Nuclear medicine and molecular imaging advances in the 21st century

Abstract

Currently, Nuclear Medicine has a clearly defined role in clinical practice due to its usefulness in many medical disciplines. It provides relevant diagnostic and therapeutic options leading to patients' healthcare and quality of life improvement. During the first two decades of the 21st^t century, the number of Nuclear Medicine procedures increased considerably.

Clinical and research advances in Nuclear Medicine and Molecular Imaging have been based on developments in radiopharmaceuticals and equipment, namely, the introduction of multimodality imaging. In addition, new therapeutic applications of radiopharmaceuticals, mainly in oncology, are underway.

This review will focus on radiopharmaceuticals for positron emission tomography (PET), in particular, those labeled with Fluorine-18 and Gallium-68. Multimodality as a key player in clinical practice led to the development of new detector technology and combined efforts to improve resolution. The concept of dual probe (a single molecule labeled with a radionuclide for single photon emission computed tomography)/positron emission tomography and a light emitter for optical imaging) is gaining increasing acceptance, especially in minimally invasive radioguided surgery. The expansion of theranostics, using the same molecule for diagnosis (γ or positron emitter) and therapy (β minus or α emitter) is reshaping personalized medicine.

Upcoming research and development efforts will lead to an even wider array of indications for Nuclear Medicine both in diagnosis and treatment.

Introduction

Nuclear Medicine has established itself in clinical practice in a large variety of indications. Recent innovation in radiopharmaceuticals and equipment has led to a significant increase in diagnostic and therapeutic applications. According to the World Nuclear Association ¹ more than 40 million nuclear medicine procedures are performed each year worldwide. In developed countries, the frequency of diagnostic nuclear medicine is 1.9% per year, and the frequency of therapy with radioisotopes is about 1/10 of this. ^99mTc is the most common radioisotope used in diagnosis, representing about 80% of all nuclear medicine procedures.

In the 21st century, several radiopharmaceuticals have been developed. In the last two decades, the number of PET radiopharmaceuticals has increased almost exponentially. However, ¹⁸F-fludeoxyglucose (FDG) is still the radiopharmaceutical with the widest applicability. In this paper, we focus on positron emission tomography (PET) radiopharmaceuticals due to their increased availability and importance in current clinical practice. The use of ¹⁸F-FDG was initially approved by the Food and Drug Administration (FDA) in 1994 only for epileptic foci identification. In 2000, applications in oncology (mapping of tumor metabolism) were added. In 2005, the FDA approved its use for the differential diagnosis of dementias, mainly between Alzheimer’s disease and frontotemporal dementia. ¹⁸F-FDG was approved by the European Medicines Agency (EMA) in 2012 for clinical use in oncology and neuropsychiatry predominantly. ¹⁸F-FDG represents the most important PET radiopharmaceutical used nowadays, due to its wide range of clinical applications, ranging from oncology to neuropsychiatry, and also including cardiology, inflammatory/infectious diseases, orthopedics and rheumatology as other areas of clinical interest.

Nuclear Medicine has been widening its clinical applications due to technology innovation in hardware and software. In this century, the wider availability of PET scanners is demonstrated in a report by www.globalinforeaserch.com (https://www.globalinforesearch.com/global- positron-emission-tomography ). It reports a global revenue of PET of nearly 782 million USD in 2019, expecting to reach 819 million USD in 2025. Meanwhile, in current state-of-the-art scanners, spatial resolution has already improved by a factor of 10 and sensitivity by a factor of 40 in comparison to the scanners from the early 1970’s. Multimodality configurations emerged (e.g. single photon emission CT/CT (SPECT/CT), PET/CT, PET/MRI and now it is possible to complete whole body PET/CT scans in less than 10 min. ²

The concept of dual probe (the same molecule labeled with a γ or positron emitter for SPECT/PET and a light emitter for optical imaging) is gaining wider acceptability for guidance of high precision and less invasive robotic surgery. Sentinel lymph node detection and improved lymphadenectomy procedures are prominent examples of dual probe applications in clinical practice. ^3,4

At present, it is possible to label the pharmaceutical compound with either a γ or positron emitting radionuclide for diagnostic applications (SPECT or PET), or a β-minus or α radionuclide emitter for therapeutic purposes. This concept is the fundamental basis of theranostics. The 21st century has been seeing the development of new radiopharmaceuticals for theranostics to reshape personalized medicine with expanding indications mainly in neuroendocrine tumor and prostate cancer patients. Pharmaceutical companies are investing in radiopharmaceuticals with therapeutic purposes, which may reach an estimated revenue of 13 billion USD in 2025. ⁵

Finally, artificial intelligence, using machine learning algorithms based on features extracted from images, is also emerging in the Nuclear Medicine and promising developments to use functional imaging as a biomarker are expected. ⁶

For the sake of simplification, this review of the 21st century advances in Nuclear Medicine and Molecular Imaging is subdivided into three sections: (1) Advances in PET radiopharmaceuticals; (2) Developments in equipment; (3) Radiopharmaceutical applications in therapy and theranostics (Figure 1).

Figure 1.

Main fields of advances in Nuclear Medicine in the 21st century.

Advances in PET radiopharmaceuticals

PET radiopharmaceuticals enable the functional study of several pathologies within the majority of medical specialties (Table 1 and Figure 2). During the 20th century, ^99mTc labeled radiopharmaceuticals were the cornerstone of Nuclear Medicine clinical practice and examinations. In the 21st century, PET has proved its important clinical role through the use of established Flourine-18 labelled radiopharmaceuticals. More recently, Gallium-68 labelled radiopharmaceuticals are increasingly used due to the availability of DOTA chelators, Germanium-68/Gallium-68 generators, and their pharmacological properties for theranostics.

Table 1.

Radiopharmaceuticals used in clinical practice in different medical fields

Medical Field	Radiopharmaceuticals	FDA approval	EMA approval
Oncology	18F-FDG (Fludeoxyglucose)	2000 – cancer applications	2012
	68Ga/18F-PSMA (prostate specific membrane antigen)	2012
	18F-Fluciclovine	2016	2017
	68Ga-DOTA-conjugated peptides (DOTA-NOC, DOTA-TOC and DOTA-TATE)	2016
	18F-FDOPA (Dihydroxyphenylalanine)	NA	2016
	Hypoxia tracers 18F-FMISO (fluoromisonidazole), 18F-FAZA (fluoroazomycin-arabinozide) and 7 Cu-ATSM (diacetyl-bis-methylthiosemicarbazone)	FMISO-1986 ATSM-1997 FAZA −1999
	18F-FLT (Fluorothymidine)	2009	NA
	68Ga-FAPI (fibroblast activation protein inhibitors)	2018
	18F-FES (Fluoroestradiol)	NA
	89Zr-trastuzumab	NA
	Iodine-124	NA
Neurology And Psychiatry	18F-FDG (Fludeoxyglucose)	1994 – epilepsy application 2005 – dementia application	2012
	β-Amyloid tracers (Florbetaben, Florbetapir and Flutemetamol)	2015
	Perfusion tracers (Rubidium-82 chloride, 13N-Ammonia, 15O-Water and 18F-Flurpiridaz)	Rb-1989 Ammonia-2000 Flurpiridaz-2020	Rb-2009
	Amino-acids tracers 11C-MET (methionine) and 18F-FET (Fluoro-ethyl-Tyrosine)	NA
	Tau-tracers (18F-Flortaucipir, 18F-THK5317, and 11C-PBB3)	NA
	18F-DOPA (Dihydroxyphenylalanine)	NA	2016
Cardiology	18F-FDG (Fludeoxyglucose)	1994 – epilepsy application 2000 – cancer applications 2005 – dementia application	2012
	Perfusion tracers	Rb-1989 Ammonia-2000 Flurpiridaz-2020	Rb-2009
	Hypoxia tracers	FMISO-1986 ATSM-1997 FAZA-1999
Musculoskeletal	18F-FDG (Fludeoxyglucose)	1994 – epilepsy application 2000 – cancer applications 2005 – dementia application	2012
	18F-NaF (Sodium-fluoride)	1972	2015

NA, not approved yet.

Radiopharmaceuticals without FDA/EMA approval are displayed in gray.

Figure 2.

Images of the physiologic distribution of PET radiopharmaceuticals used in clinical practice: ¹⁸F-FDG, ⁶⁸Ga-PSMA, ⁶⁸Ga-FAPI, ⁶⁸Ga-DOTANOC and ¹⁸F-Florbetaben. ¹⁸F-FDG, fludeoxyglucose; FAPI, fibroblast-activation-protein inhibitor; PET, positron emmision tomogrpahy.

In the following section, PET radiopharmaceuticals bearing a major impact in oncology, neuropsychiatry, cardiology and musculoskeletal medical fields will be discussed.

Oncology

¹⁸F-FDG (Fludeoxyglucose) is a glucose analog, which enters the cell via glucose transporters and then is subsequently phosphorylated by a hexokinase. ¹⁸F-FDG-6-phosphate is not a substrate for glucose-6-phosphate isomerase and does not undergo further metabolism. Therefore, ¹⁸F-FDG is trapped within the cells as ¹⁸F-FDG-6-phosphate. It quickly became the most important PET radiopharmaceutical of the 21st century. ¹⁸F-FDG PET/CT is now recommended ⁸ in a wide variety of both solid and hematological cancers for staging, restaging and assessment of response to therapies. In addition, it is useful in the detection of primary tumors in patients with paraneoplastic syndromes and occult cancers, and it may help to distinguish between benign and malignant lesions. In some cases, it will be able to differentiate tumor recurrence/persistence from post-treatment fibrosis/necrosis, for example in colorectal and head and neck cancers following post chemoradiotherapy. ^9,10 Last but not the least, ¹⁸F-FDG is more often used for metabolic-based radiotherapy planning of a wide variety of primary and/or secondary tumors as well as guide location for biopsies.

PSMA (prostate specific membrane antigen) is a transmembrane protein expressed in prostatic tissues. Significant advances have occurred in prostate cancer staging and monitoring, with the development of PSMA ligands for PET in 2012. ¹¹ PSMA expression is increased in both benign and malignant lesions. ¹² According to the “Joint Guideline of the European Association of Nuclear Medicine and Molecular Imaging and the American Society of Nuclear Medicine and Molecular Imaging” ¹³ and the “Consensus on molecular imaging and theranostics in prostate cancer,” ¹⁴ PSMA-ligand PET is recommended in the following situations: initial staging of high-risk disease, targeted biopsy after previous negative biopsy, biochemical recurrence, and monitoring of systemic treatment in metastatic prostate cancer.

Currently, it is accepted that PSMA is expressed by a variety of malignant and benign non-prostate entities, due to its presence on the neovasculature of endothelial cells. ¹⁵ Although many different PSMA-ligands are available, fluorinated compounds seem to offer advantages, such as the ¹⁸F-PSMA-1007 that shows a unique distribution, with hepatobiliary rather than urinary excretion. ^16,17

¹⁸F-Fluciclovine (Axumin^®) is a leucine analog (FACBC amino-acid) with high cancer uptake due to increased protein turnover and nucleotide synthesis. It was approved by the FDA in 2016 and by the EMA in 2017. According to the “European Association of Nuclear Medicine (EANM) Guideline/ Society of Nuclear Medicine and Molecular Imaging (SNMMI) Procedure Standard on ¹⁸F-Fluciclovine PET/CT for Prostate Cancer Imaging” ¹⁸ its clinical indications are similar to those of PSMA-ligands PET/CT. However, it seems to have low specificity (32%–40%) for recurrent disease and low sensitivity (21%–39%) for nodal disease if PSA values are less than 1 ng ml⁻¹. ¹⁸

DOTA-conjugated peptides/ somatostatin analogs (SSA) (i.e. DOTA-NOC, DOTA-TOC and DOTA-TATE) have high affinity for somatostatin receptors, which are expressed by most neuroendocrine tumors. ¹⁹ Studies with somatostatin analogs started in the early 21st century with ¹¹¹In-Octreotide (e.g. OctreoScan^®) for scintigraphy, but the use of DOTA-conjugated peptides for PET starting in 2016 contributed to the popularity and widespread use of this examination. Despite all these radiopharmaceuticals bind to somatostatin receptor 2, they have different affinity profiles for other somatostatin receptor subtypes. ¹⁹ The “Guidelines of the European Association of Nuclear Medicine” ¹⁹ and “2016 ENETS Consensus Guidelines for the Diagnosis and Treatment of Neuroendocrine Tumours” (https://www.enets.org/basics.119.html) recommend using ²⁰ Ga-DOTA-conjugated peptides PET in well (Ki-67 <2%) and moderately differentiated (Ki-67 <20%) neuroendocrine tumors to detect the primary tumor site, to stage and restage, as well as to assess prognosis and select patients for somatostatin receptor radionuclide therapy with ¹⁷⁷Lu-DOTA-peptides SSA.

There are some other solid and hematological malignancies capable of expressing somatostatin receptors. ²¹ There is also new literature in molecular imaging with ²⁰ Ga-DOTA-conjugated peptides in cardiovascular research (e.g. cardiac sarcoidosis – NCT01729169, ²² residual post-infarction myocardial inflammation ²³ and imaging arterial wall inflammation in atherosclerosis – VISION study, NCT02021188. ²⁴

¹⁸F-DOPA is a marker of the dopa-decarboxylase activity within the pre-synaptic vesicles, and therefore capable of mapping endogenous catecholamine availability. According to “EANM Practice Guideline/SNMMI Procedure Standard 2019 for radionuclide imaging of pheochromocytoma and paraganglioma,” ^{25 18}F-FDOPA is indicated to detect small and sporadic pheochromocytomas, as well as, paragangliomas, including head and neck glomus tumors. ²⁵

Hypoxia tracers, most commonly, ¹⁸F-FMISO (¹⁸F-fluoromisonidazole), ¹⁸F-FAZA (¹⁸F-fluoroazomycin-arabinozide) and ⁷ Cu-ATSM (⁶⁴Cu-diacetyl-bis-methylthiosemicarbazone) ²⁶ passively diffuse through the cell membrane due to their high lipophilicity. Hypoxia imaging has been investigated in several solid tumors (gliomas, head and neck carcinoma, non-small cell lung cancer, breast cancer and renal carcinoma) and seems to be useful in radiotherapy metabolic planning. ^26,27

¹⁸F-FLT (Fluorothymidine) is monophosphorylated by thymidine kinase 1 (increased during the S phase of the cell division cycle), trapped intracellularly and therefore reflects tumor cell proliferation. FLT has been reported as a good predictor of early response to chemo- and radiotherapy, both in solid and hematological neoplasms. FLT uptake correlates with progression-free survival and disease-free survival. ^28,29

⁶⁸Ga-FAPI (Fibroblast activation protein inhibitor) is a compound based on a fibroblast activation protein (FAP), a specific enzyme inhibitor that targets cancer associated fibroblasts. The first clinical studies on ²⁰ Ga-FAPI PET were published in 2018. ³⁰ Advantages of this tracer include is its low background signal, nearly complete cellular internalization, quick renal clearance and no significant brain, heart or liver uptake. ³⁰ FAPI is not approved for clinical practice so far. However, breast, esophagus, lung, pancreatic, head and neck and colorectal cancers have a remarkably high uptake, suggesting that FAPI might be useful in these settings. As FAPI contains the DOTA-chelator, a theranostic approach may be possible. ^30,31 A broader application of FAPI imaging in non‐oncological diseases may also be possible. ³⁰

¹⁸F-FES (Fluoroestradiol) targets estrogen receptors and is useful for breast cancer detection (e.g. staging and restaging) and molecular characterization. ^32,33

⁸⁹Zr-trastuzumab targets human epidermal growth factor receptor two and supports clinical decisions about breast cancer patients, even when HER2 status cannot be determined by standard work-up. ³⁴

Iodine-124 is useful in cases of differentiated thyroid cancer and biochemical recurrence with no detectable site of neoplastic tissue by conventional diagnostic techniques. ^{35 18}F-FDG also plays a role in differentiated thyroid cancer recurrence and it is even more useful in poorly differentiated thyroid carcinoma. ^{36,37 18}F-FDG, ¹⁸F-FDOPA and ²⁰ Ga-DOTA-conjugated peptides are useful in medullary thyroid carcinoma management. ³⁸

Neurology and psychiatry

During the 21st century, significant developments occurred in the management of movement disorders and other central nervous system diseases.

One of the radiopharmaceuticals with higher impact on neurology practice is ¹²³I-Ioflupane (DaTscan^™), ³⁹ a ligand for the pre-synaptic dopamine transporter (DAT). The reduction of its uptake in the striatum is directly correlated to pre-synaptic dopaminergic degeneration. Its main indication is therefore the “in vivo” confirmation of the characteristic nigrostriatal degeneration in patients with idiopathic Parkinson’s disease and its distinction from essential tremor, medication-induced Parkinsonism and confirmation of Parkinsonian plus syndromes.

The corresponding pre-synaptic PET radioligand is ¹⁸F-FDOPA (e.g. ¹⁸F-PE2I). ⁴⁰ However, this is a marker of the intraneuronal vesicular transport and the dopa-decarboxylase activity. Despite its different mechanism of action, ¹⁸F-FDOPA and ¹²³I-Ioflupane may have the same indications according to the “EANM Practice Guideline/SNMMI Procedure Standard for Dopaminergic Imaging in Parkinsonian Syndromes 1.0.” ⁴¹

To map the distribution and availability of D2 post-synaptic dopamine receptors, ¹²³I-IBZM (Iodobenzamide) for SPECT and ¹¹C-raclopride, ¹⁸F-fallypride or ¹⁸F-desmethoxyfallypride for PET have been used. At present, their main clinical indication is differential diagnosis between idiopathic Parkinson’s disease and other parkinsonian plus syndromes (i.e. supranuclear palsy and multisystem atrophy). Whilst in the Parkinsonian plus syndromes the D2 post-synaptic receptors availability is markedly reduced, in idiopathic Parkinson’s disease it is normal or upregulated.

¹⁸F-FDG is useful in the diagnosis and differential diagnosis of dementias. Its brain distribution in Alzheimer’s disease is different from other types of dementia, in particular Lewy Body dementia, frontotemporal lobar degeneration, vascular dementia and from cases of pseudodementia. ⁴²

β-Amyloid tracers are used in the identification of one of the neuropathological hallmarks of Alzheimer’s disease, i.e.abnormal deposition of β-amyloid in the brain. The first radiopharmaceutical to map β-amyloid in the brain was ¹⁸F-FDDNP. ⁴³ Later, the introduction of ¹¹C–labeled Pittsburgh compound B (¹¹C-PIB) ⁴⁴ in 2004 enabled detection of brain β-amyloid deposition in vivo. In 2015, the FDA and EMA approved three fluoride-18-labelled amyloid PET radiopharmaceuticals for clinical use: florbetaben (Neuraceq^®), florbetapir (Amyvid^®) and flutemetamol (Vizamyl^®). The “SNMMI Procedure Standard/EANM Practice Guideline for Amyloid PET Imaging of the Brain 1.0” ⁴⁵ suggests amyloid PET in cases of persistent or progressive and unexplained mild cognitive impairment, when core clinical criteria for possible Alzheimer’s disease are satisfied but there is a doubtful clinical presentation or dementia is progressive and early onset. Both positive and negative results significantly influence diagnosis and treatment of patients. ⁴⁶ The potential use of amyloid PET tracer accumulation in cerebral white matter as a marker of myelin is also being investigated. ⁴⁷

Tau-tracers for PET imaging include several first- and second-generation compounds used to detect mild cognitive impairment patients that are actively converting to Alzheimer disease, thus improving its early diagnosis. Tau-tracers have high correlation with neurodegenerative markers and clinical severity of dementia. ^48,49

Amino-acids tracers include ¹¹C-MET (methionine), ¹⁸F-FET (tyrosine), ¹⁸F-FACBC (fluciclovine) and ¹⁸F-FDOPA. Amino-acids are essential nutrients, involved in metabolism, cell growth, protein synthesis and gene expression. ⁵⁰ Besides glucose, certain amino-acids are also energy sources and anabolic precursors for tumors. Amino-acid PET tracers can overcome limitations of ¹⁸F-FDG because there is low amino-acid uptake in normal brain and in inflammatory cells, enabling identification of primary and metastatic brain tumors. According to the “Joint EANM/EANO/RANO practice guidelines/SNMMI procedure standards for imaging of gliomas using PET with radiolabelled amino acids and FDG,” ⁵¹ amino-acids tracers are also useful for therapy monitoring, tumor recurrence detection (differentiating true recurrent disease from pseudoprogression and radionecrosis), biopsy guidance, as well as surgery and radiotherapy planning. ^51,52

Perfusion tracers may be used to evaluate brain perfusion in the context of cerebral ischemia, through the determination of cerebral blood flow and cerebral metabolic rate of oxygen consumption. ⁵³

Cardiology

¹⁸F-FDG is helpful to evaluate myocardial viability (in case of myocardial infarction, stunned and hibernating myocardium), to detect endocarditis, infection of cardiac devices, metastatic or infectious foci and endothelial inflammation due to atherosclerosis plaque formation.

Perfusion tracers include Thallium-201 chloride in use since the 70’s and ^99mTc labelled radiopharmaceuticals (Sestamibi and Tetrofosmin) in use since the 90’s for SPECT myocardial perfusion. Recently (Table 1), PET perfusion radiopharmaceuticals became available including Rubidium-82 chloride, ¹³N-Ammonia, ¹⁵O-Water and ¹⁸F-Flurpiridaz. ^54,55 According to “ASNC imaging guidelines/SNMMI procedure standard for PET nuclear cardiology procedures,” ⁵⁵ non-invasive imaging of myocardial perfusion is useful for diagnosis and management of patients with known or suspected coronary artery disease, enabling absolute quantitative PET measurements of myocardial blood flow (millilitres per gram per minute). Moreover, it allows identification of early atherosclerosis or microvascular dysfunction and assessment of balanced reduction of myocardial blood flow in the major coronary arteries territories. ^54,55

Musculoskeletal

¹⁸F-FDG is useful when arthritis, synovitis and vasculitis (e.g. polymyalgia rheumatic and large vessel vasculitis) are suspected, mainly to locate inflammatory active sites and to monitor response to therapy. ⁵⁶

¹⁸F-NaF is a bone seeking agent that marks bone remodelling activity. Its main clinical indications are identification and anatomical extension of bone metastases and primary bone malignancies. Additionally, benign bone disease and orthopaedic lesions can be also evaluated. ⁵⁷ The clinical use of this PET radiopharmaceutical may increase due to the ongoing global Molybdenum-99 shortage and possible reduction of bone scan procedures. ⁵⁸

Developments in equipment

Advances in PET systems

Commercial preclinical PET systems can provide unprecedented high spatial resolution reaching 0.55 mm full width at half-maximum (FWHM) values. Common preclinical PET systems are based on photomultiplier tubes (analog or digital) attached to a single or multiple scintillation crystal. A different approach based on resistive plate chamber has been proposed with a preclinical prototype reaching a 0.4 mm FWHM spatial resolution. ⁵⁹ Current commercial preclinical PET systems allow combined imaging with CT, MRI or SPECT.

In terms of commercial clinical PET-imaging systems, there is a range of different PET/CT systems available from different vendors with the top-of-the-line systems now being equipped with digital detector technology. In some of them, the spatial resolution is slightly better than 4 mm. ^60,61 Digital systems are now using silicon photomultipliers (SiPM) attached to the crystal instead of analog photomultiplier tubes (PMT). The majority of PET systems use lutetium oxyorthosilicate (LSO) or lutetium yttrium oxyorthosilicate (LYSO) as scintillator materials. ⁶² They provide grossly similar compromise between energy resolution, stopping power and dead time.

Clinical PET/MRI is less available than clinical PET/CT, but significant developments have recently occurred. Currently, there are two clinical human whole-body PET/MRI commercially available: the Biograph mMR (Siemens Healthineers) and the Signa PET/MRI (GE Healthcare). Considering the advantages of MRI relatively to CT, PET/MRI systems might have potentially higher diagnostic accuracy than PET/CT especially in organs such as liver, prostate and head neck region among others. ^63,64 Furthermore, problems with co-registration of PET and MRI images performed at different moments and in different equipment settings have practically disappeared. Initial issues related to attenuation correction based on MRI are solved for the majority of tissues (bone being the exception), achieving SUV deviations less than 10%, similar to PET/CT. ^7,65

There are already clinical systems available which combine three modalities (e.g. AnyScan SPECT–CT–PET from Mediso Medical Imaging Systems). These may be a suitable and attractive option for small nuclear medicine departments.

Time of flight

Time of flight (TOF) technology has improved significantly over the last decade thanks to the development of SiPM and introduction of scintillators with better performance, like LSO and LYSO. ⁶⁶ Recent clinical PET systems have very low coincidence time resolution (CTR), e.g. currently stated as low as 210 ps FWHM. ⁶¹ Experimental set-ups have achieved CTR inferior to 100 ps FWHM. ⁶⁶ TOF information spatially narrows down the event location. A positron emission precise location of around 1.5 cm is achieved by these experimental setups based only on the time difference between the detection of both photons emitted from the positron annihilation (Figure 3). In the future, with the continuous CTR reduction, PET reconstruction algorithms may no longer be necessary, since the line of response (LOR) identification and the time difference of the detection will give an accurate positron annihilation location. So far, TOF technology has improved the reconstructed image signal to noise ratio and reconstruction algorithm convergence speed.

Figure 3.

Illustration of the TOF principle. Annihilation of the positron originates two 511 kev photon that are detected by PET detectors. Taking the time difference between detection and speed of light, annihilation distance difference to both detectors can be easily computed ( $d_1-d_2=\left(t_1-t_2\right)\times c$ , where $c$ is the speed of light and $t_1$ and $t_2$ are the times of the detection). If the time measurements had no error, the exact position of the annihilation in the LOR could be computed, assuming the two photons describe exactly a 180° angle. Uncertainty of the time measurements is modulated by the TOF probability distribution. LOR, line of response; PET, positron emmision tomography; TOF,

Total-body PET

Recently, the first total-body PET, the EXPLORER PET/CT, ^67,68 has been introduced. It has an axial field of view of 194 cm, allowing it to cover the entire adult human body in a single acquisition in more than 99% of the cases. ⁶⁸ Since it covers the entire body in a single acquisition, it is possible to perform total body dynamic acquisitions simultaneously, facilitating application of kinetic models to estimate the transfer rates between compartments. Therefore, total body radiopharmaceutical distribution studies are now possible. Despite its developmental stage, it already reaches a spatial resolution of approximately 2.9 mm, ⁶⁸ which is an improvement compared to the commercially available state-of-the-art PET/CT scanners. Another advantage is the higher sensitivity, allowing a reduction in acquisition time by 1–2 min, even with lower injected activity than in current clinical practice. This improves patient comfort, reduces movement artifacts and radiation exposure. Financial constraints and space requirements are barriers towards widespread use of these scanners.

Advances in SPECT systems

Recently, commercial preclinical SPECT systems have reached very high spatial resolution, partly even higher than PET. For instance, the U-SPECT from the MILabs has a 0.12 mm FWHM (ex vivo examinations) and 0.25 mm (in vivo examinations).

Solid-state detectors based on cadmium zinc telluride (CZT) have better energy and spatial resolutions compared to conventional systems (crystals coupled to PMT). These new detectors have already been incorporated into SPECT systems. An example is the NM/CT 870 CZT SPECT/CT (GE Healthcare) with planar arrays of detectors. Other example are the VERITON and VERITON-CT (Spectrum Dynamics) with 12 independent detector arms providing 360° coverage to perform whole-body SPECT scans. The remarkably improved CZT’s energy resolution is more suitable for dual radionuclide acquisition studies than sodium iodide scintillators used in conventional γ cameras. ²⁰ It is also often used for dedicated cardiac SPECT cameras.

An approach similar to the VERITON, but not based on CZT technology, is proposed by MILabs G-SPECT with a 3 mm FWHM spatial resolution. ⁶⁹ This was developed for large animals and may be suitable for human brain SPECT.

In this paper, we focused mainly on whole-body imaging solutions, but there are several clinical SPECT and PET systems designed for specific applications. ²⁰

Quantification

PET/CT is a quantitative technique and, frequently, semi-quantitative techniques rather than absolute quantification (real radiopharmaceutical concentration) have been used. The standardized uptake value, mostly used in PET/CT, has now been implemented to SPECT/CT. Ratios between a region of interest and a reference region uptake have also been frequently used. ^70,71 In 2006, the leadership of the EANM launched EANM Research Ltd (EARL^©http://earl.eanm.org/cms/website.php) to promote multicentre nuclear medicine and research. The main aim was to harmonize quantification among different equipment in a wide range of tumor types, with focus on therapy assessment using either the European Organization for Research and Treatment of Cancer (EORTC) criteria, PET Evaluation Response Criteria in Solid Tumors (PERCIST) and Deauville score for lymphoma. The accreditation program is available for ¹⁸F-FDG PET/CT, ⁷² Zr-PET/CT and PET/MRI. ^73,74 Nevertheless, some authors have evaluated the impact these reconstructions algorithms may have on image interpretation and advised that new reconstruction algorithms should not be used alone for response assessment, but rather complemented with a second data set reconstruction with another algorithm (e.g. ordered subset expectation maximization (OSEM) reconstruction for Deauville score). ⁷⁵

Dynamic acquisitions allow kinetic parameters quantification, such as transference rates between tissue compartments. They have been used only in a research setting due to practical reasons, because long acquisition time and arterial cannulation are needed. In some specific applications, arterial input function obtained from arterial cannulation may be replaced by the concentration over time in a reference region, ⁷⁶ usually the heart, a vessel or a region without specific uptake. This has been shown to be comparable to quantification with arterial sampling.

Radiopharmaceutical applications in therapy and theranostics

Dual probes and optical imaging

Radio-guided surgery actively encompasses non-invasive molecular imaging and minimally invasive surgery. Handheld detectors are mobile devices used intraoperatively to detect radiopharmaceutical distribution during surgery after diagnostic localization. These are mostly γ handheld detectors, depending on the type of radioisotopes administered. Initially used to locate parathyroid adenomas early in 21st century, at present, the most common image-guided surgery applications are for sentinel node procedures ³ using ^99mTc-labelled radio-nanocolloids (melanoma, breast, ⁷⁷ cervical, ⁷⁸ vulvar, penile and head and neck cancers ⁷⁹ and radioguided occult lesion localization procedures using ^99mTc-labelled macroaggregates (breast, lung and thyroid cancers). Additionally, clinical reports on metabolic targeted surgical resections using different radiopharmaceuticals (e.g. ¹⁸F-FDG ⁶⁸Ga-PSMA and ⁶⁸Ga-DOTATATE) for other tumors have been published. ^3,80–82

During the last decade, there has been a significant development of bimodal imaging probes applicable in PET as well as in optical imaging (OI). ^4,83 The main advantages are related to the combination of higher tissue penetration of γ radiation resulting from positron emitter radionuclides (allowing non-invasive quantitative imaging and tumor detection) and light emitted by the fluorescent probe for optical imaging during surgery, in particular, robotic surgery.

Different types of optical imaging can be used with hybrid PET/OI procedures ⁸³ : (i) fluorescent protein molecules, (ii) Cherenkov luminescence imaging, (iii) near-infrared light and (iv) quantum dots from Cd/Te or Cd/Se materials. Substances emitting light within the near-infrared and infrared spectrum (700–900  nm) are most useful, as light of these wavelengths exhibit “in vivo” the highest tissue permeability from several millimetres to slightly more than 1 cm. ⁸³ This feature offers the possibility to use hybrid probes during both open and laparoscopic surgery. Recently, it has been shown that an integration of hybrid detection probes with surgical navigation systems is able to produce three-dimensional fluorescence tomography reconstructions (e.g. freehand fluorescence scans) ^83,84 (Figure 4). It is likely that in the near future the increasing trend to combine radioguidance with other imaging signatures (fluorescence, Cerenkov, optical coherence tomography, and ultrasonography) and software-based guidance solutions (surgical navigation and augmented mixed/virtual reality displays) will lead to significant changes in surgical procedures. ^3,80

Figure 4.

Evolution sequence of radioguided surgery (adapted from Van Oosterom et al). ³ Both γ and positron emitting radiopharmaceuticals can be used.

Theranostics

There is a significant growth in number of therapeutic applications of radiopharmaceuticals. This opens new avenues of clinical interest to the Nuclear Medicine specialty. Theranostics is its most important concept. It combines diagnostic and therapeutic capabilities with radiopharmaceuticals derived from binding to a specific molecular target. Theranostic applications use the same molecule labeled with a γ or positron emitter radionuclide for diagnosis and a β minus or α emitter radioisotope for therapy. ^85,86

For almost 80 years, the best-known theranostic paradigm is represented by radioactive iodine, namely the pair Iodine-123 (γ emitter) – Iodine-131 (β minus emitter) for thyroid disease diagnosis and therapy, respectively. The first Iodine-131 treatments for hyperthyroidism were in 1941 ⁸⁷ and 1946 for thyroid cancer. ⁸⁸

Another example is metaiodobenzylguanidine (MIBG) labeled with Iodine-123 or Iodine-131 for advanced pheochromocytoma and neuroblastoma diagnosis and treatment, respectively. Bone imaging and palliation with radiolabeled bisphosphonates (e.g. ^99mTc-HDP and ¹⁸⁸Re-HEDP) is another longstanding example.

Recently, several studies demonstrated the efficacy of systemic therapy with peptide receptor radionuclide therapy in patients with advanced metastatic neuroendocrine neoplasms, using somatostatin-analogs (e.g. DOTA-TATE and DOTA-TOC) labeled with either Yttrium-90 or Lutetium-177. The first randomized controlled Phase III study, NETTER-1, ⁸⁹ showed a significant clinical benefit from this therapy, achieving a prolonged progression-free survival of around 40 months, an overall response rate of 18% and presumably, a longer overall survival (median not reached) than standard treatment. This treatment, ¹⁷⁷Lu-DOTA-TATE (Lutathera^®), was approved by EMA in 2017 and FDA in 2018.

During the last 5 years, several studies have demonstrated treatment efficacy of ¹⁷⁷Lu-PSMA ligands, reaching biochemical response in more than 50% of the patients. Partial response, measured by imaging, was achieved in more than one-third of the total number of patients. ⁷² Several clinical trials are ongoing. The VISION Phase III trial aims for approval of ¹⁷⁷Lu-PSMA-617 (NCT03511664).

Despite the utility of β-minus emitters (Yttrium-90 and Lutetium-177), α-emitters (Actinium-225 and Astatine-211) have the major advantage of lower penetration power, resulting in a more potent absorbed dose to the tumoral lesions. Good overall treatment response and reduced adverse effects have led to increasing research and development in this field and new therapeutic agents will soon be available. ^90–95

Conclusion

Nuclear Medicine and Molecular Imaging are versatile specialties with significant impact on both diagnosis and therapy. Their success and future depends on further innovation of radiopharmaceuticals, hardware equipment, regulatory acceptance and approval.

The development and success of new radiopharmaceuticals is expected. Onsite labelling using generators will positively affect clinical practice within Nuclear Medicine departments.

Both PET and SPECT technologies are rapidly evolving, embedded in hybrid devices, and the adjunction of MRI makes the field even more versatile. Multimodality imaging will continue to enhance PET use in the coming years. The evolution of PET systems will further improve significantly in terms of sensitivity and spatial/timing resolution with the continuous improvement of scintillators and electronics. Also, total-body scanners, dual-probes and optical imaging may bring significant benefits to diagnostic accuracy, radiation exposure and cost-efficiency, ultimately leading to highly personalized imaging and subsequent treatment.

Finally, theranostics encompasses two worlds, introducing the concept of personalized and targeted-treatment into state-of-the-art clinical routine. Further accelerated developments and wider use of radiolabeled nuclide therapies is likely to happen in the years to come within the 21st century.