Molecular imaging is the visualization, characterization and measurement of biological processes at the molecular and cellular levels in humans and other living systems. Molecular imaging agents are probes used to visualize, characterize and measure biological processes in living systems. These two definitions were put forth by the Sociey of Nuclear Medicine (SNM) in 2007 as a way to capture the interdisciplinary nature of this relatively new field. The emergence of molecular imaging as a scientific discipline is a result of advances in chemistry, biology, physics and engineering, and the application of imaging probes and technologies has reshaped the philosophy of drug discovery in the pharmaceutical sciences by providing more cost effective ways to evaluate the efficacy of a drug candidate and allowing pharmaceutical companies to reduce the time it takes to introduce new therapeutics to the marketplace. Finally the impact of molecular imaging on clinical medicine has been extensive since it allows a physician to diagnose a patient’s illness, prescribe treatment and monitor the efficacy of that treatment non-invasively.

Single Photon Emission Computed Tomography (SPECT) and Positron Emission Tomography (PET) were the first molecular imaging modalities used clinically. SPECT requires the use of a contrast agent labeled with a gamma emitting radionuclide, which should have an ideal gamma energy of 100-250 keV. These gamma rays are recorded by the detectors of a dedicated gamma camera or SPECT instrument and after signal processing can be converted into an image indentifying the localization of the radiotracer. PET requires the injected radiopharmaceutical to be labeled with a positron emitting radionuclide. As the radionuclide decays it ejects a positron from its nucleus which travels a short distance before being annihilated with an electron to release two 511 keV gamma rays 180° apart that are detected by the PET scanner (Figure 1). After sufficient acquisition time the data are reconstructed using computer based algorithms to yield images of the radiotracer’s location within the organism. When compared to SPECT, PET has greater advantages with respect to sensitivity and resolution and has been gaining in clinical popularity, with the number of PET-based studies expected to reach 3.2 million by 2010.1 While SPECT and PET technology has been around for decades, its use remained limited because of the limited availability of relevant isotopes which had to be produced in nuclear reactors or particle accelerators. However, the introduction of the small biomedical cyclotron, the self-contained radionuclide generator and the dedicated small animal or clinical SPECT and PET scanners to hospitals and research facilities has increased the demand for SPECT and PET isotopes.



Figure 1

Cartoon depicting the fundamental principle of Positron Emission Tomography (PET). As the targeting group interacts with the cell surface receptor, the positron emitting radio-metal decays by ejecting β+ particles from its nucleus. After traveling ...



Traditional PET isotopes such as 18F, 15O, 13N and 11C have been developed for incorporation into small molecules, but due to their often lengthy radio-syntheses, short half-lives and rapid clearance, only early time points were available for imaging, leaving the investigation of biological processes, which occur over the duration of hours or days, difficult to explore. With the continuing development of biological targeting agents such as proteins, peptides, antibodies and nanoparticles, which demonstrate a range of biological half-lives, a need arose to produce new radionuclides with half-lives complementary with their biological properties. As a result, the production and radiochemistry of radiometals such as Zr, Y, In, Ga and Cu have been investigated as radionuclide labels for biomolecules since they have the potential to combine their favorable decay characteristics with the biological characteristics of the targeting molecule to become a useful radiopharmaceutical (Tables ​(Tables11 and ​and22).2



Table 1

Gamma- and Beta-Emitting Radiometals





Table 2

Positron-Emitting Radiometals



The number of papers published describing the production or use of these radiometals continues to expand rapidly, and in recognition of this fact, the authors have attempted to present a comprehensive review of this literature as it relates to the production, ligand development and radiopharmaceutical applications of radiometals (excluding 99mTc) since 1999. While numerous reviews have appeared describing certain aspects of the production, coordination chemistry or application of these radiometals,2-18 very few exhaustive reviews have been published.10,12 Additionally, this review has been written to be used as an individual resource or as a companion resource to the review written by Anderson and Welch in 1999.12 Together, they provide a literature survey spanning 50 years of scientific discovery. To accomplish this goal, this review has been organized into three sections: the first section discusses the coordination chemistry of the metal ions Zr, Y, In, Ga and Cu and their chelators in the context of radiopharmaceutical development; the second section describes the methods used to produce Zr, Y, In, Ga and Cu radioisotopes; and the final section describes the application of these radiometals in diagnostic imaging and radiotherapy.

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Coordinating Radiometals of Copper, Gallium, Indium, Yttrium and Zirconium for PET and SPECT Imaging of Disease

Radiometals comprise many useful radioactive isotopes of various metallic elements When properly harnessed, these have valuable emission properties that can be used for diagnostic imaging techniques, such as single photon emission computed tomography (SPECT, eg67Ga, 99mTc, 111In, 177Lu) and positron emission tomography (PET, eg68Ga, 64Cu, 44Sc, 86Y, 89Zr), as well as therapeutic applications (eg47Sc, 114mIn, 177Lu, 90Y, 212/213Bi, 212Pb, 225Ac, 186/188Re) A fundamental critical component of a radiometal-based radiopharmaceutical is the chelator, the ligand system that binds the radiometal ion in a tight stable coordination complex so that it can be properly directed to a desirable molecular target in vivo This article is a guide for selecting the optimal match between chelator and radiometal for use in these systems The article briefly introduces a selection of relevant and high impact radiometals, and their potential utility to the fields of radiochemistry, nuclear medicine, and molecular imaging A description of radiometal-based radiopharmaceuticals is provided, and several key design considerations are discussed The experimental methods by which chelators are assessed for their suitability with a variety of radiometal ions is explained, and a large selection of the most common and most promising chelators are evaluated and discussed for their potential use with a variety of radiometals Comprehensive tables have been assembled to provide a convenient and accessible overview of the field of radiometal chelating agents

Matching chelators to radiometals for radiopharmaceuticals.

Currently, the findings of imaging procedures used for detection or staging of prostate cancer depend on morphology of lymph nodes or bone metabolism and do not always meet diagnostic needs. Prostate-specific membrane antigen (PSMA), a transmembrane protein that has considerable overexpression on most prostate cancer cells, has gained increasing interest as a target molecule for imaging. To date, several small compounds for labelling PSMA have been developed and are currently being investigated as imaging probes for PET with the (68)Ga-labelled PSMA inhibitor Glu-NH-CO-NH-Lys(Ahx)-HBED-CC being the most widely studied agent. (68)Ga-PSMA-PET imaging in combination with multiparametric MRI (mpMRI) might provide additional molecular information on cancer localization within the prostate. In patients with primary prostate cancer of intermediate-risk to high-risk, PSMA-based imaging has been reported to improve detection of metastatic disease compared with CT or mpMRI, rendering additional cross-sectional imaging or bone scintigraphy unnecessary. Furthermore, in patients with biochemically recurrent prostate cancer, use of (68)Ga-PSMA-PET imaging has been shown to increase detection of metastatic sites, even at low serum PSA values, compared with conventional imaging or PET examination with different tracers. Thus, although current knowledge is still limited and derived mostly from retrospective series, PSMA-based imaging holds great promise to improve prostate cancer management.

Current use of PSMA-PET in prostate cancer management

Noninvasive imaging is used for many different (pre)clinical purposes, ranging from disease diagnosis, disease staging, and treatment monitoring to the visualization and quantification of nanomedicine-mediated drug targeting and (triggered) drug release. Noninvasive imaging can be employed to visualize and quantify how efficient passive or active drug targeting is in individual patients and, on this basis, to preselect patients likely to respond to nanomedicine-based chemotherapeutic interventions. In addition, it can be used to visualize the off-target localization of nanomedicines, e.g., in potentially endangered healthy tissues, which under certain circumstances might lead to exclusion from targeted treatment. Moreover, by systematically integrating imaging also during follow-up and by closely monitoring therapeutic responses upon nanomedicine treatment, clinical decision making can be facilitated and improved, as decisions on whether or not to (dis)continue treatment and on whether or not to adjust drug doses can be made relatively early on. Noninvasive imaging may be particularly useful in the case of metastatic disease. By subsequently performing PET or SPECT scans with radionuclide-labeled nanomedicines, information can be obtained on the accumulation of these formulations in both primary tumors and metastases, and treatment protocols can be adapted accordingly.

Noninvasive Imaging of Nanomedicines and Nanotheranostics : Principles, Progress, and Prospects

Purpose
Gallium-68 is a metallic positron emitter with a half-life of 68 min that is ideal for the in vivo use of small molecules, such as [68Ga-DOTA,Tyr3]octreotide, in the diagnostic imaging of somatostatin receptor-positive tumours. In preclinical studies it has shown a striking superiority over its 111In-labelled congener. The purpose of this study was to evaluate whether third-generation somatostatin-based, radiogallium-labelled peptides show the same superiority.

/pdf/are-radiogallium-labelled-dota-conjugated-somatostatin-2qov92iqkz.pdf

Are radiogallium-labelled DOTA-conjugated somatostatin analogues superior to those labelled with other radiometals?

⁶⁸Ge/⁶⁸Ga radionuclide generators have been investigated for almost fifty years now, since the cyclotron-independent availability of positron emitting ⁶⁸Ga via the ⁶⁸Ge/⁶⁸Ga system had always attracted researches working in basic nuclear chemistry as well as radiopharmaceutical chemistry. However, it took decades and generations of research (and researchers) to finally approach a reliable level of ⁶⁸Ge/⁶⁸Ga generator designs, adequate to the modern requirements of radiometal labeling chemistry. ⁶⁸Ga radiopharmacy now is awaking from a sort of hibernation. The exciting perspective for the ⁶⁸Ge/⁶⁸Ga generator, now - more than ever, asks for systematic chemical, radiochemical, technological and radiopharmaceutical efforts, to guarantee reliable, highly-efficient and medically approved ⁶⁸Ge/⁶⁸Ga generator systems. The expected future broad clinical impact of ⁶⁸Ga-labelled radiopharmaceuticals - beyond the ⁶⁸Ga-DOTA-octreotide derivatives - for imaging tumors and many organs, on the other hand, identifies the development of sophisticated Ga(III) chelating structures to be a key factor. Today, open chain complexing agents have almost completely been displaced by macrocyclic DOTA and NOTA-derived conjugates. Structures of chelating moieties are being optimized in terms of thermodynamic stability and kinetic inertness, in terms of labeling efficacies at different, even acidic pH, and in terms of synthetic options towards bifunctionality, directed to sophisticated covalent coupling strategies to a variety of biologically relevant targeting vectors. Today, one may expect that the ⁶⁸Ge/⁶⁸Ga radionuclide generator systems could contribute to and facilitate the clinical impact of nuclear medicine diagnoses for PET in a dimension comparable to the established ⁹⁹Mo/⁹⁹(m)Tc generator system for SPECT.

The renaissance of the ⁶⁸Ge/⁶⁸Ga radionuclide generator initiates new developments in ⁶⁸Ga radiopharmaceutical chemistry.

(44)Ti/(44)Sc radionuclide generators are of interest for molecular imaging. The 3.97 hours half-life of (44)Sc and its high positron branching of 94.27% may stimulate the application of (44)Sc-labeled PET radiopharmaceuticals. This review describes the current status of (44)Ti production, (44)Ti/(44)Sc radionuclide generator development, post-processing of generator eluates towards medical application, identification of ligands adequate to Sc(III) co-ordination chemistry, proof-of-principle labeling of (44)Sc-DOTA-octreotides, investigation of in vitro and in vivo parameters, and initial applications for molecular imaging - both in small animals and humans.

Scandium-44: benefits of a long-lived PET radionuclide available from the (44)Ti/(44)Sc generator system.

Validation of 68Ge/68Ga generator processing by chemical purification for routine clinical application of 68Ga-DOTATOC

https://www.rsc.org/suppdata/cc/c2/c2cc37544c/c2cc37544c.pdf

Frank Roesch

Papers

The renaissance of the ⁶⁸Ge/⁶⁸Ga radionuclide generator initiates new developments in ⁶⁸Ga radiopharmaceutical chemistry.

Scandium-44: benefits of a long-lived PET radionuclide available from the (44)Ti/(44)Sc generator system.

Validation of 68Ge/68Ga generator processing by chemical purification for routine clinical application of 68Ga-DOTATOC

Structure and stability of hexadentate complexes of ligands based on AAZTA for efficient PET labelling with gallium-68.

Radiolabeling of DOTATOC with the long-lived positron emitter 44Sc.