PT  - JOURNAL ARTICLE
AU  - Kung, Hank
AU  - Kung, Mei-Ping
AU  - Goswami, Rajesh
AU  - Ponde, Datta
AU  - Hou, Catherine
AU  - Kilbourn, Michael
TI  - F-18 Fluoroalkyl dihydrotetrabenazine for imaging vesicular monoamine transporter 2 in the brain
DP  - 2006 May 01
TA  - Journal of Nuclear Medicine
PG  - 26P--26P
VI  - 47
IP  - suppl 1
4099  - http://jnm.snmjournals.org/content/47/suppl_1/26P.2.short
4100  - http://jnm.snmjournals.org/content/47/suppl_1/26P.2.full
SO  - J Nucl Med2006 May 01; 47
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