17 (c.b. 1.76 - 15.16) at one year. Relative risk estimates for LCF scale were: 3.20 (c.b. 1.74 - 5.90) at 1 month, 6.909 (c.b. 1.03 - 46.15) at 6 months, 4.22 (c.b. 0.65 - 27.10) at 12 months. Conclusions: A) there is a strong correlation between the semi quantitatively determined values of vermian relative hypermetabolism and the severity of trauma as determined by standard cognitive and performance testings; the V/C ratio may therefore be considered a reliable, although non-specific, index of brain suffering. B) there is a good statistical correlation between the semi quantitative vermian/cerebellar ratio determined shortly after the trauma, and the clinical outcome of the patients, evaluated by standard clinical performance tests and relative risk estimates.