Cyclotrons and positron emission tomography radiopharmaceuticals for clinical imaging

Positron emission tomography (PET) requires positron-emitting radionuclides that emit 511-keV photons detectable by PET imagers. Positron-emitting radionuclides are commonly produced in charged particle accelerators, eg, linear accelerators or cyclotrons. The most widely available radiopharmaceuticals for PET imaging are carbon-11-, nitrogen-13-, and oxygen-15-labeled compounds, many of which, either in their normal state or incorporated in other compounds, serve as physiological tracers. Other useful PET radiopharmaceuticals include fluorine-18-, bromine-75-, gallium-68 (68Ga)-, rubidium-82 (82Rb)-, and copper-62 (62Cu)-labeled compounds. Many positron emitters have short half-lives and thus require on-site cyclotrons for application, and others (68Ga, 82Rb, and 62Cu) are available from radionuclides generators using relatively long-lived parent radionuclides. This review is divided into two sections: cyclotrons and PET radiopharmaceuticals for clinical imaging. In the cyclotron section, the principle of operation of the cyclotron, types of cyclotrons, medical cyclotrons, and production of radionuclides are discussed. In the section on PET radiopharmaceuticals, the synthesis and clinical use of PET radiopharmaceuticals are described.     

Three-dimensional maximum a posteriori (MAP) imaging with radiopharmaceuticals labeled with three Cu radionuclides

BACKGROUND: One of the limiting factors in achieving the best spatial resolution in positron emission tomography (PET), especially in small-animal PET, is the positron range associated with the decay of nuclides, and usual PET image reconstruction algorithms do not provide a correction for the positron range. This work presents initial results obtained with the maximum a posteriori (MAP) algorithm, which has been developed to include an accurate model of the camera response, the Poisson distribution of coincidence data and the fundamental physics of positron decay including the positron range. METHODS: Phantoms were imaged with three positron emitting isotopes of Cu ((60)Cu, (61)Cu and (64)Cu), and mice and rats were imaged with two radiopharmaceuticals labeled with these isotopes in a microPET-R4 camera. These isotopes decay by positron emission with very different end-point energies resulting in wildly different spatial resolutions. Spatial resolution improvement and image quality offered by the MAP algorithm were studied with the line source phantom and a miniature Derenzo phantom. In addition, three mice and three rats were sequentially injected over a 48-h period with Cu-pyruvaldehyde bis(N(4)-methylthiosemicarbazone) (for blood flow to organs) and Cu-1,4,7,10-tetraazacyclododecane-1,4,7-tri(methanephosphonic acid) (for bone imaging) labeled with the said three isotopes of Cu. RESULTS: The line source experiment showed that comparable spatial resolution is possible with all three isotopes when using the positron range correction in MAP. The in vivo images obtained from (60)Cu and (61)Cu and reconstructed with 2D filtered back projection algorithms provided by the camera manufacturer show reduced clarity due to degraded spatial resolution arising from the extended positron ranges as compared with (64)Cu. MAP reconstructions exhibited a higher resolution with clearer organ delineation. CONCLUSION: Inclusion of a positron range model in the MAP reconstruction algorithm may potentially result in significant resolution recovery for isotopes with larger positron ranges.     

Novel chelating agents for potential clinical applications of copper.

Copper offers a unique selection of radioisotopes ((60)Cu, (61)Cu, (62)Cu, (64)Cu, and (67)Cu) with half-lives ranging from 9.8 min to 61.9 h suitable for imaging and/or radiotherapy. In peptide/antibody targeted radiotherapy one of the most studied chelating agents for copper, 1,4,8,11-tetraazacyclotetradecane-1,4,8,11-tetraacetic acid (TETA), has been employed in clinical trials, but transchelation to ceruloplasmin and/or superoxide dismutase in vivo has been noted. In this study, a series of novel hexadentate chelating agents based on N,N',N"-tris(2-pyridylmethyl)-1,3,5-cis,cis,-triaminocyclohexane (tachpyr) have been synthesized and the serum stability of their copper complexes was evaluated as compared to TETA. Copper complexes of tachpyr modified at the 3, 4, or 5 position or with replacement of pyridine by imidazole have serum stability comparable to Cu[TETA]. When the complexes were cross-challenged, Cu[TETA] versus tachpyr or 1,3,5-cis,cis,-triaminocyclohexane- N,N',N"-tris-(2-methyl-(N-methylimidazole)) (IM), tachpyr and IM appear to have superior copper chelation ability to TETA. When challenged by a large excess of non-radioactive copper, copper exchange with the tachpyr radio-copper complex was observed. However, tachpyr clearly exhibited a significant preference for Cu(II) over Zn(II) or Fe(III). Therefore, tachpyr, 1,3,5-cis,cis,-triaminocyclohexane-N,N',N"-tri-(3-methyl-2-methylpyridineimine) (tachpyr(3-Me)), 1,3,5-cis,cis,-triaminocyclohexane-N,N',N"-tri-(4-methyl-2-methylpyridineimine) (tachpyr(4-Me)), 1,3,5-cis,cis,-triaminocyclohexane-N,N',N"-tri-(5-methyl-2-methylpyridineimine) (tachpyr(5-Me)) and IM easily form copper complexes with high stability. These novel chelating agents provide an attractive lead for creation of new copper radiopharmaceuticals for diagnosis and therapy applications.     

Copper(II) bis(thiosemicarbazone) complexes as potential tracers for evaluation of cerebral and myocardial blood flow with PET

Wider application of positron emission tomography would be facilitated by the availability of positron-emitting radiopharmaceuticals labeled with nuclides, like 62Cu, that are available from parent/daughter generator systems. Using a longer-lived copper isotope (67Cu) we have examined three derivatives of copper(II) pyruvaldehyde bis(thiosemicarbazone) as potential tracers for evaluation of cerebral and myocardial blood flow: Cu(PTS), Cu(PTSM), and Cu(PTSM2) (where PTS = pyruvaldehyde bis(thiosemicarbazone), PTSM = pyruvaldehyde bis(N4-methylthiosemicarbazone), and PTSM2 = pyruvaldehyde bis(N4-dimethylthiosemicarbazone). All three lipophilic radiocopper complexes were obtained in high yield via a procedure that could be adapted to a "kit" formulation. In animal model systems Cu(PTSM) and Cu(PTSM2) show excellent uptake in the brain and heart following i.v. injection. These tracers differ in that Cu(PTSM) exhibits microsphere-like retention in the brain and heart, whereas Cu(PTSM2) substantially clears from these organs. The relative cerebral pharmacokinetics of [67Cu]Cu(PTSM) and [67Cu]Cu(PTSM2) are consistent with their known reactivity towards intracellular sulfhydryl groups.     

Evaluation of a potential generator-produced PET tracer for cerebral perfusion imaging: single-pass cerebral extraction measurements and imaging with radiolabeled Cu-PTSM

Copper(II) pyruvaldehyde bis(N4-methylthiosemicarbazone) (Cu-PTSM), copper(II) pyruvaldehyde bis(N4-dimethylthiosemicarbazone) (Cu-PTSM2), and copper(II) ethylglyoxal bis(N4-methylthiosemicarbazone) (Cu-ETSM), have been proposed as PET tracers for cerebral blood flow (CBF) when labeled with generator-produced 62Cu (t1/2 = 9.7 min). To evaluate the potential of Cu-PTSM for CBF PET studies, baboon single-pass cerebral extraction measurements and PET imaging were carried out with the use of 67Cu (t1/2 = 2.6 days) and 64Cu (t1/2 = 12.7 hr), respectively. All three chelates were extracted into the brain with high efficiency. There was some clearance of all chelates in the 10-50-sec time frame and Cu-PTSM2 continued to clear. Cu-PTSM and Cu-ETSM have high residual brain activity. PET imaging of baboon brain was carried out with the use of [64Cu]-Cu-PTSM. For comparison with the 64Cu brain image, a CBF (15O-labeled water) image (40 sec) was first obtained. Qualitatively, the H2(15)O and [64Cu]-Cu-PTSM images were very similar; for example, a comparison of gray to white matter uptake resulted in ratios of 2.42 for H2(15)O and 2.67 for Cu-PTSM. No redistribution of 64Cu was observed in 2 hr of imaging, as was predicted from the single-pass study results. Quantitative determination of blood flow using Cu-PTSM showed good agreement with blood flow determined with H2(15)O. This data suggests that [62Cu]-Cu-PTSM may be a useful generator-produced radiopharmaceutical for blood flow studies with PET.     

A comparison of PET imaging characteristics of various copper radioisotopes

Purpose PET radiotracers which incorporate longer-lived radionuclides enable biological processes to be studied over many hours, at centres remote from a cyclotron. This paper examines the radioisotope characteristics, imaging performance, radiation dosimetry and production modes of the four copper radioisotopes, ⁶⁰Cu, ⁶¹Cu, ⁶²Cu and ⁶⁴Cu, to assess their merits for different PET imaging applications. Methods Spatial resolution, sensitivity, scatter fraction and noise-equivalent count rate (NEC) are predicted for ⁶⁰Cu, ⁶¹Cu, ⁶²Cu and ⁶⁴Cu using a model incorporating radionuclide decay properties and scanner parameters for the GE Advance scanner. Dosimetry for ⁶⁰Cu, ⁶¹Cu and ⁶⁴Cu is performed using the MIRD model and published biodistribution data for copper(II) pyruvaldehyde bis(N⁴-methyl)thiosemicarbazone (Cu-PTSM). Results ⁶⁰Cu and ⁶²Cu are characterised by shorter half-lives and higher sensitivity and NEC, making them more suitable for studying the faster kinetics of small molecules, such as Cu-PTSM. ⁶¹Cu and ⁶⁴Cu have longer half-lives, enabling studies of the slower kinetics of cells and peptides and prolonged imaging to compensate for lower sensitivity, together with better spatial resolution, which partially compensates for loss of image contrast. ⁶¹Cu-PTSM and ⁶⁴Cu-PTSM are associated with radiation doses similar to [¹⁸F]-fluorodeoxyglucose, whilst the doses for ⁶⁰Cu-PTSM and ⁶²Cu-PTSM are lower and more comparable with H₂¹⁵O. Conclusion The physical and radiochemical characteristics of the four copper isotopes make each more suited to some imaging tasks than others. The results presented here assist in selecting the preferred radioisotope for a given imaging application, and illustrate a strategy which can be extended to the majority of novel PET tracers.     

Automated production of copper radioisotopes and preparation of high specific activity [64Cu]Cu-ATSM for PET studies

⁶⁰Cu and ⁶⁴Cu are useful radioisotopes for positron emission tomography (PET) radiopharmaceuticals and may be used for the preparation of promising agents for diagnosis and radiotherapy. In this study, the production and purification of ^60/64Cu starting from ^60/64Ni using a new automated system, namely Alceo, is described. A dynamic process for electrodeposition and dissolution of ^60/64Ni/^60/64Cu was developed. Preliminary production yields of ⁶⁰Cu and ⁶⁴Cu were 400 and 300 mCi, respectively. ⁶⁴Cu was used to radiolabel the hypoxia detection tracer ATSM with a specific activity of 2.2±1.3 Ci/μmol.     

Production of therapeutic quantities of (64)Cu using a 12 MeV cyclotron

(64)Cu is a useful radiotracer for positron emission tomography (PET) and a promising radiotherapy agent for the treatment of cancer. Recently, (64)Cu-labeled radiopharmaceuticals were reported to be useful for internal radiation therapy as well as PET monitoring of tumors.(64)Cu was produced at the Fukui Medical University's cyclotron using twelve MeV proton irradiation and the (64)Ni(p,n) (64)Cu nuclear reaction. A (64)Ni target was electroplated on a gold disk at a thickness of 50 to > 100 microm. Electroplating was performed at 2.5 V, at currents between 5-15 mA, and was completed in 12-24 hr. The (64)Ni target was bombarded with a 50 +/- 3 microA proton current. After bombardment, (64)Cu was separated from the (64)Ni target and other contaminants using an anion exchange column. Target (64)Ni was recovered and re-used. The yield of (64)Cu was 0.6 to > 3.0 mCi/microA*h, and averaged 1.983 mCi/microA*h. The radionuclidic purity of (64)Cu was over 99%. In this study, we obtained sufficient qualities and quantities of (64)Cu for therapeutic application and dose monitoring using PET using an ultra-small cyclotron.     

The Changing Design of Positron Imaging Systems

This is a time of rapid change in the evolution of clinical positron imaging systems, spurred by the wider availability of (18)F-fluorodeoxyglucose, continued increase in clinical research trials showing the clinical efficacy of PET in numerous cancers, coronary artery disease, and a variety of neurological disorders, recent successes in changing the FDA approval process for PET radiopharmaceuticals, and the recent decision of HCFA to reimburse for PET procedures. To adapt to this new environment for clinical positron imaging, a number of approaches are being taken to cut the cost of positron imaging systems while still maintaining the inherent sensitivity and quantitative advantages that relate to coincidence imaging. In this article, we present some of the newer developments in positron imaging systems, discuss some of the limitations with currently available "low-cost" systems, and point the way to some future developments that will rapidly result in improved systems for clinical positron imaging. It should be noted that PET scanners have gone through many generations of technology advancements. These advancements along with new detector materials, new image reconstruction algorithms that improve signal-to-noise, lower cost/higher performance computer technology, and the present infectious enthusiasm for new ideas are all converging to produce a highly competitive marketplace of new camera solutions for clinical positron imaging.     

Copper-62-labeled pyruvaldehyde bis(N4-methylthiosemicarbazonato)copper(II): synthesis and evaluation as a positron emission tomography tracer for cerebral and myocardial perfusion

Generator produced positron-emitting radionuclides could potentially expand the application of positron emission tomography (PET) to centers that do not have access to a local cyclotron. The zinc-62/copper-62 radionuclide generator system could serve as a source of positron-emitting copper-62 (62Cu) (t1/2 = 9.74 min) for physiologic imaging. Accordingly, we have prepared zinc-62/copper-62 generators capable of high output (greater than 300 mCi) and used the no-carrier-added eluate in a rapid high yield synthesis of [62Cu] Cu(PTSM) that provides the radiopharmaceutical in a form suitable for intravenous injection (where Cu(PTSM) = pyruvaldehyde bis(N4-methylthiosemicarbazonato) copper(II]. We then demonstrated in pilot studies that [62Cu]Cu(PTSM) provides high quality brain and heart images with PET, accurately delineating cerebral and myocardial perfusion in both experimental animals and in humans (corroborating results of previous experimental studies utilizing longer-lived copper isotopes). The results of this work demonstrate that 62Cu can be conveniently obtained from high-level generators and, when used to label Cu(PTSM), provides a generator-produced radiopharmaceutical capable of providing estimates of cerebral and myocardial perfusion independent of cyclotron-produced radionuclides.     

Radioarsenic from a portable (72)Se/(72)As generator: a current perspective

Positron emission tomography (PET) of slower biological processes calls for the use of longer lived positron emitting radioisotopes. Beyond radionuclide production considerations, practicality and rapidity of subsequent labeling chemistry further limits the selection of radioisotopes with potentially favorable nuclear properties. One additional limitation is the availability of PET radiotracers at the point-of-care with appropriate on-site production methodologies or robust radionuclide generator systems. The positron emitter (72)As (half-life 26 h) is generated via decay of (72)Se (half-life 8.5 d); this pair comprises and excellent generator system for clinical availability of a longer lived PET isotope. Many (72)Se/As generator systems have been introduced utilizing the rich interplay of Se(IV)/Se(VI) and As(III) /As(V) chemical behavior. This paper describes available generator concepts, and briefly outlines some current arsenic labeling methodologies for the introduction of radioarsenic into biomolecules.     

ARRONAX,a high-energy and high-intensity cyclotron for nuclear medicine

PURPOSE: This study was aimed at establishing a list of radionuclides of interest for nuclear medicine that can be produced in a high-intensity and high-energy cyclotron. METHODS: We have considered both therapeutic and positron emission tomography radionuclides that can be produced using a high-energy and a high-intensity cyclotron such as ARRONAX, which will be operating in Nantes (France) by the end of 2008. Novel radionuclides or radionuclides of current limited availability have been selected according to the following criteria: emission of positrons, low-energy beta or alpha particles, stable or short half-life daughters, half-life between 3 h and 10 days or generator-produced, favourable dosimetry, production from stable isotopes with reasonable cross sections. RESULTS: Three radionuclides appear well suited to targeted radionuclide therapy using beta ((67)Cu, (47)Sc) or alpha ((211)At) particles. Positron emitters allowing dosimetry studies prior to radionuclide therapy ((64)Cu, (124)I, (44)Sc), or that can be generator-produced ((82)Rb, (68)Ga) or providing the opportunity of a new imaging modality ((44)Sc) are considered to have a great interest at short term whereas (86)Y, (52)Fe, (55)Co, (76)Br or (89)Zr are considered to have a potential interest at middle term. CONCLUSIONS: Several radionuclides not currently used in routine nuclear medicine or not available in sufficient amount for clinical research have been selected for future production. High-energy, high-intensity cyclotrons are necessary to produce some of the selected radionuclides and make possible future clinical developments in nuclear medicine. Associated with appropriate carriers, these radionuclides will respond to a maximum of unmet clinical needs.     

The Role of the Practice of Nuclear Pharmacy in Positron Emission Tomography

As nuclear medicine evolved from an obscure research tool to a mainstream clinical diagnostic and therapeutic modality, so has the role of the practice of pharmacy in nuclear medicine also evolved. A similar evolution is unfolding today in the practice of positron emission tomography (PET). The skills of many diverse professionals, including pharmacists, are essential for the safe and efficient operation of a modern PET facility. The importance of the role of pharmacists in PET has been increasing as the use of PET radiopharmaceuticals has matured from research to clinical to commercial arenas. While it is clear that pharmacists can contribute clinical and technical skills to the operation of a PET center, perhaps one of the most important factors influencing the increased role of pharmacists in PET is their expertise and experience in the drug regulatory process. The commercial distribution of PET radiopharmaceuticals, primarily [18F]2-fluorodeoxyglucose (FDG), is currently being performed by a variety of corporate and institutional facility partnerships, with the likelihood of several new players entering the marketplace in the near future. This factor has served to dramatically increase the role for nuclear pharmacy in PET. The practice of nuclear pharmacy is a well-established component of PET. The role of nuclear pharmacists in PET is complementary to the many other professionals currently practicing in this specialty. With the rapidly increasing clinical demand for FDG imaging, it is likely that the number of facilities and institutions entering into the commercial distribution of PET radiopharmaceuticals will also increase. Such growth will also serve to solidify and expand the role for the practice of nuclear pharmacy in PET.     

Electronic Generators for the Production of Positron-Emitter Labeled Radiopharmaceuticals. Where Would PET Be Without Them?

The emergence of clinical positron emission tomography (PET) has enabled a routine and noninvasive assessment of cancer, neurological disorders, and coronary artery disease in humans. Vital to a sustained growth and widespread utilization of this novel methodology, in a clinical environment, is the ready and convenient availability of positron-emitter labeled radiopharmaceuticals. This requirement is aptly met by integrated radiopharmaceutical production systems or electronic radiopharmaceutical generators that comprise of: (1) a low energy, self-shielded negative ion cyclotron; (2) small volume targets for the production of positron emitting precursors; and (3) unit operations based automated synthesizers all under the full control of a personal computer (PC) and entirely operated by a technician. Efforts by both academia and industry during the past 20 years have now led to the inception of such integrated systems that are efficient and highly suitable for the production of multiple doses of numerous radiotracers in clinical settings. The theme of this review is the evolution, over the years, of integrated automated synthesis units from the standpoint of the cyclotrons, targetry, and automated synthesizers. PET radiopharmacies are now making a reality the availability of positron-emitter labeled radiopharmaceuticals for clinical use and are positioning themselves to extend the availability of new PET probes to research environments stimulated by the micro-PET technology. Stand alone automatic synthesis modules also offer a unique avenue to PET radiopharmaceuticals for research. The new Food and Drug Administration (FDA) regulatory environment mandated by the Food and Drug Administration Modernization Act (FDAMA) in 1997, combined with these developments will permit the accessibility of PET radiopharmaceuticals at low cost for a variety of clinical and research applications.     

Design of hypoxia-targeting radiopharmaceuticals: selective uptake of copper-64 complexes in hypoxic cells in vitro

The well-known perfusion tracer CuPTSM, labelled with ⁶²Cu or ⁶⁴Cu, is believed to be trapped in cells non-selectively by a bioreductive mechanism. It is proposed that by modifying the ligand to increase its electron donor strength (for example by adding alkyl functionality or replacing sulphur ligands with oxygen ligands), the copper complexes will become less easily reduced and tracers with selectivity for hypoxic tissues could thus be developed. The aim of this work was to prepare ⁶⁴Cu-labelled complexes of two series of ligands, based on the bis(thiosemicarbazone) (13 ligands) and bis(salicylaldimine) (3 ligands) skeletons, and to evaluate the hypoxia dependence of their uptake in cells. The complexes were incubated with Chinese hamster ovary cells under normoxic and hypoxic conditions, and the cells isolated by centrifugation to determine radioactivity uptake at various time points up to 90 min. Several members of both series demonstrated significant (P<0.05) or highly significant (P<0.01) hypoxia selectivity, indicating that both series of complexes offer a basis for development of hypoxia-targeting radiopharmaceuticals for positron emission tomography (⁶⁰Cu, ⁶¹Cu, ⁶²Cu, ⁶⁴Cu) and targeted radiotherapy (⁶⁴Cu, ⁶⁷Cu). Received 30 March 1998     

Advantages and disadvantages of PET and SPECT in a busy clinical practice

The continued high utilization of rest-stress single-photon emission computed tomographic (SPECT) myocardial perfusion imaging (MPI) is supported by its known clinical benefits, established reimbursement, and wide availability of cameras and radiopharmaceuticals. However, traditional rest-stress SPECT protocols tend to be lengthy and inefficient, and the prevalence of equivocal studies continues to be a problem. The use of stress-only SPECT protocols in selected patients, and a new generation of ultrafast SPECT cameras have led to improved image quality, reduced dosimetry and shorter, more efficient MPI protocols. The utilization of positron emission tomographic (PET) MPI has been accelerated by the availability of radiopharmaceuticals that can be generated on-site, and by the availability of more PET cameras. Emerging evidence consistently demonstrates that PET provides improved image quality, greater interpretive certainty, higher diagnostic accuracy, lower patient dosimetry, and shorter imaging protocols as compared to SPECT. Importantly, PET imaging allows assessment of left ventricular function at peak-stress, and evaluation of microvascular function through the measurement of absolute myocardial blood flow at rest and at peak-stress. Wider utilization of PET MPI is hindered by a high cost of entry, high on-going costs, and an immature reimbursement structure.     

Positron emission tomography: a technical introduction for clinicians

Up to a few years ago, positron emission tomography (PET) was known as a very expensive research tool using positron emitting radiopharmaceuticals to study metabolic processes in vivo. Recent developments in detector technology enabled the detection of the distribution of positron emitting radionuclides inside the human body through dual-headed gamma camera systems. These much cheaper cameras did move the focus of PET from research to clinical applications. The improved availability of [(18)F]fluorodeoxyglucose has promoted clinical PET. Ongoing developments in detector and image reconstruction technology may lead to even more accurate imaging in the clinical setting. New applications in diagnosing and staging of cancer patients came across and more will arise. In this paper, we present a short historical overview and a technical introduction of PET.     

Contribution of [64Cu]-ATSM PET in molecular imaging of tumour hypoxia compared to classical [18F]-MISO--a selected review

During the carcinogenesis process, tumour cells often have a more rapid proliferation potential than cells that participate in blood capillary formation by neoangiogenesis. As a consequence of the poorly organized vasculature of various solid tumours, a limited oxygen delivery is observed. This hypoxic mechanism frequently occurs in solid cancers and can lead to therapeutic resistance. The present selected literature review is focused on the comparison of two positron emitting radiopharmaceuticals agents, which are currently leaders in tumour hypoxia imaging by PET. {18F}-fluoromisonidazole (=FMISO) is most commonly used as an investigational PET agent with an investigational new drug exemption from the FDA, while {64Cu}-diacetyl-bis(N4-methylthiosemicarbazone) (64Cu-ATSM) has been presented as an alternative radiopharmaceutical not yet readily available. The comparison of these two radiopharmaceutical agents is particularly focused on isotope properties, radiopharmaceutical labelling process, pharmacological mechanisms, dosimetry data in patients, and clinical results in terms of image contrast. PET imaging has demonstrated a good efficacy in tumour hypoxia imaging with both FMISO and Cu-ATSM, but FMISO has presented too slow an in vivo accumulation and a weak image contrast of the hypoxia area. Despite a less favourable dosimetry, 64Cu-ATSM appears superior in terms of imaging performance, calling for industrial and clinical development of this innovative radiopharmaceutical.     

Radiopharmaceutical development of radiolabelled peptides

Receptor targeting with radiolabelled peptides has become very important in nuclear medicine and oncology in the past few years. The overexpression of many peptide receptors in numerous cancers, compared to their relatively low density in physiological organs, represents the molecular basis for in vivo imaging and targeted radionuclide therapy with radiolabelled peptide-based probes. The prototypes are analogs of somatostatin which are routinely used in the clinic. More recent developments include somatostatin analogs with a broader receptor subtype profile or with antagonistic properties. Many other peptide families such as bombesin, cholecystokinin/gastrin, glucagon-like peptide-1 (GLP-1)/exendin, arginine-glycine-aspartic acid (RGD) etc. have been explored during the last few years and quite a number of potential radiolabelled probes have been derived from them. On the other hand, a variety of strategies and optimized protocols for efficient labelling of peptides with clinically relevant radionuclides such as (99m)Tc, M(3+) radiometals ((111)In, (86/90)Y, (177)Lu, (67/68)Ga), (64/67)Cu, (18)F or radioisotopes of iodine have been developed. The labelling approaches include direct labelling, the use of bifunctional chelators or prosthetic groups. The choice of the labelling approach is driven by the nature and the chemical properties of the radionuclide. Additionally, chemical strategies, including modification of the amino acid sequence and introduction of linkers/spacers with different characteristics, have been explored for the improvement of the overall performance of the radiopeptides, e.g. metabolic stability and pharmacokinetics. Herein, we discuss the development of peptides as radiopharmaceuticals starting from the choice of the labelling method and the conditions to the design and optimization of the peptide probe, as well as some recent developments, focusing on a selected list of peptide families, including somatostatin, bombesin, cholecystokinin/gastrin, GLP-1/exendin and RGD.     

A broad overview of positron emission tomography radiopharmaceuticals and clinical applications: what is new?

Positron emission tomography (PET)/computed tomography (CT) is a rapidly expanding imaging modality, thanks to the availability of compact medical cyclotrons and automated chemistry synthesis modules for the production of PET radiopharmaceuticals. Despite the availability of many radiotracers, [(18)F]fluorodeoxyglucose (FDG) is currently the most widely used radiopharmaceutical in PET, and the field of molecular imaging is anxiously awaiting the introduction of new PET radiopharmaceuticals for routine clinical use. During the last five years, several proprietary PET radiopharmaceuticals have been developed by major companies, and these new agents are in different stages of clinical evaluation. These new PET drugs are designed for imaging brain beta amyloid, myocardial perfusion, amino acid transport, angiogenesis, and tumor antigen expression. In addition, the National Cancer Institute, Society of Nuclear Medicine Clinical Trials Network, and the American College of Radiology Imaging Network have been conducting multicenter clinical trials with several nonproprietary PET drugs such as sodium [(18)F]fluoride, [(18)F]fluorothymidine, [(18)F]fluoromisonidazole, and (64)Cu-labeled diacetyl-bis (N(4)-methylthiosemicarbazone. All new PET radiopharmaceuticals, like any other drugs, must be manufactured under current good manufacturing practices as required by the Food and Drug Administration before clinical evaluation (phases I, II, and III) and submission of new drug application. This review briefly describes the chemistry, mechanisms(s) of localization, and clinical application of both proprietary and nonproprietary new PET drugs under multicenter clinical evaluation.