Research ArticleSupplement

The Role of Total-Body PET in Drug Development and Evaluation: Status and Outlook

Xiangxi Meng, Xiangxing Kong, Lei Xia, Runze Wu, Hua Zhu and Zhi Yang
Journal of Nuclear Medicine May 2024, 65 (Supplement 1) 46S-53S; DOI: https://doi.org/10.2967/jnumed.123.266978

Abstract

Total-body PET, an emerging technique, enables high-quality simultaneous total-body dynamic PET acquisition and accurate kinetic analysis. It has the potential to facilitate the study of multiple tracers while minimizing radiation dose and improving tracer-specific imaging. This advancement holds promise for enhancing the development and clinical evaluation of drugs, particularly radiopharmaceuticals. Multiple clinical trials are using a total-body PET scanner to explore existing and innovative radiopharmaceuticals. However, challenges persist, along with the opportunities, with regard to the use of total-body PET in drug development and evaluation. Specifically, considerations relate to the role of total-body PET in clinical pharmacologic evaluations and its integration into the theranostic paradigm. In this review, state-of-the-art total-body PET and its potential roles in pharmaceutical research are explored.

Since the beginning of the 20th century, the field of drug discovery and development has undergone continuous evolution in the pursuit of finding the zauberkugel (magic bullet) (1) that specifically interacts with the molecular and cellular targets associated with diseases. As a realization of this concept, radiopharmaceuticals have been engaged in molecular imaging, radioisotope therapy, and related theranostic strategies.

The development of radiopharmaceuticals is a complex and time-consuming process. Compared with regular drugs, additional challenges relate to their special requirements, such as dosage dependence, radiation safety, and short shelf-life (2). Because PET and SPECT imaging play a crucial role in the application of radiopharmaceuticals, advancements in imaging technologies can thus expedite drug development in both preclinical and clinical study stages.

PET imaging visualizes the administration and biodistribution of labeled molecules in living organisms, accurately quantifying the metabolism of positron emitters. Through PET images, the pharmacologic characteristic of the drug can be noninvasively assessed in living animals and human subjects. In the development and evaluation of positron-emitting radiopharmaceuticals, PET imaging inevitably assumes the central role. Beyond PET tracer development, PET imaging is used to assess the effects in clinical trials of other therapeutic products. In general, PET imaging provides insights into the pharmacokinetics, pharmacodynamics, safety, efficacy, toxicity, dosage regimen, and response monitoring in the clinical trials (3).

Facing uncertainties and unknown properties, the use of PET imaging in drug development is more challenging than in clinical routines. Clinical trials often demand unconventional scanning conditions, such as ultrashort duration, ultralow dose, and ultralong uptake time, and these special requirements challenge conventional PET scanners. Equipment developers strive to pursue higher performance to meet these demands.

Several technologies mark the paradigm shift in PET imaging, and among them, total-body PET is especially intriguing. After the successful introduction of the world’s first total-body PET/CT scanner, the United Imaging uEXPLORER PET/CT scanner (4), several other models with the long-axial-field-of-view feature have emerged (5), including PennPET EXPLORER (6) and Siemens Biograph Quadra (7). Other long-axial-field-of-view or total-body scanners are being developed, but uEXPLORER is the only clinically available total-body scanner (5). Despite its high investment cost, the unparalleled image quality and enhanced detection ability of total-body PET indicate particular advantages in clinical scenarios (8). Clinical evidence is being accumulated, and the comparative value of total-body PET scanners versus conventional PET scanners with a shorter axial field of view has been manifested.

Therefore, it is not surprising that total-body PET technology is poised to have substantial influence on drug development, particularly in the field of radiopharmaceuticals. This review commences by introducing possibilities brought by total-body PET and assessing their potential impact on drug development. Next, we review the current research experience of using total-body PET to study novel tracers. In the end, we discuss the challenges and the opportunities of total-body PET in drug development and evaluation.

NEW POSSIBILITIES IN DRUG DEVELOPMENT WITH TOTAL-BODY PET

The physical attributes and imaging characteristics of total-body PET have been elaborated upon extensively in previous review articles (9–11). This new technology dramatically improves sensitivity and system performance, enabling a series of applications. Some of these applications are likely to profoundly affect drug development and evaluations.

High-Quality Whole-Body Dynamic Imaging and Kinetic Studies

PET imaging has been used in the study of physiologic mathematic models of tracer kinetics since its early days (12). Conventional PET acquisition comes from the time-weighted distribution of tracers within a given duration. To study the kinetic behavior, a sequence of frames can be reconstructed to obtain tracer distribution at multiple time points. However, in vivo transport phenomena and various physiologic processes often occur at rates faster than most PET scanners could capture. Processes such as blood circulation, respiration, and heartbeat require subsecond-temporal-resolution image reconstruction, which is challenging to achieve with conventional PET scanners. Therefore, state-of-the-art technologies are indispensable when conducting kinetic studies using PET.

Total-body PET brings time resolution to another level. Using the kernel expectation maximization method, a temporal resolution of 0.1 s was achieved for dynamic PET reconstruction of the initial stage after tracer injection with total-body PET (13). This unprecedentedly high frame rate is sufficient for the study of blood flow and cardiac cycles, visualizing the circulation of a drug molecule in the distribution stage.

Dynamic PET images represent tracer distribution across a period, facilitating the application of mathematic modeling in the study of tracer kinetics. The most widely used model in kinetic modeling is the compartment model, followed by spectral analysis. In studies with [18F]FDG, the kinetic parameter Ki is important, because it correlates with the glucose metabolic rate (14). However, for some more sophisticated applications, parameters such as the distribution volume, binding potential, and microparameters (K1, k2, k3, …) should be used to elucidate the pharmacokinetic properties. Kinetic parameters reflect multiple facets of pharmacologic effects, such as influx, drug–receptor interaction, and elimination. For drug development in particular, correlating kinetic parameters with biologic processes at the molecular and cellular levels provides a functional interpretation of tissue activity. These parameters can be calculated voxel by voxel, and the parameter map thus obtained may provide information about metabolism and disease progression. Total-body PET enables simultaneous acquisition of dynamic images of the entire body, allowing the calculation of parameter maps that cover all organs and tissues of interest. This capability proves especially beneficial when comprehending the physiologic characteristics of the entire body (15) and studying systematic diseases, as well as brain–body interactions.

Studying Multiple Tracers with a Lower Radiation Dose

Molecular imaging provides tools for molecular medicine by visualizing and quantifying in vivo processes, as well as interactions, among various molecular and cellular entities, enabling precise and personalized disease identification. PET tracers can be used to study metabolic pathways involving glucose, glutamine, and nucleotides (16,17); signaling pathways such as ErbB, VEGF, and PARP (18–20); and immune mechanisms involving CD4/CD8, PD1/PD-L1 (21,22), and more. However, because of the complexity of the physiologic system, the combination of multiple PET tracers is often required in the development of drugs or to diversify the application strategy of these drugs. For example, for certain neuroendocrine cancer patients, a [68Ga]Ga-DOTATATE and [18F]FDG dual-scan protocol has been proven to achieve favorable prognostic performance by evaluating somatostatin receptor expression and glycolysis level, respectively (23).

However, clinical applications and clinical trials involving a protocol of repeated PET scans raise concerns related to radiation protection and medical ethics, because patients or volunteers are exposed to an extra radiation dose from the tracer and the CT scans compared with scenarios in which only 1 tracer is used. The higher sensitivity of total-body PET presents a potential solution to obtain satisfactory diagnostic images with a fraction of the dose level required by conventional PET (24). Ultra-low-dose (0.37 MBq/kg for [18F]FDG) acquisition is even feasible in dynamic PET acquisitions (25).

Traditionally, in PET imaging, a CT scan often has been necessary to obtain the attenuation map for implementing physical corrections, such as attenuation and scattering corrections. However, in drug development studies that involve multiple tracers and repeated scans, the cumulative x-ray exposure from these CT scans can be a concern. In total-body PET scanners, the prompt γ-photons accompanied by the β− decay of 176Lu from the lutetium–yttrium oxyorthosilicate crystals are sufficient to provide a transmission scan of the subjects. Through algorithms such as maximum-likelihood transmission reconstruction, the background radiation acquired around 307 keV can be reconstructed to attenuation maps without introducing extra radiation to the patients receiving total-body PET scans (26,27).

Continual efforts have been undertaken to achieve simultaneous PET images of multiple tracers through several proposed signal-unmixing methods (28). Total-body PET technology may bring new solutions to this long-sought objective.

Tracer-Specific Image Enhancement with Total-Body PET

Supervised learning, as well as weakly or semisupervised learning, in medical image enhancement requires high-quality images as labels. With its unprecedented image quality, total-body PET provides an excellent platform for such scenarios (29,30). In this way, the image quality of short-axis PET can be improved, as shown in Figure 1.

FIGURE 1.
FIGURE 1.

Representation of image enhancement model trained with total-body PET scans and its application with short-axis PET. OSEM = ordered-subset expectation maximization.

Several learning strategies based on this concept have been proposed. The deep progressive learning reconstruction algorithm constructs 2 neural networks to perform image denoising and image enhancement, respectively, and to incorporate them into the reconstruction process (31,32). The deep progressive learning reconstruction algorithm has shown nice performance in clinically oriented scenarios, but it has been tested only on [18F]FDG scans.

However, discrepancies among images of different tracers are likely to deteriorate the generalization ability of such models, given the inherent differences in their noise distribution and other statistical characteristics. There is a need to accumulate images of different tracers for the models to adapt to different tracer-specific applications (33).

TRACERS DEVELOPED WITH TOTAL-BODY PET

Total-body PET scanners in top medical centers have already been involved in the clinical trials of tracers. Table 1 summarizes some registered clinical trials. Initial experiences can be learned from these trials, which can be roughly categorized into trials that further develop the clinically available tracers and those involving innovative, often first-in-humans tracers.

View this table:
TABLE 1.

Selected Registered Clinical Trials Related to New Tracers

Extending the Scope of Clinically Available Tracers and Classic Targets

In recent years, positron-emitting tracers have been emerging. Among them, several types of tracers have received extra research interest, namely, prostate cancer imaging probes targeting the prostate-specific membrane antigen (PSMA) receptor or prostate-specific antigen (34), neuroendocrine tumor imaging probes targeting the somatostatin receptor (35), radiolabeled fibroblast active protein (FAP) inhibitors (FAPIs) focusing on FAP and cancer-associated fibroblasts (36), and metabolite positron tracers involving biomolecules, such as amino acid, nucleotide, and other small molecules (37). Although a handful of these tracers have already been approved for clinical use in at least 1 country or region, trials after approval or investigator-initiated trials using total-body PET are continuously updating our knowledge on their pharmaceutical aspect. Moreover, a “me-better” version of drug innovation can be derived from these targets.

Recently, PSMA-targeted compounds for diagnostic and therapeutic uses have been the focus of the radiopharmaceutical development, and clinical trials involving PSMA tracers have been conducted with total-body PET. When [68Ga]Ga-PSMA-11 is used, the image quality of total-body PET has been demonstrated to be superior to that of conventional scanners, bringing a higher detection rate of lesions (38). A half-dose [68Ga]Ga-PSMA-11 scan was found to provide noninferior diagnostic ability in patients with biochemical recurrent prostate cancer (39), whereas a single-center retrospective study with total-body PET found that the SUVmax of the prostate can be an independent predictor for prostate cancer diagnosis (40). With dynamic imaging using total-body PET, the optimal imaging time window of [68Ga]Ga-PSMA-11 has been revealed to be 35–59 min after injection (41). A study on another long-axial-field-of-view scanner also proposed late-stage imaging with the same tracer (42). Dynamic imaging was performed with [68Ga]Ga-PSMA-11 and fitted with 2-tissue- and reversible 2-tissue-compartment models. Further diagnostic analysis showed that microparameters are capable of distinguishing normal organs from lesions (43). Using the irreversible 2-tissue-compartment model, the parametric images of this tracer were prepared and showed better lesion detectability than static images (44). Kinetic analysis of the 18F-labeled [18F]AlF-PSMA-11 was also performed, assuming a reversible 2-tissue model (45). In PSMA radioligand therapy, the salivary glands are among the dose-limiting organs. Total-body dynamic PET verified the effectiveness of oral vitamin C administration in radiation protection of the salivary glands with [68Ga]Ga-PSMA-11 (46). Besides PSMA, [18F]fluciclovine has been imaged with a total-body scanner in a center (47).

Among the somatostatin receptor probes, DOTATATE is the best-studied one because of its merits in diagnosis and peptide receptor radionuclide therapy. In combination with [18F]FDG, [68Ga]Ga-DOTATATE can fully exploit the comprehensive diagnostic capability of total-body PET, and low-dose acquisition is sufficient in such scenarios (48). To optimize the acquisition scheme, a time regimen adjusted with patient body weight was proposed and validated on total-body PET (49). Taking advantage of the dynamic imaging ability, the kinetic behavior of [68Ga]Ga-DOTATATE in normal organs has also been studied (50).

FAPI PET is an emerging diagnostic tool in oncology and other fields, such as cardiology and immunology. As with other tracers, the low-dose acquisition of FAPI has also been studied. [68Ga]Ga-FAPI-04 PET images can be acquired at half-dose (∼0.1 MBq/kg) and a 120-s duration after 35–75 min of uptake time with total-body PET and maintain diagnostic efficiency (51). The earliest optimal time window, 34–60 min after half-dose [68Ga]Ga-FAPI-04 injection, was validated using dynamic imaging with total-body PET (52). Alternatively, a full-dose injection of [68Ga]Ga-FAPI-04 with an acquisition of 30 s at 5 min after injection was conducted. This ultraearly and fast acquisition scheme was found to meet the clinical requirement and thus can be used in patients with poor tolerance (53). As shown in Figure 2, a 1-stop dual-tracer imaging protocol was devised to provide information about the tumor and the stroma simultaneously, using low-dose [18F]FDG and [68Ga]Ga-FAPI-04 (54). The kinetic behavior of [68Ga]Ga-FAPI-04 has also been studied using total-body PET, and with the reversible 2-tissue compartment model, parametric maps for pancreatic and gastric cancer patients were obtained (55). Another study established the correlation between the tumor-to-blood ratio and the distribution volume Vt of pancreatic cancer lesions (56). Clinical applications of FAPI imaging beyond oncology were explored using a total-body PET scanner, including a case of MDA5 dermatomyositis showing high muscle uptake of [68Ga]Ga-FAPI-04 (57) and a comparative study using [18F]AlF-FAPI-42 and [18F]FDG to evaluate acute kidney injury in cancer patients (58). [18F]AlF-FAPI-42 has also been systematically studied using total-body PET (59).

FIGURE 2.
FIGURE 2.

Schematic of 1-stop [18F]FDG and [68Ga]Ga-FAPI-04 imaging protocol. D30–40 = static reconstruction of dual-tracer acquisition between 30 and 40 min after [68Ga]Ga-FAPI injection; D50–60 = static reconstruction of dual-tracer acquisition between 50 and 60 min after [68Ga]Ga-FAPI injection.

Metabolite PET tracers are usually small molecules that are often labeled with low-atomic-number positron emitters with a short radioactive half-life. Using total-body PET, these tracers can be visualized in an extended time window. Metabolite tracers with a short-half-life positron emitter that have been studied with total-body PET include [13N]ammonia (60), 1-[11C]butanol (61), and [11C]methionine (62). Their kinetic behavior, pathologic correlations, and accurate dosimetry have been studied using this technique.

Studies have also been conducted using multiple tracers on total-body PET. A case was reported in which [18F]FDG, [68Ga]Ga-PSMA, and [68Ga]Ga-DOTATATE PET images were acquired separately on a patient who had metastatic prostate adenocarcinoma with neuroendocrine differentiation, taking advantage of ultra-low-dose imaging (63). Dynamic PET images of [18F]FDG, [68Ga]Ga-PSMA-11, and [68Ga]Ga-FAPI-04 were acquired using total-body PET on different cohorts, and the biodistribution and radiation dosimetry of these tracers were analyzed (64).

Early-Stage Trials of Innovative Tracers

An investigator may initiate a clinical trial with an innovative positron tracer once the institutional review board and other administrative entities have granted permission. At this stage, it is most likely to be a first-in-humans study of a pharmaceutical entity. Several trials in the early stage are using total-body PET to develop innovative tracers.

With understanding of the structure–activity relationship of the tracer molecules, the tracer [18F]AlF-FAPITG was designed on the basis of the FAPI pharmacophore. A glucosamine-conjugated Asp2Glu peptide with a di(ethylene glycerol) linker moiety was inserted into the molecular structure of NOTA-FAPI-42. This modification significantly altered the hydrophilicity of the molecule and the tracer biodistribution and reduced the gallbladder and bile duct concentration (65). A slightly modified molecule, [18F]AlF-FAPIT, showed similar performance. Using total-body PET, the biodistribution of the tracer was compared with that of [18F]AlF-FAPI-42 in a healthy volunteer, validating the lowered gallbladder uptake (66).

The use of radiolabeled molecules for noninvasive visualization and targeting of specific biomarkers, such as nectin-4 in various malignancies, may lead to significant advancement in diagnostic imaging and potential therapeutic applications. In this context, a bicyclic peptide, BT8009 (Bicycle Therapeutics), targeting nectin-4 was radiolabeled with 68Ga, and the resulting tracer, [68Ga]Ga-N188, was validated in animal models, as well as a cohort of healthy volunteers and patients with advanced urothelial carcinoma. Total-body PET imaging was conducted to evaluate the dynamic characteristics and organ distribution of the tracer (67), as shown in Figure 3

FIGURE 3.
FIGURE 3.

(A) [68Ga]Ga-N188 PET image of healthy volunteer 30–35 s after injection. (B) SUVmax in organs (kidney, aorta, liver, spleen, lung, and brain) obtained from dynamic total-body PET images of patients injected with 1.23 MBq/kg [68Ga]Ga-N188. (C) Organ uptake in all 16 healthy volunteers and patients at 40 min after injection, as shown by static [68Ga]Ga-N188 PET imaging and indicated by SUVmax. (Reprinted from (67).)

Total-body PET imaging, combined with physiologically based pharmacokinetic modeling, offers insights into the kinetic behavior of pharmaceuticals across multiple organs and tissues. Aptamer is a class of oligonucleotides with targeting ability, and their pharmaceutical applications recently have been recognized. Among aptamers, SGC8 is a promising one that targets protein tyrosine kinase 7, a key member of cancer-related signaling pathways. With total-body PET, radiolabeled [68Ga]Ga-NOTA-SGC8 was studied in cancer patients. Dynamic images over durations of 15, 30, and 60 min were acquired, and a physiologically based pharmacokinetic model was developed using dynamic PET data (68).

Antibody derivatives include the fragments of monoclonal antibodies and other engineered peptides with similar properties. Minibodies, single-domain antibodies, Affibody molecules (Affibody AB), and other antibody derivatives constitute a set of versatile tools for designing molecular probes, and they demonstrate diverse biologic behaviors. In a recent study (69), a minibody targeting human CD8 (∼80 kDa) was radiolabeled with 89Zr (78.4-h half-life) to obtain the tracer [89Zr]Zr-Df-crefmirlimab. This tracer was used to reveal the distribution of CD8+ cells. Total-body PET images at different time points, ranging from 30–90 min to 48–49 h, were acquired in a cohort of healthy individuals and coronavirus disease 2019 patients. Various compartment models were used to evaluate the tracer kinetics in different organs, and it was found that the influx rate Ki, as well as the tissue-to-blood ratios of the bone marrow, showed a significant difference between healthy volunteers and coronavirus disease 2019 patients. A Nanobody (Ablynx)-based tracer, [68Ga]Ga-HNI01, was developed to visualized the in vivo distribution of carcinoembryonic antigen. Colorectal carcinoma patients were recruited and underwent total-body PET scans using [68Ga]Ga-HNI01. The dynamic images were acquired and reconstructed, showing the biodistribution of the tracer (70). In another study (71), 2 Affibody-based tracers were compared, namely, [18F]AlF-RESCA-HER2-BCH and [18F]AlF-NOTA-HER2-BCH. Although the only difference between them is the chelator, the RESCA tracer showed significantly lower renal accumulation than the NOTA tracer, as demonstrated by total-body PET imaging at 2 and 4 h after injection. In those pharmacologic evaluations, total-body PET played a central role.

CHALLENGES AND OPPORTUNITIES

Total-body PET/CT scanners have shown promise in advancing drug development and clinical evaluations, but there is considerable potential for further use of this technology. In the future, we expect to witness the increased influence of total-body PET on drug development and clinical evaluations.

In drug development, elucidating pharmacokinetic behavior not only is required by regulatory bodies during the investigational new drug phase but also constitutes a crucial factor in pharmacologic evaluation. Since its inception, total-body PET has shown significant promise in optimizing kinetic studies of positron-emitting drugs, offering several advantages over conventional PET scans, because total-body PET achieves better image quality and total-body coverage simultaneously. Total-body PET has the potential to expedite the drug development process by offering detailed insights into drug behavior at various stages of development.

Regulatory bodies around the world have established a series of guidelines for pharmacokinetic studies of new drugs. Table 2 shows current guidelines in China, the European Union, and the United States. In these guidelines, the blood clearance characteristics are often directly measured by repeated blood sampling, which is associated with risks and discomfort, and often only the peripheral blood can be obtained easily. The activity concentration in the arterial or cardiac regions obtained from the reconstructed dynamic PET images has been considered a good representation of the presence of the drug in the arterial blood, which is called the image-derived input function (72). However, using the image-derived input function from PET imaging for pharmacokinetic studies has its own set of challenges, including equilibrium establishment, standardization and reliability of the PET measurement, PET image resolution, and quantification precision (73). With the state-of-the-art dynamic imaging of total-body PET, the quality of the image-derived input function and other blood time–activity curves in central and peripheral blood vessels has been dramatically improved. This can be illustrated by the demonstrative experiment in Figure 4. Although the reliability of the image-derived method in the blood clearance study still requires validation, total-body PET could offer a promising, noninvasive way to investigate the spatiotemporal distribution of tracers within central venous and arterial blood and potentially reduce the need for the vascular puncture procedure. Moreover, as already demonstrated (68), the whole-body dynamic PET images with total-body PET may provide a shortcut for physiologically based pharmacokinetic studies.

View this table:
TABLE 2.

Selected Current Regulatory Guidelines Concerning Pharmacokinetic Study of New Drugs in China, European Union, and United States

FIGURE 4.
FIGURE 4.

(A) Maximum-intensity projections of representative frames in dynamic PET image of healthy volunteer who received intravenous injection of 113.3 MBq of [18F]FDG on right hand. (B) Blood time–activity curves of aorta, carotid artery, and cephalic vein as measured on image without applying partial-volume correction, and time–activity curve of venous blood collected from left median cubital vein during PET acquisition. All activity concentrations were decay-corrected to start of acquisition. Conc. = concentration.

As shown earlier, total-body body PET can also provide information on clinical pharmacodynamics, including determination of the optimal imaging time window and mapping of organ uptake. It may also be feasible to use total-body PET to study the interaction between the drug and the immune system. In this way, the proposed mechanism of action of the drug can be validated by the sophistication of total-body PET. Regulatory bodies require robust evidence of the accuracy, precision, and consistency of these imaging techniques before considering their integration into drug development guidelines. Continued research efforts aimed at validating total-body PET imaging for pharmacologic studies will be crucial in establishing its role as a reliable tool in understanding drug distribution, pharmacokinetics, and pharmacodynamics in a noninvasive manner.

Total-body PET has stimulated research in kinetic modeling, and with the plethora of data generated, more sophisticated modeling techniques have been proposed or validated, providing more opportunities in the validation of drug kinetics. For example, time delay and dispersion corrections have been applied in dynamic total-body PET imaging with high temporal resolution of the lung to obtain high-quality kinetic parameters (74). Statistical inference methods are also being developed to improve parametric imaging of total-body PET. Despite these advancements, challenges persist (75), especially in the context of drug development. These include determining the input function and deviation from the ideal compartment model because of transport phenomena and nonuniform mixing within tissues.

Total-body PET may provide important information for tailoring treatment regimens to individual patients, personalizing dosages and treatment planning, and minimizing potential side effects in radionuclide therapy and theranostics, including previously mentioned peptide receptor radionuclide therapy and PSMA radioligand therapy. However, unsolved problems in these fields related to radiopharmaceuticals necessitate further research and development. Personalized dosimetry and treatment planning with PET, prognosis and patient selection, treatment monitoring, and evaluation all require further research and development. One specific case is the direct imaging of 90Y, which generates only 32 positrons per million decays. In radioembolization with 90Y microspheres, total-body PET can capture the sparse signal and perform voxelwise dosimetry based on the Monte Carlo simulation (76). In general, the theranostic application of total-body PET is worthy of more investigation.

Several additional research topics, although not extensively exploited at the current time, are likely to achieve expectations in the intersection between total-body PET and drug development. The first idea is about using total-body PET to develop drugs for immunotherapy. One of the key challenges in immunotherapy involves finding potent biomarkers (77), and the toolbox of immuno-PET (78) may provide a strategy for engineering key molecules into PET tracers. This strategy has already been used with total-body PET in some preliminary applications (69,70,79). Besides, because of the extended axial field of view, total-body PET provides an opportunity to study systematic metabolic characteristics across different organs, especially brain–body interactions. Several studies have been conducted with [18F]FDG (80), and using new drugs will expand the matrix of combination to another dimension.

In this review, we have gone through the impacts of total-body PET on drug development. Total-body PET imaging has substantially affected the spectrum of drug development, including the initial phases 0 and I, which focus on establishing the basic validity of the pharmaceuticals, and the latter phases II and III, which involve a larger, often randomized cohort. Figure 5 provides a summary of these impacts in different aspects of the clinical investigation of new drugs. With the active involvement of all stakeholders, including the PET imaging community, pharmaceutical scientists, and the pharmaceutical industry, the potential of total-body PET is expected to be gradually unlocked, and we will witness more exciting new applications in the near future.

FIGURE 5.
FIGURE 5.

Potential role of total-body PET in different aspects of clinical investigation and different phases of clinical trials of new drugs.

CONCLUSION

Total-body PET is pushing the limits of PET imaging and offers immense potential in tracer development, innovative drug development or enhancement, and clinical evaluation of pharmaceuticals. It brings possibilities in clinical research and translation acceleration. Such potential has been validated in studies of several new tracers. We believe this technology may continue to flourish and benefit the pharmaceutical and medical imaging communities in the era of theranostics.

DISCLOSURE

No potential conflict of interest relevant to this article was reported.

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  • Received for publication October 31, 2023.
  • Revision received January 23, 2024.
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