New Imaging Modality of COVID-19 Pneumonia Developed on the Basis of Alzheimer’s Disease Research

Abstract

Viral pneumonia caused by highly infectious SARS-CoV-2 poses a higher risk to older people and those who have underlying health conditions, including Alzheimer’s disease. In this work we present newly designed tacrine-based radioconjugates with physicochemical and biological properties that are crucial for the potential application as diagnostic radiopharmaceuticals. A set of ten tacrine derivatives was synthesized, labelled with gallium-68 and fully characterized in the context of their physicochemical properties. Based on these results, the final two most promising radioconjugates, [68Ga]Ga-NODAGA-Bn-NH(CH2)9Tac and [68Ga]Ga-THP-NH(CH2)9Tac, were selected for biodistribution studies. The latter compound was proven to be a good inhibitor of cholinesterases with significant affinity toward the lungs, according to the biodistribution studies. On the basis of molecular modelling combined with in vitro studies, we unraveled which structural properties of the developed tacrine derivatives are crucial for high affinity toward acetylcholinesterase, whose increased levels in lung tissues in the course of coronavirus disease indicate the onset of pneumonia. The radiopharmaceutical [68Ga]Ga-THP-NH(CH2)9Tac was ultimately selected due to its increased accuracy and improved sensitivity in PET imaging of lung tissue with high levels of acetylcholinesterase, and it may become a novel potential diagnostic modality for the determination of lung perfusion, including in inflammation after COVID-19.

Design, Synthesis and Molecular Modeling Study of Radiotracers Based on Tacrine and Its Derivatives for Study on Alzheimer’s Disease and Its Early Diagnosis

“…The most convenient procedure for the synthesis of diagnostic radiopharmaceuticals in clinical conditions is to perform a labeling reaction with generator radionuclides ( 99m Tc, 68 Ga) of the active substance (tacrine or its derivative, often previously coupled with an appropriate chelator) included in the so-called kit [33][34][35][36] (kits are ready-made sets containing, in lyophilized form, the appropriate reagents in the appropriate quantities needed for the synthesis of a given radiopharmaceutical). However, the use of chelators significantly changes both the size of the final radiopreparation and its lipophilicity.…”

“…Studies on radioconjugates, still based on the same tacrine derivatives, in which five various chelators were used to complex the 68 Ga radionuclide, were presented in the work of Koźmi ński et al [35]. The chelators used for the synthesis of the 68 Ga-radioconjugates were 2,2 ′ -( 7 In order to obtain the highest possible lipophilicity of the synthesized radioconjugates (recommended for radiopreparations capable of crossing the blood-tissue and blood-brain barriers), a tacrine derivative containing nine methylene groups in the aliphatic hydrocarbon chain was used for the synthesis of the 68 Ga-radioconjugates.…”

“…Compared to previously used tacrine derivatives [33][34][35], the structural modification of tacrine additionally consisted of replacing the six-membered tetrahydroacridine ring with a five-membered ring. As previously reported [33][34][35], 6-hydrazinonicotinamide (HYNIC, radionuclide 99m Tc complexing agent) was attached to the amino group of tacrine through a hydrocarbon chain with a different number of (CH2)n groups, where n = 2 ÷ 9. Biochemical tests performed spectrophotometrically using the Ellman method showed that tacrine derivatives with the long hydrocarbon chain (n = 7 ÷ 9) have higher inhibition activity and are more selective towards acetylcholines- In a review article focusing on potential radiotracers based on tacrine and its analogues, it is worth presenting the radioconjugates synthesized and tested by Szyma ński et al [36].…”

“…Biochemical tests performed spectrophotometrically using the Ellman method showed that tacrine derivatives with the long hydrocarbon chain (n = 7 ÷ 9) have higher inhibition activity and are more selective towards acetylcholines- In a review article focusing on potential radiotracers based on tacrine and its analogues, it is worth presenting the radioconjugates synthesized and tested by Szyma ński et al [36]. Compared to previously used tacrine derivatives [33][34][35], the structural modification of tacrine additionally consisted of replacing the six-membered tetrahydroacridine ring with a five-membered ring. As previously reported [33][34][35], 6-hydrazinonicotinamide (HYNIC, radionuclide 99m Tc complexing agent) was attached to the amino group of tacrine through a hydrocarbon chain with a different number of (CH 2 ) n groups, where n = 2 ÷ 9.…”

“…Computational studies of the interaction of some tacrine derivatives as well as potential radiotracers based on them (Table 3) with acetyl-and/or butyrylcholinesterase were discussed in the works of Gniazdowska et al [33,34], Koźmi ński et al [35] and Szyma ński et al [36]. The conjugates and radioconjugates selected for the molecular docking studies are listed in Table 3.…”