Abstract
1040
Objectives Positron Emission Tomography (PET) tracers can be used for the diagnosis of the diseases of the central nervous system (i.e., epilepsy, psychosis, Parkinson’s disease, Alzheimer’s disease). 18F-Fluorodopa, where the 18F atom is selectively attached to the aromatic ring, undergoes conversion to 18F-fluorodopamine enabling measurement of dopamine synthetic rate. Although its decarboxylation rate in neurological disorders could be illustrated by PET, its F2 carrier-added chemistry affords low yield and has subsequently hampered broad application. Conversely, a chelator-based imaging agent would have the advantage of rapid synthesis and high radiolabeling yields. Tyrosine is known to be transformed to DOPA by tyrosine hydroxylase, followed by decarboxylation to form dopamine. This study aimed to evaluate a 68Ga-labeled tyrosine analog, known as N4-Tyr (or VYT-204), as an alternative probe for imaging dopaminergic pathways in neurological disorders.
Methods N4-tyrosine was synthesized using a 5-step procedure. A bromopropyl chain was added to the phenolic group of tyrosine. Two of the nitrogens on the cyclam (N4) backbone were protected with oxalate, reacted with bromopropyl tyrosine, and de-protected to yield N4-Tyr. Incubation with 68Ga afforded 68Ga-N4-Tyr in 15 min. In the imaging studies, breast tumor-bearing rats and VX-2 tumor-bearing rabbits were administered 18F-FDG, 68Ga-N4 and 68Ga-N4-Tyr at 500 µCi/rat and 1.5 mCi/rabbit (iv), respectively, and imaged from 5-45 min post-injection.
Results The total synthesis yield for N4-Tyr ranged from 32-38%. The precursor in each step was analytically pure as determined by HPLC, and was readily optimized. In imaging studies with tumor-bearing animal models, both tumors and brain had high uptake with tracers as early as 5 min post-administration. Imaging studies with rabbits showed high uptake in the striatum and substantia nigras in basal ganglia regions with 68Ga-N4-Tyr, but not with 68Ga-N4. 18F-FDG accumulation was primarily in the hypothalamus region. Average SUVs in the striatum and substantia nigras for 68Ga-N4-Tyr were 1.82-1.95.
Conclusions 68Ga-N4-Tyr could be efficiently prepared using kit-based methods and represents a practical approach for neurological probe development. The imaging studies indicate that 68Ga-N4-Tyr has the potential to image dopaminergic associated neurological disorders.