Abstract
We report [18F]nifene binding to α4β2* nicotinic acetylcholinergic receptors (nAChRs) in Parkinson’s disease (PD). The study used transgenic Hualpha-Syn(A53T) PD mouse model of α-synucleinopathy for PET/CT studies in vivo and autoradiography in vitro. Additionally, postmortem human PD brain sections comprising of anterior cingulate were used in vitro to assess translation to human studies. Because the small size of mice brain poses challenges for PET imaging, improved methods for radiosynthesis of [18F]nifene and simplified PET/CT procedures in mice were developed by comparing intravenous (IV) and intraperitoneal (IP) administered [18F]nifene. An optimal PET/CT imaging time of 30–60 min post injection of [18F]nifene was established to provide thalamus to cerebellum ratio of 2.5 (with IV) and 2 (with IP). Transgenic Hualpha-Syn(A53T) mice brain slices exhibited 20–35% decrease while in vivo a 20–30% decrease of [18F]nifene was observed. Lewy bodies and α-synuclein aggregates were confirmed in human PD brain sections which lowered the [18F]nifene binding by more than 50% in anterior cingulate. Thus [18F]nifene offers a valuable tool for PET imaging studies of PD.
Highlights
Dysfunction of neuronal α4β2* nicotinic cholinergic receptors has been implicated in numerous pathologies, including Parkinson’s disease (PD)
In order to image these receptors using positron emission tomography (PET) and single photon emission computed tomography (SPECT), we developed several α4β2* nicotinic acetylcholinergic receptors (nAChRs) fluorine-18 and iodine-123 labeled radiotracers (Figure 1)
In order to establish the use of [18 F]nifene imaging in mice, we report here the following: (1) Improved radiosynthesis using a new trimethylammonium salt precursor; (2) PET/CT studies in normal mice and evaluation of quantitation methods using mouse brain MRI template; (3) evaluation of [18 F]nifene binding in α-synucleinopathy mice model of PD; and (4) binding in post-mortem human anterior cingulate brain sections of control and PD subjects
Summary
Dysfunction of neuronal α4β2* nicotinic cholinergic receptors (nAChRs) has been implicated in numerous pathologies, including Parkinson’s disease (PD). Due to this clinical importance of α4β2* nAChRs, evaluating these receptors can potentially assist in the treatment of these human diseases. In order to image these receptors using positron emission tomography (PET) and single photon emission computed tomography (SPECT), we developed several α4β2* nAChRs fluorine-18 and iodine-123 labeled radiotracers (Figure 1). These include 5-fluoropropyl derivatives, [18 F]nifrolidine [1], [18 F]nifzetidine [2],. Both PET and SPECT studies with the identical molecule was made possible by using [18 F]niofene or [123 I]niofene, which contains both a fluorine and iodine substituent [7]
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