RT Journal Article
SR Electronic
T1 F-18 Fluoroalkyl dihydrotetrabenazine for imaging vesicular monoamine transporter 2 in the brain
JF Journal of Nuclear Medicine
JO J Nucl Med
FD Society of Nuclear Medicine
SP 26P
OP 26P
VO 47
IS suppl 1
A1 Kung, Hank
A1 Kung, Mei-Ping
A1 Goswami, Rajesh
A1 Ponde, Datta
A1 Hou, Catherine
A1 Kilbourn, Michael
YR 2006
UL http://jnm.snmjournals.org/content/47/suppl_1/26P.2.abstract
AB 75 Objectives: Imaging vesicular monoamine transporter 2 (VMAT2) in the brain by C-11-DTBZ (dihydrotetrabenazine) has been demonstrated as useful in the diagnosis and monitoring of neurodegenerative diseases such as Parkinson’s and Huntington’s diseases. Further development of F-18 labeled analogs of TBZ with a longer half life (t1/2 =109 min vs 20 min for C-11) will provide a wider usefulness for this PET tracer. Methods: 9-Fluoroethyl (FE) and 9-fluoropropyl (FP)-9-demthyl-DTBZ derivatives and the corresponding hydroxyl derivatives were prepared. The no-carrier-added F-18-FP-DTBZ derivatives were synthesized by [F-18]fluoride displacement of the corresponding mesylates. Binding for VMAT2 was assessed by in vitro homogenate binding assay and in vitro autoradiography. In vivo biodistribution studies were evaluated in normal male mice. Results: Fluorinated DTBZ derivatives, FE-DTBZ and FP-DTBZ, displayed excellent binding affinities (Ki = 0.76 and 0.56 nM) for VMAT2 in mouse striatal homogenates. Consistently, the [F-18]FP-DTBZ exhibited a Kd value of 0.48 nM and a Bmax value of 222 fmol/mg protein for VMAT2 (based on S.A.= 2000 Ci/mmole). Film autoradiography results showed an excellent uptake in striatal region and a distribution pattern consistent to the localization of VMAT2 in the mouse brain. Non-radioactive TBZ efficiently blocked the specific labeling of the F-18 labeled derivative in these regions. Biodistribution studies in mice after an iv injection showed that [F-18]FP-DTBZ exhibited an excellent brain uptake (7.08 % ID/g at 2 min) as was expected from the lipophilicity (partition coefficient = 411). A high target (striatum, ST) to background (cerebellum, CB) signal ratio was observed ( ST/CB = 2.95 at 30 min post-injection of the tracer). Conclusions: These findings strongly suggest that the novel F-18 labeled DTBZ derivatives may be potentially useful as molecular imaging agents for VMAT2. Further in vivo non-human primate imaging studies are warranted. Research Support (if any): NIH EB-002171 Table 1. Biodistribution of 18F-FP-DTBZ in normal mice