Research article Open Access
What’s New for 68Ga in the World of Molecular Imaging?
Mai Lin1, Vincenzo Paolillo1, Robert Ta1, Elmer B Santos2, Gregory C Ravizzini2 and Dao Le1,2*
1Cyclotron Radiochemistry Facility, The University of Texas MD Anderson Cancer Center, Houston, USA
2Department of Nuclear Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA
*Corresponding author: Dao Le, Cyclotron Radiochemistry Facility and Department of Nuclear Medicine, The University of Texas MD Anderson Cancer Center, Houston, USA, Tel: +1- 713-792-7320; Fax: +1- 713-792-6098; E-mail: @
Received: September 17, 2018; Accepted: September 27, 2018; Published: October 01, 2018
Citation: Le Dao, Mai Lin, Vincenzo P, Robert Ta, et al. (2018) What’s New for 68Ga in the World of Molecular Imaging?. SOJ Pharm Pharm Sci, 5(4) 1-12. DOI: 10.15226/2374-6866/5/4/00191
Abstract
During the last decade, the utilization of 68Ga for the development of imaging agents has increased considerably due to the increased accessibility of 68Ge/68Ga generators, straightforward labeling procedures, and the recent approval of 68Ga-DOTATATE by the FDA for routine clinical practice. This article is intended to provide an overview on current imaging applications of 68Ga-based radiopharmaceuticals in terms of their clinical significance and the alternative solution to overcome the innate limitation from a 68Ge/68Ga generator.

Keywords: 68Ga; Molecular Imaging; Radiopharmaceutical; Cyclotron
Introduction
Molecular imaging was first introduced in 2001 but its concept actually began way back in the 1950s when 131I was used to image recurrent thyroid carcinoma [1, 2]. As the term is defined as the visual representation, characterization, and quantification in biological processes at the cellular or molecular level of living organisms with negligible perturbation, molecular imaging can be considered as an extension of nuclear medicine in which radioactive compounds are used in diagnostic/theranostic purposes [3, 4].

Among all conventional imaging techniques, positron emission tomography (PET) has played a critical role in the field of molecular imaging over the last decade due to its capability of imaging quantification and superb sensitivity without the limitation in tissue penetration. While 11C, 13N, 15O, and 18F are commonly used as “standard PET radionuclides”, the requirement of an onsite cyclotron or shipment from a closely located commercial source decreases the availability and flexibility of the radiopharmaceuticals labeled with these radionuclides. On the contrary, because of the increased accessibility of 68Ge/68Ga generators, straightforward labeling procedures, and the recent approval of 68Ga-DOTATATE by the FDA for routine clinical practice [5], PET imaging with 68Ga-labeled tracers has seen a dramatic increase over the past five years.

Gallium-68 is a short-lived radionuclide (T1/2:68 min) and primarily decays through positron emission (87.94%) with a maximum energy of 1.9 MeV (mean energy: 0.89 MeV). Because cationic 68Ga can form stable complexes with various chelators and macromolecules, this characteristic allows for the development of radiopharmaceutical kits. This article is intended to provide an overview on current imaging applications of 68Ga-labeled tracers and recent breakthroughs in 68Ga production.
68Ga-radiopharmaceuticals for PET imaging
It is common to consider [18F]-fluorodeoxyglucose ([18F] FDG)-PET as part of a routine post treatment surveillance tool; however, the clinical applications of 68Ga actually begin long before [18F]FDG was introduced in 1978 [6] and was used to localize brain tumors [7]. Because 68Ga was initially required to be eluted in complex with ethylenediaminetetraacetic acid (EDTA) from early 68Ga generators [8], destruction of the complex was needed before preparation of the radiopharmaceuticals could be done. Due to this time-consuming process, the radiochemical yields of 68Ga-labeled molecules were poor and thus resulted in very limited clinical applications.

When Obninsk first made a commercially available 68Ge/68Ga generator that could be eluted by diluted hydrochloric acid to provide cationic 68Ga in 1996 [9], it opened new possibilities of 68Ga in preclinical and clinical applications. As cationic 68Ga is able to form stable complexes with chelators (e.g. diethylenetriaminepentaacetic acid (DTPA), 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid (DOTA), etc.) that have already been widely used to the agents for magnetic resonance imaging (MRI) and single-photon emission computed tomography (SPECT), the amount of 68Ga related research has greatly increased since 2000, especially after the first successful clinical trial of 68Ga-DOTATOC in 2001[10]. Currently most 68Ga clinical studies can be found in the areas of neuroendocrine tumors (NET), prostate cancer, and infection/ inflammation.
68Ga-based radiopharmaceuticals for neuroendocrine tumors (NET)
Neuroendocrine tumors (NET) begin with a heterogeneous group of neoplasms that arise from cells of the endocrine and nervous systems. Although the population of patients with NET remains relatively small, recent epidemiologic study has shown an increasing incidence [11]. In addition to common laboratory tests and biopsy as typical diagnostic tools to confirm patients with NET, conventional imaging techniques such as computed tomography (CT), ultrasound (US), MRI, SPECT, and PET also play an important role in diagnosing and staging/restaging; however, only images from SPECT and PET are attributed to specific biological information (e.g. cell metabolic condition, particular receptor expression, etc.) of tumors.

The importance of somatostatin receptors (SSTR) as the target for imaging NET was recognized when Krenning et al. performed SSTR scintigraphy with more than 1,000 patients using either [123I-Tyr3]- or [111In-DTPA-D-Phe1]-octreotide (111In-octreoscan) [12], in which most NET carry a high density of somatostatin receptors (SSTR). Even though SSTR can be found in some normal tissues, an increased density of SSTR in NET make them visible with radiolabeled somatostatin or its analogues; however, due to several drawbacks of using 123I, (such as a relatively timeconsuming and difficult labeling procedure compared to 111In), 111In-octreoscan has consequently been broadly used to visualize NET expressing SSTR.

As PET has overall better spatial resolution than SPECT and the capability to perform quantitative analyses, the next generation of SSTR-targeted imaging for clinical applications was initiated by Hofmann et al. for 68Ga-DOTATOC PET in 2001 [10]. Of note, the group found that tumor-to-normal tissue ratios based on 68Ga-DOTATOC PET are superior to those achieved with 111In-octreoscan SPECT (Figure 1), and more than 30% additional lesions were detected by 68Ga-DOTATOC PET. These encouraging results not only paved the way of this particular radiopharmaceutical to the clinical acceptance for imaging patients with NET, but also redefined the role of 68Ga in modern nuclear medicine.
Figure 1:
a: Maximum-intensity-projections of a 54-year-old male patient, suffering from multiple liver, lung, abdominal and bone metastases of abdominal carcinoid. The scan was started 90 min following the intravenous injection of 220 MBq of 68GaDOTATOC, and six bed positions were acquired. BM, Bone metastases; LM, liver metastases; K, kidney; S, spleen; L, liver; PG, pineal gland; TG, thyroid gland; VLD, anterior view; DRV, view from the right; LDR, posterior view.
b: The planar whole-body scintigraphy acquired 24 h after the injection of 110 MBq 111In-octreoscan does not reveal the true extent of liver involvement as visualization is impaired by intensive renal accumulation of the tracer. Multiple bone marrow and lung metastases are not as clearly delineated as in the 68Ga-DOTATOC PET scan. RVL, Anterior view; LDR, posterior view. Reprinted with permission from European Journal of Nuclear Medicine, originally published by Hofmann et al [10].
Continuing the huge success of 68Ga-DOTATOC, other octreotide-like analogues such as 68Ga-DOTANOC and 68Ga- DOTATATE (Figure 2) have also been studied extensively for imaging NET. The major difference among these tracers is their different binding affinities for the five subtypes of SSTR (SSTR1- 5)[13]. A previous report indicates that 68Ga-DOTATATE has a high affinity for SSTR2, whereas 68Ga-DOTATOC binds to SSTR2 and SSTR5, and 68Ga-DOTANOC to SSTR2, SSTR3 and SSTR5. Although over-expression levels of SSTR1-5 vary in different tumors, no significant impact on patient management with NET has been observed when applying these tracers in large clinical studies [14]. In June, 2016, the U.S. FDA approved the use of 68Ga- DOTATATE as a PET diagnostic agent for patients with SSTRpositive NET [5].
Figure 2:Chemical structures of 68Ga-DOTATOC, 68Ga-DOTATATE, and 68Ga-DOTANOC.The differences in structures are highlighted
68Ga-based radiopharmaceuticals for prostate cancer
Prostate cancer is the most common cancer in men in the United States [15] and the second most common cancer in men worldwide [16]. It is typically diagnosed with biopsy and its risk is classified by the concentration of prostate-specific antigen (PSA) in serum, Gleason score, and the clinical stage [17]. Conventional imaging of prostate cancer is currently limited in staging, restaging after cancer recurrence, and assessment for therapeutic response. Although structural imaging techniques such as MRI are advantageous in assessing intraprostatic progression of the disease, PET is superior in the detection of extraprostatic metastases.

11C-choline and 18F-fluciclovine are currently the major PET tracers used for the imaging of prostate cancer on a routine basis. It was not until Afshar-Oromieh et al. reported the first evaluation of Glu-urea-Lys-(Ahx)-[68Ga(HBED-CC)] (68Ga-PSMA-11) as a novel peptide-based PET tracer for prostate cancer that great attention began for applying 68Ga for imaging prostate cancer [18]. Unlike 11C/18F-choline and 18F-fluciclovine that differentiate tumor cells from normal tissues through involving biological metabolic pathways, the uptake of 68Ga-PSMA-11 is proportional to the cellular expression level of prostate-specific membrane antigen (PSMA).

PSMA is a type II transmembrane glycoprotein that is expressed in all types of prostatic tissue. The expression of PSMA is low in normal prostatic tissue; however, its expression level increases in both localized and metastatic prostate cancer and highly correlates with tumor grade [19]. Because PSMA is also expressed in the neovasculature of many solid tumors other than prostate cancer, PSMA can be an excellent target not only for prostate cancer, but also for other malignancies [20]. The concept of utilizing PSMA as the target to reveal patients with prostate cancer and its metastases was first realized by using the 111In-labeled monoclonal antibody, capromab pendetide (ProstaScint®, Cytogen Corporation, and Princeton, NJ). Nevertheless, the diagnostic capability of ProstaScint® in tumors within the prostate gland and seminal vesicles is very limited [21]. This is likely due to the fundamental issue of ProstaScint® that only binds to an intracellular domain of PSMA and fails to recognize viable cancer cells.

In order to overcome the fundamental issue that ProstaScint® has encountered, several small molecule-based PSMA inhibitors, differing slightly in chemical structure, have been developed to target external epitopes of PSMA with hopes of improving lesion detectability. Among these molecules, 68Ga-PSMA-11 is perhaps the most widely used PET agent for imaging prostate cancer. Afshar-Oromieh et al. initiated the evaluation of 68Ga-PSMA-11as a novel PET agent for prostate cancer [18]. The researchers found that 68Ga-PSMA-11 detects recurrent and metastatic prostate cancer through binding to the extracellular domain of PSMA and through internalization of the compound/agent into the cell. Since then, multiple studies have been conducted to compare 68Ga-PSMA-11 with other conventional PET tracers for imaging patients with prostate cancer.

A recent prospective study conducted by Caroli et al. [22], which involved 314 patients with recurrent prostate cancer, showed an overall positive 68Ga-PSMA-11 PET/CT detection rate of 62.7%. The accuracy was increased with increasing PSA values: 42% for 0-0.2 ng/ml, 58% for 0.2-1 ng/ml, 75% for 1–2 ng/ml, and 94.8% for >2 ng/ml. In addition, the researchers found that of the 88 patients with negative 18F-choline PET/CT scans, 59 (67%) were positive on 68Ga-PSMA-11 PET/CT. Of these positive scans, 57% had a PSA value < 2 ng/ml and 81% had a Gleason score of ≥7. In agreement to these findings, a positive 11C-choline PET/ CT detection rate was also reported with poor correlation when patients with a PSA value < 2 ng/ml [23]. Furthermore, while a prospective trial is still underway, a preliminary comparison from 10 patients with recurrent prostate cancer also suggests improved detection rates for 68Ga-PSMA-11 PET/CT when compared with 18F-fluciclovine PET/CT[24] (Figure 3).

With encouraging results continuously shown in prospective studies and meta-analysis [22-29], several analogues based on PSMA-11 have also been evaluated as potential imaging agents for prostate cancer [30-34]. Among these molecules, PSMA-617 (Figure 4) has received the most clinical attention. Through pre-clinical studies, Benešová et al. observed that the binding
Figure 3: Maximum-intensity-projection of 18F-fluciclovine PET A and 68Ga-PSMA-11 PET B in a 74-year-old male patient. Arrows indicate intense uptake in pelvic, abdominal, thoracic, and supraclavicular LNs. Corresponding LNs on 18F-fluciclovine PET showed no uptake. Reprinted with permission from Journal of Nuclear Medicine, originally published by Calais et al.[24]
Figure 4: Patient was a 70-year-old woman (weight: 69 kg), with multiple background diseases, who was admitted to hospital because of back pain and high fever. Both 68Ga-citrate (a, c, e) and 18F-FDG PET/CT (b, d, f) showed vertebral osteomyelitis (spondylodiscitis) in Th12 (red arrows) and pneumonia in both lungs. MRI showed oedema in Th12 (g, h). 68Ga-citrate PET/CT also revealed uptake in the left parotid gland (unspecific; (a), blue arrow), neck lymph nodes (reactive), and inferior vena cava (thrombosis; (e), blue arrow). There was no 18F-FDG uptake in these areas. The injected radioactivity dose of 18F-FDG was 279 MBq and the PET acquisition started 50 min after injection. The injected radioactivity dose of 68Ga-citrate was 199 MBq and the PET acquisition started 100 min after injection. MRI sequences were as follows: T2-weighted short inversion time inversion recovery (STIR) on the coronal view image (left) and T2-weighted on the sagittal view image (right). Reprinted with permission from Contrast Media & Molecular Imaging, originally published by Salomaki et al.[51]
affinity of PSMA-617 is significantly improved toward PSMA (Ki for PSMA-11: 12 ± 2.8 nM, PSMA-617: 2.3 ± 2.9 nM) as well as its internalized ratio into prostate cancer cells (internalized ratio for PSMA-11: 9.47% ± 2.56% injected activity/106LNCaP cells, PSMA-617: 17.67% ± 4.34% injected activity/106 LNCaP cells) [35]. As DOTA is used as a chelator for PSMA-617, this tracer can be labeled with 68Ga, 111In, 177Lu, 90Y thus served as a theranostic agent.; however, when comparing with 68Ga-PSMA-11, though both tracers showed the highest uptake in the kidneys and salivary glands [32, 36], the pharmacokinetics of 68Ga-PSMA-617 is slower in patients. Because most nuclear medicine clinical workflow is designed to conduct PET/CT scans within 1 h after injection of 68Ga-labeled tracers, it remains unclear if 68Ga-PSMA-617, even with its higher PSMA binding affinity and internalization nature, could detect more prostate cancer lesions than 68Ga-PSMA-11. Therefore, 68Ga-PSMA-11 with its putatively faster clearance provides a clear advantage over 68Ga-PSMA-617.

Besides imaging patients with recurrent prostate cancer, 68Ga-PSMA-11 PET/CT can also be a valuable tool for evaluating primary prostate cancer and detecting lymph node and bone metastases. Kabasakal et al. imaged 28 prostate cancer patients with 68Ga-PSMA-11 PET/CT either 5 or 60 min post injection and found that images acquired on the early time point (5 min p.i.) can help better distinguish between urinary bladder and tumor lesions [37]. Perveen et al. further confirmed this observation by performing dynamic 68Ga-PSMA-11 PET/CT in 15 prostate cancer patients within a time frame of 1 to 10 min, and then compared these images to the static ones that were acquired between 45 and 60 min after injection from the same patients [38].
68Ga-based radiopharmaceuticals for infection/ inflammation
Infection is usually triggered by the invasion of diseasecausing agents such as bacteria and virus. Inflammation is part of the immune response to harmful stimuli; however, because autoimmune (e.g. lupus Erythematosus, rheumatoid arthritis, and etc.) and cancerous diseases can both result in chronic inflammation, infection is not the only source that leads to inflammatory responses. It continues to be a major cause of morbidity and mortality worldwide [39].

X-ray, US, CT, and MRI are conventional imaging techniques to reveal infectious/inflammatory lesions. Although they are generally helpful, diagnoses based on these techniques are not specific to neither inflammation nor infection type since they heavily depend on the presence of anatomic abnormalities; however, nuclear medicine techniques that provide functional images hold great promise to evaluate disease progression before noticeable changes in anatomical structure [40].

In spite of strong medical need, the research and development of 68Ga-labeled tracers for the diagnosis and discrimination of inflammation and infection was only accelerated during the past decade [41-45]. Among all published reports, 68Ga-citrate seems to have a great potential of becoming a radiopharmaceutical for routine clinical practice.

The concept of using 68Ga-citrate to image infections and inflammations was originated from the routine clinical application of 67Ga-citrate. 67Ga-citrate has been well known for decades as an infection/inflammation imaging agent and its production, quality control as well as its value in the evaluation of various infections has been well documented [46-50]. After the development of 68Ge/68Ga generators, the initial idea to produce 68Ga-citrate was discarded since images are usually obtained after 24-72 h injection of 67Ga-citrate which is far beyond the half-life of 68Ga. After the first attempt by Nanni et al. to explore the possible advantages of 68Ga-citrate PET/CT over 67Ga-citrate SPECT for evaluating patients with infections of the bone [45], interest of using 68Ga-citrate as an alternative infection/inflammation imaging agent began to rise. Salomäki et al. recently performed a direct comparison between 68Ga-citrate and 18F-FDG PET/CT for the detection of infectious foci in four consecutive patients with Staphylococcus aureus bacteraemia [51]. The researchers found that both tracers are comparable for the imaging of osteomyelitis (Figure 4). Encouraging results have also been reported by Vorster et al. when the group evaluated the use of 68Ga-citrate in the imaging of patients with confirmed tuberculosis or pulmonary fibrosis [52]. These preliminary results demonstrate the potential of 68Ga-citrate in the evaluation of various infectious and inflammatory diseases.
Other potential 68Ga-based radiopharmaceuticals and research
Since 2008 major generator manufacturers (iThemba LABS and Eckert & Ziegler Radiopharma GmbH) entered the market, thus the utilization of 68Ga for the development of imaging agents focused in oncology has considerably increased [9]. In addition to the scope of using 68Ga in imaging NET, prostate cancer, and infection/inflammation, 68Ga-labeled tracers have been developed to target various cells and their receptors. Some examples of 68Ga-labeled tracers as potential imaging agents are summarized in Table 1.
Table 1: Examples of 68Ga-based imaging agents investigated preclinically and clinically

Receptor/mechanism

Imaging agent

Disease/Target (Study Type)

Integrins

68Ga-PRGD2

Lung cancer (clinical) [71],
Rheumatoid arthritis (clinical)
[72]

Glucagon-like peptide 1
receptor (GLP1R)

68Ga-Exendin-4

Insulinoma (clinical) [73]

Hypoxia

68Ga-HP-DO3A-nitroimidazole

Tumor hypoxia (preclinical)
[74]

Cholecystokinin-2 (CCK2)

68Ga-minigastrin

Tumor with overexpressed
CCK2 (preclinical) [75, 76]

Chemokine receptor-4
(CXCR4)

68Ga-Pentixafor

Glioblastoma (clinical) [77]

Melanocortin-1 receptor
(MC1-R)

68Ga-NAPamide

Melanoma (preclinical) [78]

Glycolysis

68Ga-DOTA-2-deoxy-D-
glucosamine

Tumor metabolism
(preclinical) [79]

Neurotensin Receptor 1
(NTS1)

68Ga-neurotensin peptides

Tumor with overexpressed
NTS1 (preclinical) [80]

Human epidermal growth
factor receptor 2 (HER2)

68Ga-DTPA anti-HER2

Breast cancer (clinical) [81]

lymphatic pathways

68Ga-nanocolloid

Prostate cancer (clinical) [82]

Gastrin-Releasing Peptide
Receptors (GRPRs)

68Ga-Bombesin analogues

Tumor with overexpressed
with GRPRs (preclinical) [83]

Figure 5: Maximum-intensity-projection of pre-targeted immuno-PET images recorded in one patient of each cohort using TF2 BsMAb and 68Ga-IMP288 peptide. Arrows showed foci considered as pathologic by immuno-PET: supradiaphragmatic nodes in C1 (A) cervical node; lumbar and femoral bones foci in C2 (B); supradiaphragmatic nodes and liver and heart lesions in C3 (C); supradiaphragmatic nodes, lung, liver, and bone foci in C4 (D); and supradiaphragmatic nodes and liver foci in C5 (E). Reprinted with permission from Journal of Nuclear Medicine, originally published by Bodet-Milin et al.[55]
Other than the 68Ga-labeled tracers that are developed to directly target particular cells or receptors, interest in the application of 68Ga for pre-targeted imaging has also gradually emerged. The concept of pre-targeted imaging began as early as three decades ago and is comprised of two major steps: 1) a functionalized antibody that is first administered for target localization and clearance from blood and normal tissue and 2) a radiolabeled small molecule that is capable of binding to the functionalized antibody then administered [53, 54]. Considering the short half-life of 68Ga, pre-targeted imaging provides an alternative way to overcome this limitation, especially when it comes to applying 68Ga in immuno-PET imaging studies.

The first-in-human feasibility of 68Ga-based pre-targeted imaging was recently demonstrated by Bodet-Milin et al. using the trivalent humanized TF2 bispecific monoclonal antibody (TF2 BsMAb) and 68Ga-IMP288 peptide [55]. TF2BsMAb can specifically bind to carcinoembryonic antigen (CEA)-expressing tumor cells, histamine-succinyl-glycine (HSG) motif, and IMP288 which is the hapten molecule that comprises HSG motif through a DOTA chelator for complexation with 68Ga. Although further studies are needed to compare with conventional imaging techniques, excellent tumor uptake and contrast have been obtained when using this strategy to image patients with recurrent medullary thyroid carcinoma (MTC) (Figure 5).
Current limitation of 68Ge/68Ga generators and production of 68Ga by cyclotron
The dramatic rise in PET imaging with 68Ga-labeled tracers during the last decade has been a result of increased interest in applying 68Ga-radiopharmaceuticals for theranostic purposes. The theranostic concept is when a diagnostic scan is first performed using a 68Ga-labeled molecule then the same molecule is labeled with a therapeutic radionuclide (e.g. 90Y, 177Lu, or 188Re) for treatment [56-58]. Currently 68Ga is commonly provided through 68Ge/68Ga generators. There are multiple methodologies developed to produce 68Ge [59]. The production in general is sophisticated and time-consuming. Furthermore, commercially available 68Ge/68Ga generators nominally deliver up to 3.7 GBq (100 mCi) when fresh, but the lifespan of generators do not usually parallel with the long half-life of 68Ge. This fact is a result of decreasing elution efficiencies of 68Ga [60], which in turn lead to limited production and distribution of 68Ga-labeled tracers to a few daily doses per generator. Importantly, the use of 68Ge/68Ga generators is inevitably accompanied by the concern of 68Ge breakthrough in the eluate [60]. This parameter is known to increase as the generator ages. With these regards, the development of an alternative way to meet the increasing demand for 68Ga is warranted.

Because of high cost and limited activity per elution from a 68Ge/68Ga generator, several attempts have been made to produce 68Ga via 68Zn(p,n) 68Ga reaction using cyclotron. Jensen and Clark reported the first attempt to produce 68Ga using a cyclotron with a liquid target filled with a 68ZnCl2 solution [61]. Since then, other groups have tried to optimize 68Ga production through liquid targetry [62, 63]. Based on recent study performed by Alves et al., a liquid targetry containing 200 mg of 68Zn resulted in 0.3 GBq/μA•h at End of Bombardment (EOB) when the target was irradiated by 14.2 MeV proton [62]. Although producing 68Ga via a liquid target does ease the process of target preparation and avoid the need of target dissolution during separation procedure after cyclotron irradiation, the available activity of 68Ga at end of processing is not significantly higher than generator produced isotope.

The possibility of producing 68Ga with a solid target was first explored by Engle et al. using natZn as the target material [64]. Derived from cross section measurements, the theoretical production yield can be up to 5.81 GBq/μA•h when an enriched 68Zn solid target is irradiated by 15 MeV proton [65]; however, high zinc and HCl acid contents in the final 68Ga solution are two potential challenges for cyclotron-produced 68Ga. Although most 68Zn can be removed by using the AG50W cation resin alone [62- 64], additional processing is usually required to reconstitute.

68Ga solution with a low concentration of HCl for radiolabeling use. Considering the relatively short half-life of 68Ga, a simple, fast, and cost-efficient processing procedure of 68Ga post target irradiation is required.

At MD Anderson Cancer Center, we have recently developed a reliable and cost-efficient procedure for cyclotron production using solid target and chemical separation of 68Ga [66]. To optimize target thickness for maximum yield, targets with a diameter of 7 mm and a mass of 68Zn between 60-120 mg were irradiated with 14.5 MeV protons. We found that the 68Ga activity at EOB correlated well with irradiation time and amount of 68Zn metal present. Targets containing 104.1 ± 2.7 mg of 68Zn (n = 3) irradiated for 1 hr at a beam current of 30 μA resulted in 44.5 ± 1.4 GBq of 68Ga with the production yield as 2.72 ± 0.08 GBq/μA•h, which is close to 10 times the value reported by Alves et al. using a liquid target [62]. In addition, by applying a dualcolumn system that was originally used for processing 68Ga from a 68Ge/68Ga generator [67], we are not only able to recover most of cyclotron-produced 68Ga activity (75-85%) and minimize zinc content (0.004 ± 0.002 μg/GBq) to the level that is lower than the generator-produced 68Ga (0.37 ± 0.09 μg/GBq) determined by ICP-MS analysis, but also allows the reconstitution of the final 68Ga solution in a low concentration of HCl at the same time. Most importantly, the whole separation process takes less than 10 min, which is especially important for 68Ga production.

To explore the potential applications of cyclotron-produced 68Ga in radiopharmaceutical compounding, we further used PSMA-11 as the model molecule for our labeling tests. In like fashion to the 68Ge/68Ga generator-produced 68Ga, we found that the cyclotron-produced 68Ga was also able to label these molecules directly in the range of curie level when the reaction was performed in FDA approved buffer solutions such as sodium acetate; however, because a large scale of activity (18.5-37 GBq) was used, decomposition of 68Ga-PSMA-11 has been observed during or soon after the labeling reaction (Figure 6B). In order to overcome this issue that is likely caused by radiolysis, we added L-ascorbic acid as the free radical scavenger during the reaction
Figure 6: HPLC analyses of cold Ga-PSMA-11 and 68Ga-PSMA-11 using the activity (less than 1 GBq) from itG 68Ge/68Ga generator A; 68Ga-PSMA-11 using the activity (18.5-37 GBq) from cyclotron-produced 68Ga B; 68Ga-PSMA-11 using the activity (18.5-37 GBq) from cyclotron-produced 68Ga with L-ascorbic acid as the free radical scavenger C. 68Ga-PSMA-11 remained intact after 4 h at room temperature
and found that 68Ga-PSMA-11 remained intact after 4 h at room temperature (Figure 6C). Whereas the studies to demonstrate similarity between the compounds labeled by either 68Ge/68Ga generator or cyclotron-produced 68Ga are currently underway, our preliminary data indicate the potential for large scale production of 68Ga-labeled radiopharmaceuticals that can meet the increasing demand and facilitate regional distribution of these imaging agents.
Conclusions
The PET radiopharmaceuticals in nuclear medicine have gained a tremendous growth during the last decade as a result of considerable progress made in PET technologies and image analysis methodologies. In particular, 68Ga-DOTATATE and 68Ga- PSMA-11 are recognized to have great impact on the management of NET and prostate cancer, respectively; however, as more 68Galabeled tracers have shown their promise in clinical application, streamlining the transition from bench to bedside becomes more important than ever. Whereas 68Ga-DOTATOC (listed in European Pharmacopeia [68]) and 68Ga-DOTATATE (approved by the FDA [5]) pave the way on the regulatory side for using 68Ga in routine clinical settings, current 68Ga-PET/CT imaging is still limited due to high cost and relatively small activity per elution from a 68Ge/68Ga generator.

Recently we have developed a reliable, on-demand and costeffective method for the routine production of Curie amounts of 68Ga with a medical cyclotron [66]. More importantly, our data suggests that the quality of cyclotron-produced 68Ga is equal if not better when compared to that of its generator-produced counterpart. In addition, by successfully labeling PSMA-11 with our cyclotron-produced 68Ga at 0.5-1.0 Ci level, we provide an alternative way to produce 68Ga-labeled tracers not only for meeting the increasing market demand but also facilitating their regional distribution. Based on the recent report of 68Ge/68Ga generator licensing guidance from the Nuclear Regulatory Commission (NRC), we might be able to use cyclotron-produced 68Ga to prepare radiopharmaceuticals under the same policy as 18F (10 CFR 35.200) [69]. While further investigations are needed to meet possible regulatory requirements, minor metal impurities presented in the cyclotron-produced 68Ga solution such as 67Ga are likely to be reconciled through the specification of 67Ga-citrate [70].

In this review article, we have summarized the application of 68Ga-based radiopharmaceuticals in terms of their clinical significance and the alternative solution to overcome the innate limitation from a 68Ge/68Ga generator. As a direct result of the aforementioned and the superior performance of PET/ CT compared to other conventional imaging techniques, we anticipate that 68Ga will play a significant role in the field of molecular imaging in the near future.
Acknowledgement
We thank Gregory J. Waligorski, Ganna Ajdari-Devillarin and Dr. Julius Balatoni for helpful discussion regarding the possible impact of cyclotron-produced 68Ga to current 68Ga- labeled radiopharmaceuticals. We would also like to thank Jaquline Jones for proofreading and writing assistance.
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