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Radiopharmaceutical Labelling for Lung Ventilation/Perfusion PET/CT Imaging: Comparison
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Please note this is a comparison between Version 1 by Frédérique Blanc-Béguin and Version 2 by Lindsay Dong.

Lung ventilation/perfusion (V/Q) positron emission tomography-computed tomography (PET/CT) is a promising imaging modality for regional lung function assessment. The same carrier molecules as a conventional V/Q scan (i.e., carbon nanoparticles for ventilation and macro aggregated albumin particles for perfusion) are used, but they are labeled with gallium-68 (68Ga) instead of technetium-99m (99mTc). 

  • V/Q PET/CT
  • [68Ga]Ga-MAA
  • 68Ga-labelled carbon nanoparticles

1. Introduction

Lung ventilation-perfusion (V/Q) scintigraphy allows the regional lung function distribution of the two major components of gas exchanges, namely ventilation and perfusion, to be assessed [1]. Regional lung ventilation can be imaged after inhaling inert gases or radiolabelled aerosols that reach alveoli or terminal bronchioles. Regional lung perfusion can be assessed after intravenous injection of radiolabelled macroaggregated albumin (MAA) particles trapped during the first pass in the terminal pulmonary arterioles [2][3][2,3].
Pulmonary embolism (PE) diagnosis is the main clinical indication of lung V/Q scintigraphy in pulmonary embolism (PE) diagnosis. V/Q scanning was the first non-invasive test validated for PE diagnosis. The technique was then further improved with the introduction of single-photon emission computed tomography (SPECT) and, more recently, SPECT/computed tomography (CT) imaging [4]. There are many other clinical situations in which an accurate assessment of regional lung function may improve patient management besides PE diagnosis. This includes predicting post-operative pulmonary function in patients with lung cancer, radiotherapy planning to minimize the dose to the lung parenchyma with preserved function and reduce radiation-induced lung toxicities, or pre-surgical assessment of patients with severe emphysema undergoing a lung volume reduction surgery. However, although lung scintigraphy should play a central role in these clinical scenarios, its use has not been widely implemented in daily clinical practice [5]. One of the likely explanations could be the inherent technical limitations of SPECT imaging for the accurate delineation and quantification of regional ventilation and perfusion function [4].
Lung V/Q positron emission tomography (PET)/CT is a novel promising imaging modality for regional lung function assessment [6][7][6,7]. The technique has shown promising results in various clinical scenarios, including PE diagnosis [8], radiotherapy planning [9], or pre-surgical evaluation of lung cancer patients [10]. Several large prospective clinical trials are underway, such as (NCT04179539, NCT03569072, NCT04942275, and NCT05103670). The rationale is simple [5]. PET/CT uses the same carrier molecules as conventional V/Q scanning, i.e., carbon nanoparticles for ventilation imaging and MAA particles for perfusion imaging. Similar physiological processes are therefore assessed with SPECT or PET imaging. However, carrier molecules are labelled with gallium-68 (68Ga) instead of technetium-99m (99mTc), allowing the acquisition of images with PET technology. PET has technical advantages compared with SPECT, including higher sensitivity, higher spatial and temporal resolution, superior quantitative capability and much greater access to respiratory-gated acquisition [11].

2. Challenges of the Transition from 99mTc- to 68Ga-Labelled Radiopharmaceuticals for Lung Imaging

The first challenge of the switch from 99mTc- to 68Ga-labelled radiopharmaceuticals for lung V/Q imaging is to maintain the pharmacological properties of V and Q tracers. Both MAA and carbon nanoparticles labelled with 99mTc have been largely studied. They have been shown to have a biodistribution throughout the lungs that allow an accurate assessment of regional lung perfusion and ventilation function. The principle of lung V/Q PET/CT imaging is to assess similar physiological processes than with conventional V/Q scan, but with greater technology for image acquisition. The technique needs to be easy to implement in nuclear medicine facilities to enable routine use. The preparation should be fast, simple, GMP-compliant and safe for the operators. Furthermore, radiopharmaceutical production should use unmodified commercially available kits of carrier molecules and similar equipment and devices as much as possible as those used for conventional V/Q scans.

3. Lung Perfusion Imaging

3.1. [

99m

Tc]Tc-MAA

3.1.1. Chemical Aspects of [99mTc]Tc-MAA Particles

Among the various type of human serum albumin (HSA) available for radionuclide labeling, MAA is the most commonly used form in nuclear medicine facilities. The nature of the complex [99mTc]Tc-MAA has not been fully elucidated. It was hypothesized that the labelling of proteins with 99mTcO4− involved reduction of the anionic Tc(VII) to a cationic Tc by the tin Sn(II) contained in the commercial kit, which was then complexed with electron-donating groups [12][13][14][15,16,17]. Some authors have assumed that 99mTcO4− reduced by the Sn(II)- albumin aggregates probably formed a (Tc = O)3+ complex with the aggregates [12][15]. More recently, high positive cooperativity was shown between 99mTc and MAA, although MAA particles did not seem to have binding pockets [15][16][18,19].

3.1.2. Technical Aspects: [99mTc]Tc-MAA Preparation

[99mTc]Tc-MAA particles are manually prepared by introducing a 99mTc solution in a commercially available MAA kit. The 99mTc is obtained from a 99Mo/99mTc generator as sodium pertechnetate (99mTcO4−, Na+). The MAA labelling with 99mTc, which occurred at pH 6, is a simple and fast (about 15 min) process, which allows the production of GMP [99mTc]Tc-MAA without heating step [15][18].

3.1.3. Pharmacological Aspects

In a [99mTc]Tc-MAA suspension, the average particle size is 20–40 µm, and 90% have a size between 10 and 90 µm. There should be no particles larger than 150 µm [17][21]. [99mTc]Tc-MAA particles reach the lung via the pulmonary arterial circulation. Due to the size of the alveolar capillaries (5.5 µm on average), the [99mTc]Tc-MAA does not reach the alveolar capillaries but largely accumulates in the terminal pulmonary arterioles. Particles inferior to 10 µm may pass through the lungs and then phagocytose by the reticuloendothelial system [17][21]. According to the requirement of the MAA suppliers, the number of MAA particles injected should range from 60,000 to 700,000 to obtain uniform distribution of activity reflecting regional perfusion (for over 280 billion pulmonary capillaries and 300 million pre-capillary arterioles) [18][22].

3.2. [

68

Ga]Ga-MAA

3.2.1. Chemical Aspects of [68Ga]Ga-MAA Particles

MAA labelling with 68Ga has been proposed using bifunctional chelators such as EDTA or DTPA, forming quite stable and inert chelates [19][20][24,25]. However, direct labelling was performed by most groups. Direct labelling uses a co-precipitation of 68Ga(III) and albumin particles [21][22][26,27]. Mathias et al. hypothesized that 68Ga was adsorbed to the surface of the MAA particles after hydrolysis to insoluble gallium hydroxide without excluding specific interactions of Ga(III) ion with ion pairs exposed at the particle surface [23][28]. As Ga is present as Ga(OH)4− at a basic pH, 68Ga does not bind to MAA at a pH above 7. The MAA behavior matches with solvent-exposed glutamate and aspartate amino acids, which should be binding sites for multivalent cations with low affinity and low cation specificity [15][18].

3.2.2. Technical Aspects: [68Ga]Ga-MAA Preparation

[99mTc]Tc-MAA preparation is a manual and simple process involving only 2 steps: generator elution and mixing the eluate with the MAA. In contrast, because of the chemical properties of 68Ga, at least four steps are required to label MAA particles with 68Ga: 68Ge/68Ga generator elution, mixing the 68Ga eluate with the MAA, heating the reaction medium and the purification of the [68Ga]Ga-MAA. The key steps of MAA labelling with 68Ga are presented in Figure 1.
Pharmaceuticals 15 00518 g001 550
Figure 1.
Key points of MAA labelling with
68
Ga.

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 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 [18][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.) [15][24][25][18,29,39].
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.

4. Lung Ventilation Imaging

4.1. Aerosolized

99m

Tc-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 [26][44]. Few data are available about the link between 99mTc and carbon nanoparticles. It was hypothesized that Tc7+ obtained from a 99Mo/99mTc generator was reduced at the crucible interface, resulting in native metal Tc which co-condensates with carbon species once in the vapor phase [26][44].

4.1.2. Technical Aspects

The 99mTc-labelled carbon nanoparticle production is a simple process that requires relatively little material: a 99Mo/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.

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. 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) [17][27][28][29][30][31][32][33][21,47,48,50,51,55,56,57]. 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 [17][33][34][35][36][21,45,49,57,58].

4.2. Aerosolized

68

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 68Ga-labelled carbon nanoparticles, prepared using a Technegas generator in the usual clinical way, were recently assessed [37][60]. 68Ga-labelled carbon nanoparticles demonstrated similar properties as 99mTc-labelled carbon nanoparticles, with primary hexagonally shaped and layered structured particles [37][60]. Although the chemical process of labelling carbon nanoparticles with 68Ga and the exact chelation structure of 68Ga in carbon nanoparticles are unknown, the physical properties of 68Ga-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. 68Ga-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][37][38][39][40][6,7,33,60,61,62]. The only difference is the nature of the eluate, which is gallium-68 chloride (68GaCl3) instead of 99mTcO4−, Na+.

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 [31][55].

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 68Ga-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 68Ga-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 68Ga 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 68Ga 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 68Ga 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% [25][39]. Moreover, whatever the labelling conditions, the obtained [68Ga]Ga-MAA suspension was described to be stable in 0.9% sodium chloride for at least one hour [25][41][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 68Ge/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][25][42][5,6,39,63]. For lung ventilation PET/CT imaging, preparing and administering aerosolized 68Ga-labelled 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 68Ga 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 68Ga eluate into two samples, one for [68Ga]Ga-MAA labelling and the other for aerosolized 68Ga-labelled carbon nanoparticle production, which has been developed [25][39]. Besides radiopharmaceutical production, many factors may facilitate the implementation of V/P PET/CT imaging in nuclear medicine facilities. 68Ge/68Ga generators are increasingly available in the nuclear medicine departments due to 68Ga 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 68Ga-MAA would be of interest. In conclusion, recent data support the ease of using well-established carrier molecules and 68Ga 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.

 
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