Development and screening of contrast agents for in vivo imaging of Parkinson's disease
The invention provides compounds and a method for imaging aggregated α-synuclein, e.g., Lewy bodies or Lewy neurites, in a tissue or organ.
1. A method for in vivo imaging of an α-synuclein aggregate, the method comprising:
a) administering, to a subject in need thereof, a detectable amount of a compound selected from the group consisting of 3,3′-diethylthiadicarbocyanine iodide (3-3′-DTDCI); 4-[4-[4-(dimethylamino)phenyl]-1,3-butadienyl]-1-ethyl-pyridinium perchlorate (LDS 722); LDS 759; 4-[4-[4-(dimethylamino)phenyl]-1,3-butadienyl]-1-ethyl quinolinium (LDS 798); 9-diethylamino-5-benzo[α]phenoxazinone (Nile Red); THK-265; 2-[4-[4-(dimethylamino)phenyl]-1,3-butadienyl]-1,3,3-trimethyl-3H-indolium perchlorate (LDS 730); 5-amino-9-(diethylamino)-benzo[a]phenoxazin-7-ium perchlorate (Nile Blue 690 ClO 4 ); 2-[7-(1,3-dihydro-1,3,3-trimethyl-2H-indol-2-ylidene)-1,3,5-heptatrienyl]-1,3,3-trimethyl-3H-indolium perchlorate (HITC ClO 4 ); 2,2″-([1,1′-biphenyl]-4.4′-diyldi-2,1-ethenediyl)bis-benzenesulfonic acid disodium salt (Stilbene 420); analogs, isomers and pharmaceutically acceptable salts thereof; and any combinations thereof; and
b) detecting the contrast agent bound to the α-synuclein aggregate to image the α-synuclein aggregate.
2. The method of claim 1 , wherein the subject is suspected of having a Lewy body or Lewy neurite associated disorder.
3. The method of claim 2 , wherein the Lewy body or Lewy neurite associated disorder is Parkinson's disease.
4. The method of claim 1 , wherein the α-synuclein aggregate is located in the brain of the subject.
5. The method of claim 1 , wherein the detectable amount of the compound is from about 1 μg/kg body weight to about 250 mg/kg body weight.
6. The method of claim 1 , wherein said administering is by intravenous injection.
7. The method of claim 1 , wherein the subject is human.
8. The method of claim 1 , wherein said detecting is by infrared imaging, multiphoton imaging, gamma imaging, magnetic resonance imaging (MRI), magnetic resonance spectroscopy, or a combination thereof.
9. The method of claim 1 , wherein said detecting is by near-infrared fluorescence (NIRF) imaging, position emission tomography (PET) imaging, single-photon emission computed tomography (SPECT or SPET) imaging, X-ray fluorescence imaging, PET with concurrent computed tomography (PET/CT), PET with concurrent magnetic CT imaging (SPECT/CT), or a combination thereof.
10. The method of claim 1 , wherein the compound is labeled with a radiolabel, fluorescent label, chemiluminescent label, or a combination thereof.
11. The method of claim 1 , wherein the compound is labeled with a beta-emitter, gamma-emitter, positron-emitter, x-ray emitter, or a combination thereof.
12. The method of claim 1 , wherein the compound is labeled with a radionuclide selected from the group consisting of 3 H, 11 C, 13 C, 14 C, 13 N, 15 O, 17 O, 18 F, 19 F, 75 Br, 76 Br, 77 Br, 82 Br, 82 Rb, 99m Tc, 123 I, 124 I, 125 I, 131 I, and any combinations thereof.
13. The method of claim 1 , further comprising allowing to pass a sufficient period of time after said administration of the contrast agent for achieving binding between the contrast agent and the α-synuclein aggregate.
14. The method of claim 1 , wherein the compound is a near infrared (NIR) fluorophore.
15. A method for detecting, diagnosing, or determining regression, progression, or onset of a Lewy body or Lewy neurite associated disorder, the method comprising:
a) administering, to a subject in need thereof, a detectable amount of a compound selected from the group consisting of 3-3′-DTDCI, LDS 722, LDS 759, LDS 798, Nile Red, THK-265, LDS 730, Nile Blue 690 ClO 4 , HITC ClO 4 , Stilbene 420, and any combinations thereof; and
b) detecting the compound bound to α-synuclein aggregate to determine the level of binding of the contrast agent, wherein an increase in the level of binding relative to a control level of binding indicates that the subject is suffering from or is at risk of developing an α-synuclein aggregate associated disorder.
16. A method of evaluating a treatment for a Lewy body or Lewy neurite associated disorder, the method comprising:
a) administering a first detectable amount of a compound to a subject undergoing treatment for a Lewy body or Lewy neurite associated disorder to obtain a first level of binding of the compound to α-synuclein aggregate in the subject;
b) detecting the compound bound to α-synuclein aggregate to determine the first level of binding of the compound;
c) administering a second detectable amount of the compound, wherein the second administration is at a time subsequent to the first administration, to obtain a second level of binding of the compound to α-synuclein aggregate in the subject;
d) detecting the compound bound to α-synuclein aggregate to determine the second level of binding of the compound; and
e) comparing the first level of binding with the second level of binding as an indication of the effectiveness of the treatment on the level of α-synuclein aggregate in the subject,
wherein the compound is selected from the group consisting of 3-3′-DTDCI, LDS 722, LDS 759, LDS 798, Nile Red, THK-265, LDS 730, Nile Blue 690 ClO 4 , HITC ClO 4 , Stilbene 420, and any combinations.
17. A method of detecting α-synuclein aggregates in a tissue, the method comprising:
a) contacting a compound with a tissue, wherein the contrast agent is selected from the group consisting of 3-3′-DTDC1, LDS 722, LDS 759, LDS 798, Nile Red, THK-265, LDS 730, Nile Blue 690 ClO 4 HITC ClO 4 , Stilbene 420, and any combinations thereof; and
b) detecting the compound bound to α-synuclein aggregate to determine the level of binding of the compound, wherein the level of biding indicates the amount of α-synuclein aggregate in the tissue.
18. The method of claim 17 , wherein the tissue is a brain tissue.
19. The method of claim 17 , wherein said contacting is in vitro.
20. The method of claim 17 , wherein said contacting is in vivo.