• MAA

As shown in Table 1, almost all authors used commercial kits available to prepare [ 99mTc]Tc-MAA for labelling MAA particles with <sup>68</sup>Ga. The use of commercially available kits is an important consideration to facilitate the implementation of the technique in nuclear medicine facilities. However, commercially available MAA kits contain SnCl<sup>2</sup> and free albumin. Consequently, many groups carried out MAA labelling with washed MAA to remove the excess of free albumin and SnCl<sup>2</sup> (stannous chloride), which is usually used as a reduction component, from the kit and thus improve the labelling yields (Table 1). Ay¸se et al. obtained a better final product RCP by washing the MAA particles before the labelling (RCP = 99.0 ± 0.1%) rather than not washing (RCP = 95.0 ± 0.1%) [38]. On the other hand, Mueller et al. found no significant difference in the radiolabelling yields using non-washed and pre-washed MAA (80% and 75%, respectively) [35]. In studies that used unmodified commercially available MAA kits, radiolabelling yields were consistently superior to 75.0% (Table 1) [28,35,39]. Furthermore, Jain et al. found lower radiolabelling yields using in-house synthesized MAA without SnCl<sup>2</sup> than MAA with SnCl<sup>2</sup> (49.9 ± 1.3% and 84.5 ± 5.3%, respectively). They found that stannous chloride present in the MAA kits used had a strong influence on the [68Ga]Ga-MAA formation (radiochemical yield, mean particle diameter, serum stability), suggesting that Sn could be linked to MAA or <sup>68</sup>Ga [29]. Consequently, using unmodified non-washed commercially available MAA kits produced for 99mTc seems to be a suitable solution for [68Ga]Ga-MAA labelling;

• <sup>68</sup>Ga eluate

<sup>68</sup>Ga eluate obtained from currently available generators are contaminated with longlived parent nuclide <sup>68</sup>Ge and cationic metal ion impurities such as titanium (Ti)4+ from the column material, zinc (Zn)2+ from the decay of <sup>68</sup>Ga or iron (Fe)3+. These impurities might compete with <sup>68</sup>Ga in the complexation reaction [40,41].

Pre-purification of the eluate has been proposed by several groups, with various methods such as anion exchange chromatography, cationic cartridge, fractionation or eluate pre-concentration (Table 1) proposed to overcome this issue. Most groups performed an eluate pre-purification using an SCX cartridge or an equivalent pre-conditioned with hydrochloric acid (HCl) and water (Table 1).

In contrast, a few groups did not perform <sup>68</sup>Ga eluate pre-purification before MAA labelling and obtained <sup>68</sup>Ge impurity levels lower than 0.0001% and radiolabelling yields superior to 96.0% (Table 1) [28,29,34,39]. Based on these results and the fact that this is time-consuming, the pre-purification of the <sup>68</sup>Ga eluate does not seem mandatory and could be avoided for [68Ga]Ga-MAA preparation.

• Labelling conditions

The three key points of the MAA labelling with <sup>68</sup>Ga are the pH, the heating temperature, and the reaction medium's heating time (Figure 1).

Among the various [68Ga]Ga-MAA labelling processes published, the labelling pH ranges from 3 to 6.5, with the radiolabelling yield varying from 65.0 to 97.4% (decay corrected or not) (Table 1). The optimal pH range seems to be between 4 and 6.5, where <sup>68</sup>Ga is a water-soluble cation [14]. Importantly, it has been shown that Ga does not bind to albumin at a pH above 7 [19]. For assessing the optimal pH for the labelling reaction, three buffers or equivalents have been used: acetate buffer, sodium acetate solution and HEPES buffer (Table 1). HEPES and acetate buffers are biocompatible with no toxicity issue [40]. They have demonstrated better characteristics to stabilize and prevent <sup>68</sup>Ga(III) precipitation and colloid formation [40]. Nevertheless, in contrast to sodium acetate, HEPES is not approved for human use, and thus, purification and additional quality control analyses are required, resulting in further time and resource consumption [40].

The labelling temperatures reported in the literature ranged from 40 ◦C to 115 ◦C (Table 1). Whatever the labelling conditions, the radiolabelling yields were superior to 75.0% in all but one study (Table 1). Several studies have tested various labelling conditions and obtained increasing radiolabelling yield by increasing the heating temperature (from 25 to 100 ◦C, pH: 4–6) [29,38]. On the other hand, low heating temperature (40–70 ◦C) has been described to preserve MAA structure and size because high temperatures may induce the rupture of bigger macroaggregates [34,36,39]. Accordingly, the heating temperature range seems quite large, as long as MAA integrity is maintained.

Finally, the labelling heating time ranged from 5 to 20 min (Table 1). Some studies have compared various heating times (from 3 to 50 min) and found higher labelling yields with heating times between 7 and 20 min [31,38,39]. Due to the short half-life of <sup>68</sup>Ga and for practical considerations, the heating step should be as short as possible.

## <sup>68</sup>GaGa-MAA purification

Many authors have shown that the final product RCP was improved by performing a purification step at the end of the labelling (Table 2). Various processes were used to purify [ <sup>68</sup>Ga]Ga-MAA suspension. The most commonly used process was to wash the labelled MAA with saline and centrifuge to isolate [68Ga]Ga-MAA particles. Another process was to increase the reaction mixture to 10 mL with sterile water at the end of the heating step and to pass the suspension through a Sep-Pak C18 cartridge. Then, the cartridge was washed two times with sterile water. The RCP of the obtained final product was superior to 97% (Table 2).

**Table 2.** Process of [68Ga]Ga-MAA purification and radiochemical purity according to the various authors.


While purification processes have only been manual to date, an innovative automated procedure was recently proposed for the purification step using a low protein-binding filter. At the end of the heating step, the reaction medium was passed through the filter from the bottom. Then, [68Ga]Ga-MAA was removed from the filter and transferred into the final vial by passing 10 mL of saline from the top to the bottom of the filter (see Figure 2) [39]. The RCP of the obtained [68Ga]Ga-MAA suspension was 99.0 <sup>±</sup> 0.6%.

• Manual or Automated Process

Most of the [68Ga]Ga-MAA preparation processes described in the literature were manual and were carried out in 20 to 40 min (See Table 1) [28,31,32]. Mueller et al. showed that an automated process reduced the preparation time from 20 to 14 min [35]. A few automated processes were described in the literature to perform the synthesis from the elution to the end of the heating steps (see Table 1). More recently, a fully automated process has been proposed, including both MAA labelling and [68Ga]Ga-MAA purification, which was carried out in 15 min (see Tables 1 and 2) [39]. To the best of our knowledge, this is the only fully automated process to date.

Mueller et al. [35] No purification >95.0 Shannehsazzadeh et al. [22] Centrifugation Manual 100.0 Persico et al. [36] No purification 97.0 Gultekin et al. [37] Centrifugation Manual 99.0

Blanc-Béguin et al. [39] Filtration Automated 99.0 ± 0.6

**Figure 2.** Schematic representation of the [68Ga]Ga-MAA purification stage based on the process by Blanc-Béguin et al. Used with permission from Blanc-Béguin et al. [39]. **Figure 2.** Schematic representation of the [68Ga]Ga-MAA purification stage based on the process by Blanc-Béguin et al. Used with permission from Blanc-Béguin et al. [39].

#### 3.2.3. Pharmacological Aspects

• Manual or Automated Process Most of the [68Ga]Ga-MAA preparation processes described in the literature were manual and were carried out in 20 to 40 min (See Table 1) [28,31,32]. Mueller et al. showed that an automated process reduced the preparation time from 20 to 14 min [35]. A few automated processes were described in the literature to perform the synthesis from the elution to the end of the heating steps (see Table 1). More recently, a fully automated process has been proposed, including both MAA labelling and [68Ga]Ga-MAA purification, which was carried out in 15 min (see Tables 1 and 2) [39]. To the best of our knowledge, this is the only fully automated process to date. An important challenge of the switch from 99m Tc- to <sup>68</sup>Ga-labelled MAA is maintaining the pharmacological properties of particles to ensure similar biodistribution throughout the terminal pulmonary arterioles. Accordingly, the key parameter is the particle size, which should range between 10.0 and 90.0 µm, with no particles size superior to 150.0 µm. On the other hand, particles should not be inferior to 10.0 µm because the target organs would be the reticuloendothelial system and the bones instead of the lungs [22]. Most of the literature data reported a mean diameter ranging from 10 to 90 µm (15.0–75.0 µm for Blanc-Béguin et al., 52.9 ± 15.2 for Jain et al. and 43.0–51.0 for Canziani et al.) (Table 3) [18,29,39]. Furthermore, all published data on [68Ga]Ga-MAA described a preserved structure of radiolabelled particles, whatever the labelling conditions (see Table S1).

3.2.3. Pharmacological Aspects An important challenge of the switch from 99m Tc- to 68Ga-labelled MAA is maintaining the pharmacological properties of particles to ensure similar biodistribution through-Hence, [99mTc]Tc-MAA and [68Ga]Ga-MAA particles have similar sizes and structures. The number of [68Ga]Ga-MAA particles injected should range from 60,000 to 700,000, no differently from [99mTc]Tc-MAA, to obtain uniform distribution of activity reflecting regional perfusion.

out the terminal pulmonary arterioles. Accordingly, the key parameter is the particle size, which should range between 10.0 and 90.0 µm, with no particles size superior to 150.0 µm. On the other hand, particles should not be inferior to 10.0 µm because the target organs would be the reticuloendothelial system and the bones instead of the lungs [22]. Most of the literature data reported a mean diameter ranging from 10 to 90 µm (15.0–75.0 µm for Blanc-Béguin et al., 52.9 ± 15.2 for Jain et al. and 43.0–51.0 for Canziani *et al.*) (Table 3) [18,29,39]. Furthermore, all published data on [68Ga]Ga-MAA described a preserved structure of radiolabelled particles, whatever the labelling conditions (see Table S1). Hence, [99mTc]Tc-MAA and [68Ga]Ga-MAA particles have similar sizes and structures. The number of [68Ga]Ga-MAA particles injected should range from 60,000 to 700,000, no differently from [99mTc]Tc-MAA, to obtain uniform distribution of activity reflecting regional perfusion. All studies that assessed the biodistribution of labelled MAA particles in the animals described an almost complete retainment of activity in the lungs from 5 min to 30, 45, 60 All studies that assessed the biodistribution of labelled MAA particles in the animals described an almost complete retainment of activity in the lungs from 5 min to 30, 45, 60 min, or 4 h after the injection of [68Ga]Ga-MAA particles, and very low activity in other organs, especially in the liver [22,29,33,34]. Indeed, experiments performed with rats or mice have shown that more than 80% of the injected activity was located in the lungs from 15 min to 4 h post-injection [22,29,34]. In female wild-type rats, the peak of activity occurred 1 min and 35 min post-injection in the kidneys and bladder, respectively, whereas it was from 10 to 20 min in the lungs [22]. In Sprague-Dawley rats, less than 2% of the injected dose per organ (ID/o) activity was measured in other organs from 2 to 4 h post-[68Ga]Ga-MAA administration in the tail vein [34]. It is noteworthy that, as compared with the [99mTc]Tc-MAA, [68Ga]Ga-MAA exhibited better in vivo stability after intravenous injection in Sprague-Dawley rats [34]. Indeed, the percentage of decay-corrected ID/o (DC-ID/o) of [68Ga]Ga-MAA located in the lung did not change over the study period, i.e., the 4 h following the injection (98.6 ± 0.7 at 2 h and 98.6 ± 0.1 at 4h), whereas the % DC-ID/o of [99mTc]Tc-MAA located in the lung decreased from 86.6 <sup>±</sup> 0.7 at 2 h to 79.2 ± 1.5 at 4 h [34]. After injection in the rat tail vein, the main activity was extracted by the kidneys to the bladder, and the free <sup>68</sup>Ga remained in the blood after two and four hours (84.9 <sup>±</sup> 4.5% and 63.1 <sup>±</sup> 3.9% of DC-ID/o, respectively), presumably as <sup>68</sup>Ga native transferrin complex [22,34].


**Table 3.** Summary of important factors of the switch from 99mTc to <sup>68</sup>Ga.

<sup>68</sup>Ga(III) has a high binding affinity to the blood serum protein transferrin (log K1 = 20.3). The main requirement for [68Ga]Ga-MAA stability is thermodynamic stability towards hydrolysis and formation of Ga(OH)<sup>3</sup> [42]. As shown in Table 3, whatever the labelling conditions, the obtained [68Ga]Ga-MAA suspension had at least a 45 min in vitro stability in animal serum or plasma, which is largely sufficient given that images are acquired immediately after injection and that the acquisition time is approximately 5 min [33].

To the best of our knowledge, no data were published on the biodistribution of [ <sup>68</sup>Ga]Ga-MAA in humans. However, Ament et al., who performed an exploratory study on five patients with clinical suspicion of PE who underwent V/Q PET/CT, have observed that perfusion imaging was homogeneous in most cases [33]. No significant retention and no visual uptake of [68Ga]Ga-MAA particles in the liver were detectable [33].

However, many clinical studies reported consistent activity distribution on PET imaging in various pulmonary conditions after injection of [68Ga]Ga-MAA [1,5,8,33,35,43].

#### **4. Lung Ventilation Imaging**

*4.1. Aerosolized 99mTc-Labelled Carbon Nanoparticles (Technegas)*

4.1.1. Physical and Chemical Aspects

99mTc-labelled carbon nanoparticles consist of primary hexagonally structured carbon nanoparticles, which can agglomerate into larger secondary aggregates. Primary nanoparticles are structured with graphite planes oriented parallel to the technetium surface to form nanoparticles with a thickness of about 5 nm [44]. Few data are available about the link

between 99mTc and carbon nanoparticles. It was hypothesized that Tc7+ obtained from a <sup>99</sup>Mo/99mTc generator was reduced at the crucible interface, resulting in native metal Tc which co-condensates with carbon species once in the vapor phase [44].

Some authors have hypothesized that 99mTc-labelled carbon nanoparticles consisted of 99mTc atoms trapped by a structure similar to a fullerene cage [45,46]. Indeed, Mackey et al. have demonstrated the presence of fullerenes during the generation of the aerosolized 99mTc-labelled carbon nanoparticles available to form metallofullerenes with the 99mTc atom attached either exohedrally or endohedrally to the fullerene molecules [46]. However, this hypothesis was controversial especially because of the hexagonal platelet structure of the labelled carbon nanoparticles [44].

#### 4.1.2. Technical Aspects

The 99mTc-labelled carbon nanoparticle production is a simple process that requires relatively little material: a <sup>99</sup>Mo/99mTc generator, a Technegas generator (Cyclomedica Pty Ltd., Kingsgrove, Australia) and a pure argon bottle. There are three main stages in 99mTc-labelled carbon nanoparticle production: the loading of the crucible, the simmer stage and the burning stage.

• Crucible loading

Using a syringe with a needle, 0.14 mL to 0.30 mL (140–925 MBq) of 99mTc eluate is introduced in a graphite crucible previously humidified with 99% ethanol to increase its wettability and placed between the generator electrodes [6,47–51]. As the volume of the crucible is limited to 0.14 mL or 0.30 mL according to the supplier, it is possible to perform several crucible loadings to introduce all the 99mTc eluate needed;

• Simmer stage

The simmer stage, performed immediately after the crucible loading, reduces 99mTc7+ to metallic 99mTc under a pure argon atmosphere [44]. The use of pure argon is a determining parameter for the structure and the physical properties of the 99mTc-labelled carbon nanoparticles [45,48,52–54]. During the simmer stage, the graphite crucible is heated for 6 min at 70 ◦C. However, it has been shown that increasing the number of simmers increases the median size of the 99mTc-labelled carbon nanoparticles [45];

• Burning stage

The simmer cycle is followed by the crucible heating to 2550 ◦C ± 50 ◦C for 15 s. Metallic Tc and carbon species are vaporized and co-condensed during this burning stage to obtain aerosolized 99mTc-labelled carbon nanoparticles [44]. At the end of this stage, the switching off of the Technegas generator fills the 6 L chamber with aerosolized 99mTclabelled carbon nanoparticles ready for use via inhalation by the patient.

All process parameters (heating temperature and time) used for clinical production are fixed. The machine allows a 10 min window in which the 99mTc-labelled carbon nanoparticles may be administered to the patient. However, the longer the administration delay is, the higher the median size of the particles is [45,51].

#### 4.1.3. Pharmacological Aspects

The size of primary carbon nanoparticles ranges from 5 to 60 nm, while the size of the aggregates is approximately 100–200 nm (See Table 4). Hence, aerosolized 99mTc-labelled carbon nanoparticles are considered an ultrafine aerosol with ventilation properties similar to radioactive gasses, such as krypton-81m (81mKr) and xenon-133 (133Xe) [21,47,48,50,51,55–57]. Many authors agree on the mainly alveolar deposition of the 99mTc-labelled carbon nanoparticles and the stability of the nanoparticles in the lungs over time [21,45,49,57,58].



**Table 4.** 99mTc and 68Ga-labelled carbon nanoparticle size, shape and structure according to the literature.

## *4.2. Aerosolized <sup>68</sup>Ga-Labelled Carbon Nanoparticles*

#### 4.2.1. Physical and Chemical Aspects

The physical properties of aerosolized particles are important parameters in determining their penetration, deposition, and retention in the respiratory tract. The physical properties of <sup>68</sup>Ga-labelled carbon nanoparticles, prepared using a Technegas generator in the usual clinical way, were recently assessed [60]. <sup>68</sup>Ga-labelled carbon nanoparticles demonstrated similar properties as 99mTc-labelled carbon nanoparticles, with primary hexagonally shaped and layered structured particles [60]. Although the chemical process of labelling carbon nanoparticles with <sup>68</sup>Ga and the exact chelation structure of <sup>68</sup>Ga in carbon nanoparticles are unknown, the physical properties of <sup>68</sup>Ga-labelled carbon nanoparticles suggest a method of labelling similar to labeling with 99mTc.

#### 4.2.2. Technical Aspects

In contrast with MAA labelling, the process for 99mTc-labelled carbon nanoparticle preparation is very similar across studies in the literature. <sup>68</sup>Ga-labelled carbon nanoparticles are produced using an unmodified Technegas generator and following the same stages as for the preparation of 99mTc-labelled carbon nanoparticles: the crucible loading with an eluate volume range from 0.14 mL to 0.30 mL, the simmer stage and the burning stage with similar heating time and temperature [6,7,33,60–62]. The only difference is the nature of the eluate, which is gallium-68 chloride (68GaCl3) instead of 99mTcO<sup>4</sup> <sup>−</sup>, Na<sup>+</sup> . Few authors performed an eluate pre-concentration using an anion exchange cartridge or by fractionating to purify and reduce the volume of the eluate [33,62]. However, <sup>68</sup>Ga-labelled carbon nanoparticles obtained using an unmodified eluate from the <sup>68</sup>Ge/68Ga generator demonstrated similar physical properties as 99mTc-labelled carbon nanoparticle properties and were suitable for pulmonary ventilation PET/CT [6,7,60,61].

#### 4.2.3. Pharmacological Aspects

From the pharmacological point of view, an important parameter of the switch from lung ventilation SPECT to PET/CT is to maintain the physical properties of aerosolized carbon nanoparticles to ensure similar alveolar deposition and stability in the lungs.

The size is a key factor in determining the degree of aerosol particle penetration in the human pulmonary tract [55]. To the best of our knowledge, only one recently published work has studied the physical properties of <sup>68</sup>Ga-labelled carbon nanoparticles, and few pharmacological data are available in the literature. However, it was reported that using an unmodified Technegas generator, the mean diameter of primary <sup>68</sup>Ga-labelled carbon nanoparticles was in the same range as primary 99mTc-labelled carbon nanoparticles (22.4 ± 10.0 nm and 20.9 ± 7.2 nm, respectively) with similar agglomeration into larger secondary aggregates measuring several hundreds of nm [60].

These results suggested similar lung distribution of 99mTc- and <sup>68</sup>Ga-labelled carbon nanoparticles, as confirmed by a study on healthy piglets [62]. Later, V/Q PET performed in Sprague-Dawley rats reported complete incorporation of <sup>68</sup>Ga-labelled carbon nanoparticles in the lungs without extrapulmonary activity (urinary bladder, abdomen, blood pool) [33]. Moreover, animal studies performed with aerosolized <sup>68</sup>Ga-labelled carbon nanoparticles have demonstrated greater differences between poorly and well-ventilated regions, suggesting higher resolution than 99mTc-labelled carbon nanoparticles [62].

Moreover, in healthy human volunteers, the activity distribution in the lungs after inhalation of <sup>68</sup>Ga-labelled carbon nanoparticles was intense, without bronchial deposit 15 min after the inhalation. Furthermore, the activity (decay corrected) over the lung was constant at 3.5 h without elimination via blood, urine (only trace radioactivity in urine bladder was observed) or feces suggesting the stability of the deposition of <sup>68</sup>Galabelled carbon nanoparticles over this time [7]. Another exploratory study performed on five patients with clinical suspicion of PE observed homogeneous ventilation imaging in two cases and inhomogeneous accumulation with central deposition of labelled carbon nanoparticles in three cases [33].

Finally, many clinical studies reported consistent activity distribution in the lungs on PET imaging in various pulmonary conditions after inhalation of <sup>68</sup>Ga-labelled carbon nanoparticles [5,6,8,33].

#### **5. Practical Considerations for an Optimal Clinical Use**

Lung V/Q PET/CT is a promising imaging modality for regional lung function assessment. Indeed, PET imaging has great technical advantages over SPECT imaging (higher sensitivity, spatial and temporal resolution, superior quantitative capability, easier to perform respiratory-gated acquisition). PET may also be a useful alternative to SPECT imaging in a 99mTc shortage. The success of the switch from conventional scintigraphy to PET imaging, and therefore from 99mTc- to <sup>68</sup>Ga-labelled radiopharmaceuticals, relies on two main factors: preserving the pharmacological properties of the labelled MAA and carbon nanoparticles, whose biodistribution is well known; and facilitating the implementation in nuclear medicine departments. In that respect, several studies have been conducted on the production of both perfusion and ventilation <sup>68</sup>Ga-labelled radiopharmaceuticals, which have led to simplification, optimization and, more recently, automation of the processes.

For lung perfusion PET/CT imaging, various processes have been used for [68Ga]Ga-MAA labelling, with different options in the key steps of the preparation, including the choice of MAA particles, the need for <sup>68</sup>Ga eluate pre-purification, the labelling conditions or the [68Ga]Ga-MAA suspension purification. However, simpler processes appear to be suitable for optimal clinical use. This includes using a non-modified commercially available MAA kit, with no need for a <sup>68</sup>Ga eluate pre-purification, use of an easy to use buffer such as sodium acetate solution, and a short reaction medium heating time (5 min). Automated processes have been developed to facilitate processing time and reduce the radiation dose to the operator. Thus, a simple and fast (15 min) automated GMP compliant [68Ga]Ga-MAA synthesis process was proposed, using a non-modified MAA commercial kit, a <sup>68</sup>Ga eluate without pre-purification and including an innovative process for [68Ga]Ga-MAA purification, which maintains the pharmacological properties of the tracer and provided labelling yields >95% [39]. Moreover, whatever the labelling conditions, the obtained [ <sup>68</sup>Ga]Ga-MAA suspension was described to be stable in 0.9% sodium chloride for at least one hour [35,39]. Given the radioactive concentration of [68Ga], Ga-MAA obtained at the end of the synthesis (i.e., from 300MBq/10 mL to 900 MBq/10 mL according to the age of the <sup>68</sup>Ge/68Ga generator) and the dose injected (i.e., around 50 MBq), up to 6 perfusion PET/CT scans can be performed with one synthesis [5,6,39,63].

For lung ventilation PET/CT imaging, preparing and administering aerosolized <sup>68</sup>Galabelled carbon nanoparticles is very straightforward. The process is very similar to the production of 99mTc-labelled carbon nanoparticles and, therefore, fairly easy to implement in nuclear medicine facilities. Indeed, adding a <sup>68</sup>Ga eluate instead of 99mTc eluate in the carbon crucible of an unmodified commercially available Technegas™ generator provides carbon nanoparticles with similar physical properties. Furthermore, recently, an automated process included a step to fractionate the <sup>68</sup>Ga eluate into two samples, one for [68Ga]Ga-MAA labelling and the other for aerosolized <sup>68</sup>Ga-labelled carbon nanoparticle production, which has been developed [39].

Besides radiopharmaceutical production, many factors may facilitate the implementation of V/P PET/CT imaging in nuclear medicine facilities. <sup>68</sup>Ge/68Ga generators are increasingly available in the nuclear medicine departments due to <sup>68</sup>Ga tracers for neuroendocrine tumors and prostate cancer imaging. PET/CT cameras are also increasingly accessible due to the development of digital PET/CT cameras and might be total-body PET/CT in the future. Most nuclear medicine facilities already have the necessary equipment to carry-out V/P PET/CT imaging, including carbon nanoparticle generators and MAA kits. Automating the MAA labelling is now possible; commercial development of ready-to-use sets for automated synthesis radiolabelling of <sup>68</sup>Ga-MAA would be of interest.

In conclusion, recent data support the ease of using well-established carrier molecules and <sup>68</sup>Ga to enable the switch from SPECT to PET imaging for regional lung function. The technology may be easily implemented in most nuclear medicine facilities and open perspectives for the improved management of patients with lung disease.

**Supplementary Materials:** The following supporting information can be downloaded at: https: //www.mdpi.com/article/10.3390/ph15050518/s1, Table S1: [68Ga]Ga-MAA particles size and biodistribution study according to the various authors.

**Author Contributions:** Conceptualization, P.-Y.L.R. and F.B.-B.; formal analysis, F.B.-B.; data curation, F.B.-B.; writing—original draft preparation, F.B.-B. and P.-Y.L.R.; writing—review and editing, F.B.-B., S.H., P.R., R.T., P.-Y.S. and P.-Y.L.R.; visualization, F.B.-B. and P.-Y.L.R.; supervision, P.-Y.L.R., P.R. and P.-Y.S.; project administration, P.-Y.L.R. All authors have read and agreed to the published version of the manuscript.

**Funding:** This research received no external funding.

**Institutional Review Board Statement:** Not applicable.

**Informed Consent Statement:** Not applicable.

**Data Availability Statement:** Not applicable.

**Conflicts of Interest:** The authors declare no conflict of interest.

#### **References**


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