Imaging agents
The present invention provides novel amino acid compounds useful in detecting and evaluating brain and body tumors. These compounds have the advantageous properties of rapid uptake and prolonged retention in tumors and can be labeled with halogen isotopes such as fluorine-18, iodine-123, iodine-124, iodine-125, iodine-131, bromine-75, bromine-76, bromine-77, bromine-82, astatine-210, astatine-211, and other astatine isotopes. These compounds can also be labeled with technetium and rhenium isotopes using known chelation complexes. The compounds disclosed herein bind tumor tissues in vivo with high specificity and selectivity when administered to a subject. Preferred compounds show a target to non-target ratio of at least 2:1, are stable in vivo and substantially localized to target within 1 hour after administration. Preferred compounds include 1-amino-2-[ 18 F]fluorocyclobutyl-1-carboxylic acid (2-[ 18 F]FACBC) and 1-amino-2-[ 18 F]fluoromethylcyclobutyl-1-carboxylic acid (2-[ 18 F]FMACBC). The labeled amino acid compounds of the invention are useful as imaging agents in detecting and/or monitoring tumors in a subject by PET or SPECT.
1. A method of synthesizing an amino acid analog of the formula
or salt thereof comprising the step of reacting a halogenated compound with a compound of the following formula
followed by an acid to yield the amino acid analog
R1 is tert-butoxycarbonyl(Boc) or bis(4-methoxyphenyl)methyl in the compound and hydrogen in the amino acid analog;
R2 is hydrogen;
X is selected from the group consisting of halogen, haloalkyl, halocycloalkyl, halocycloalkenyl, halocycloalkynyl, haloacyl, haloaryl, haloheteroaryl, haloalkenyl, haloalkynyl, where halo or halogen in X is selected from the group consisting of F, Cl, Br, I, At, F-18, Br-76, I-123, I-124;
Y is selected from the group consisting of (CR 5 R 6 )n, n=1-4, N, O, S, and Se;
R 4 , R 5 and R 6 are independently selected from the group consisting of H, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, heteroaryl, aryl, haloaryl, haloheteroaryl, alkenyl, haloalkenyl, alkynyl, and haloalkynyl, where halo is selected from the group consisting of non-radioactive F, Cl, Br, and I; and
R 3 is selected from the group consisting of H, alkyl, haloalkyl, cycloalkyl, halocycloalkyl, cycloalkenyl, halocycloalkenyl, cycloalkynyl, halocycloalkynyl, acyl, haloacyl, aryl, haloaryl, heteroaryl, haloheteroaryl, alkenyl, haloalkenyl, alkynyl, and haloalkynyl.
2. The method of claim 1 wherein the amino acid analog is 1-amino-2-[ 18 F]fluorocyclobutyl-1-carboxylic acid.
3. The method of claim 1 , wherein X is F-18 or I-123.
4. The method of claim 1 , wherein Y is CH 2 .
5. The method of claim 1 , wherein R3 is tert-butyl in the compound and H in the amino acid analog.
6. The method of claim 1 , wherein R4 is hydrogen.
7. The method of claim 1 , wherein the halogenated compound comprises a halogen selected from F-18, Br-76, I-123, and I-124.
8. The method of claim 1 , wherein the halogenated compound is a halogen salt.
9. The method of claim 8 , wherein the halogen salt is K 18 F, K 123 I, or Na 123 I.